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WEEK 1

L1.1 Primary Gut Function

1. Identify the major anatomical components of the GI tract and accessory organs

Overview

Primary GI tract: oral cavity, pharynx, esophagus, stomach, small intestine, large intestine, rectum, anal canal. Accessory organs: salivary glands, liver, gallbladder, pancreas.

Quick location map

Head and neck: oral cavity, pharynx.
Neck and thorax: pharynx, esophagus.
Abdomen: esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas.
Pelvis: rectum, anal canal.

Accessory organs

Salivary glands: parotid, submandibular, sublingual.
Liver and gallbladder: hepatic lobes, ducts, bile storage and delivery.
Pancreas: exocrine acinar tissue with main duct, endocrine islets.

Table. Major components and where they sit

Region	Main components	Notable substructures	Typical location
Oral cavity	Teeth, tongue, salivary glands	Vallate papillae with taste buds	Head and upper neck
Pharynx	Naso-, oro-, laryngopharynx	Shared pathway for air and food	Head and neck
Esophagus	Cervical, thoracic, abdominal parts	Upper to lower sphincter transitions	Neck, thorax, abdomen
Stomach	Cardia, fundus, body, pylorus	Three muscle layers, rugae, pyloric sphincter	Upper abdomen
Small intestine	Duodenum, jejunum, ileum	Duodenal papillae, Brunner glands, circular folds	Central abdomen
Large intestine	Cecum to rectum	Haustra, semilunar folds, deep crypts	Frames small intestine, pelvis for rectum
Accessory organs	Liver, gallbladder, pancreas	Hepatic lobules, biliary tree, pancreatic duct	Right upper quadrant, epigastrium

TLDR (Objective 1): The alimentary canal runs mouth to anus through head, neck, thorax, abdomen, and pelvis. Salivary glands, liver with gallbladder, and pancreas sit alongside and feed saliva, bile, and enzymes into the tract. Know each segment’s name, position, and any special substructures listed above.

2. Outline the main functions of each segment in digestion and absorption

Global functions of the digestive system

Intake, secretion, mixing and propulsion, digestion, absorption, defecation.

Segment-by-segment functions

Oral cavity

Mechanical breakdown by teeth, manipulation by tongue.
Saliva moistens bolus and supplies enzymes: amylase for starch, lysozyme with bactericidal action.
Taste via vallate papillae helps regulate ingestion.

Pharynx

Conducts food and fluids toward esophagus, coordinates swallowing phases while also serving airway passage.

Esophagus

Rapid transit of bolus to stomach via peristalsis. Primary role is propulsion, not digestion.

Stomach

Churning and mixing convert bolus to chyme.
Acid denatures proteins and activates enzymes.
Metered delivery of chyme through pylorus to duodenum.
Notable structure-function link: three smooth muscle layers support mechanical processing.

Duodenum

Receives bile and pancreatic juice at major and minor papillae for chemical digestion of fats, proteins, and carbohydrates.
Brunner glands secrete bicarbonate-rich mucus to neutralize gastric acid and protect mucosa, supporting enzyme activity.

Jejunum and Ileum

Primary site for nutrient absorption into portal blood.
Circular folds and mucosal architecture expand surface area; vascular supply supports uptake.
Products absorbed then delivered to liver via portal vein for processing.

Large intestine

Absorbs water and electrolytes, compacts feces, and stores until defecation.
Lacks villi; numerous deep crypts and haustra support slow propulsion and fluid reclamation.

Rectum and anal canal

Temporary storage and controlled elimination of feces.

Accessory organ contributions to segment functions

Salivary glands: secrete saliva to lubricate and initiate carbohydrate digestion with amylase, and provide lysozyme activity.
Liver: processes absorbed nutrients via the portal vein and produces bile for fat emulsification.
Gallbladder: stores and concentrates bile, releases it to duodenum to aid lipid digestion.
Pancreas: exocrine secretion of digestive enzymes and bicarbonate into duodenum; endocrine islets regulate blood glucose.

Table. Segment functions and the key feature that enables them

Segment	Primary functions	Key enabling feature(s)
Oral cavity	Mechanical breakdown, lubrication, start carbohydrate digestion, antimicrobial action	Teeth and tongue mechanics, saliva with amylase and lysozyme, taste buds for sensory feedback
Pharynx	Swallowing conduit	Coordinated muscular walls and airway–foodway separation during deglutition
Esophagus	Propulsion to stomach	Peristaltic muscular tube segments
Stomach	Acid and enzyme digestion of proteins, mixing, controlled emptying	Three-layer muscular coat, rugae to expand, pyloric sphincter control
Duodenum	Neutralize acid, receive bile and pancreatic juice, begin major chemical digestion	Major/minor papillae, Brunner glands, ducts for bile and pancreatic secretion
Jejunum	Bulk nutrient absorption	Prominent circular folds and rich vascularization
Ileum	Continued absorption, including bile salts and some vitamins	Distal small-intestine mucosa adapted for absorption; continuity of circular folds
Large intestine	Water and electrolyte absorption, feces formation and storage	Deep crypts, semilunar folds, haustra with slow peristalsis
Rectum/anal canal	Storage, defecation	Muscular walls and sphincteric control
Liver and gallbladder	Bile production, storage, and delivery; nutrient processing	Hepatic lobules, biliary tree, cystic and common bile ducts
Pancreas	Enzyme and bicarbonate secretion; endocrine glucose control	Main pancreatic duct to duodenum; islet cells for insulin and glucagon

TLDR (Objective 2): Mouth prepares and starts digestion. Pharynx and esophagus move bolus. Stomach acidifies, mixes, and meters output. Duodenum neutralizes acid and accepts bile and pancreatic secretions. Jejunum and ileum absorb nutrients into portal blood. Large intestine reclaims water and electrolytes and forms stool. Salivary glands, liver with gallbladder, and pancreas supply saliva, bile, enzymes, and bicarbonate that make digestion and absorption efficient.

3. Describe the layers of the GI tract wall and relate their structure to function

The canonical wall plan, and when it differs

Most hollow segments share a four-layer plan: mucosa, submucosa, muscularis externa, and serosa or adventitia. The slides label these layers in duodenum and small intestine examples, and show specializations that tune function region by region. In the duodenum image the wall is annotated “Mucous [mucosa], Submucous, Muscular,” and highlighted specializations include Brunner glands and circular folds (valves of Kerckring) that protect against acid and increase surface area, respectively.

The stomach diverges from the generic plan by adding a third muscle layer, supporting intensive mechanical mixing before controlled delivery to the duodenum.

The large intestine trades villi for numerous deep crypts and haustra that favor fluid reclamation and slow propulsion.

Layer-by-layer structure–function map

Layer	Key structures shown	What this enables	Regional specializations shown
Mucosa	Epithelium with glands, lamina propria	Final-stage digestion, absorption, local defense	Brunner glands in duodenum secrete mucins and bicarbonate to neutralize gastric acid; circular folds (valves of Kerckring) increase area.
Submucosa	Connective tissue, vessels, submucosal glands	Vascular supply, secretion support, distension	Duodenal wall labeled “Submucous layer”; houses Brunner glands in proximal small intestine.
Muscularis externa	Smooth muscle layers drive motility	Mixing and propulsion, sphincter control	Stomach has three muscle layers for vigorous churning before pyloric delivery to the small intestine.
Serosa / Adventitia	Outer covering	Reduces friction or anchors segment	Small intestine slides label the outer “Serous” surface.
Mucosal architecture (regional)	Circular folds, villi vs crypts, haustra	Surface area and transit tuning	Jejunum/ileum show circular folds with vascular differences; colon shows deep crypts, semilunar folds, and haustra that progress slowly with peristaltic waves.

TLDR (Objective 3) The four-layer wall plan underlies the tract, then regional tweaks do the job: stomach adds a third muscle layer to churn; duodenum adds Brunner glands and large circular folds to neutralize acid and start absorption; jejunum and ileum maximize surface area for uptake; colon drops villi, deepens crypts, and forms haustra to reclaim water during slow transit.

4. Describe the roles of accessory organs in digestion, including the production and delivery of enzymes and bile

What the slides list as accessory organs and where they sit

The lecture identifies salivary glands, pancreas, and liver with gallbladder as the accessory set.

Roles and products

Salivary glands

Secrete saliva that moistens food and starts carbohydrate digestion through amylase; saliva also contains lysozyme with bactericidal action.

Liver and gallbladder

The liver receives absorbed nutrients via the portal system for metabolic processing and produces bile. Bile emulsifies fats to ease absorption. The gallbladder stores bile beneath the liver and delivers it into the duodenum via the biliary tree.
Duct anatomy shown on the slide supports this delivery path: hepatic ducts join to form the common hepatic duct, which meets the cystic duct from the gallbladder to form the common bile duct that empties into the duodenum.

Pancreas

Exocrine acini produce a watery, enzyme-rich secretion that flows through the main pancreatic duct into the duodenum, aiding digestion of macronutrients. Endocrine islet cells produce hormones including insulin and glucagon that regulate blood glucose.
Duodenal delivery points are depicted: major and minor duodenal papillae receive common bile duct and pancreatic ducts.

How these products reach the lumen and why placement matters

The upper duodenum is the mixing hub where acidified chyme from the stomach meets bile and pancreatic juice. Neutralization and emulsification there are critical for enzyme activity and lipid absorption. The slide highlights Brunner glands for bicarbonate-rich mucus and the papillae where bile and pancreatic juice enter.

Compact table

Organ	Secretions / role	Delivery route shown	Functional payoff
Salivary glands (parotid, submandibular, sublingual)	Saliva with amylase and lysozyme	Into oral cavity	Lubricates bolus, starts starch digestion, antimicrobial action.
Liver	Produces bile, processes portal nutrients	Bile flows via hepatic ducts → common hepatic duct	Emulsifies fats to aid absorption; metabolic processing.
Gallbladder	Stores and concentrates bile	Cystic duct ↔︎ common hepatic duct → common bile duct → duodenum	Timed bile delivery into upper duodenum.
Pancreas	Enzyme-rich juice, plus endocrine insulin and glucagon	Main pancreatic duct to duodenum; endocrine to blood	Enzymatic digestion in lumen; systemic glucose regulation.

TLDR (Objective 4) Accessory organs supply the chemistry. Salivary glands start starch digestion in the mouth. The liver makes bile; the gallbladder stores and sends it via the common bile duct into the upper duodenum where fats are emulsified. The pancreas delivers enzyme-rich juice through its duct to the same region, while its islets regulate blood glucose. Delivery occurs at the major and minor duodenal papillae, with local neutralization by Brunner glands enabling enzyme action.

L1.2 Microbiome

1. Describe the contribution of microbes to energy harvesting

a) Why estimates of available Calories in foods vary

The baseline estimate

We estimate food energy with the Atwater method: 4 kcal/g for carbohydrate, 4 kcal/g for protein, 9 kcal/g for fat.

Where the estimate breaks

The Atwater factors assume full host digestibility, which fits “easy” foods used to derive the model. Your slides flag that this works less well for whole-plant diets rich in digestion-resistant carbohydrates.
Different carbohydrate types have different effective caloric yield. Resistant and non-starch polysaccharides often deliver 1–3 kcal/g rather than 4 kcal/g. Processing shifts a meal toward easily digestible carbs, which raises Atwater-estimated energy; whole-plant diets shift toward resistant carbs, which lowers it.
After stomach and small intestine, what remains is enriched in digestion-resistant carbohydrates that only microbial enzymes access. This changes the usable energy profile relative to Atwater.

Role of microbial metabolism

Colonic microbes solubilize host-inaccessible polysaccharides (HI-MAC) to sugars, then ferment them to short-chain fatty acids (SCFA). We absorb SCFA, not much of the sugars. Energy yield is lower and variable.
Microbial contribution to total energy is about a minority share in humans and varies with diet composition and the person’s microbiome. Your slides summarise human energy from microbes as a non-dominant but significant fraction.
Individuals host different enzyme repertoires in their gut bacteria. This makes energy recovery from high-fibre foods hard to predict and person-specific.

Practical consequences

To reach 2000 kcal, energy-dense foods require small mass, while leafy, fibre-rich foods require large mass. The model diet examples in the slides illustrate the trade-off.

Mini-table: why the same “calories” differ in practice

Factor	Mechanism	Effect on usable kcal
Food processing	Increases simple carbs	Raises Atwater fit, higher usable kcal per gram
Fibre type and amount	Shifts carbs to HI-MAC	Lowers host-available kcal, pushes energy to SCFA route
Microbiome composition	Varies glycosidic hydrolases and fermentation	Varies SCFA output and absorption person-to-person

b) Why the microbiome determines efficiency of fibre utilization

The substrate classes in your slides

Host-accessible simple carbs (HAS) and some host-accessible complex carbs (HAC) are digested and absorbed in the small intestine.
Host-inaccessible, microbiota-accessible carbohydrates (HI-MAC) such as inulin and arabinoxylans reach the colon. They are “fibre” in dietary terms.

Microbial functions that unlock fibre

Diverse bacterial glycosidic hydrolases in the colon break HI-MAC into sugars and ferment to SCFA (acetate, propionate, butyrate). These SCFA are absorbed by the host and contribute to energy.
Microbial growth also “packages” nutrients in microbial biomass. In some species or gut designs, host digestion of microbial cells adds protein and vitamins. Your slides note this explicitly in pre- and post-host “fermentation tank” models.

Evidence that microbes change energy capture

Germ-free animals on the same diet eat more mass to meet energy needs and still lay down less fat than conventional controls. This shows lower energy harvest without microbes and reduced growth efficiency.
In humans, your slides place most energy capture in host-encoded digestion, with a significant minority from microbes that rises with fibre load. Inter-individual microbiome differences shift the payoff from fibre.

Schematic you can sketch in your notes

Stomach and small intestine: host enzymes digest HAS/HAC → monosaccharides → absorbed.
Colon: microbes digest HI-MAC → SCFA → absorbed by host; microbes also synthesize vitamins and amino acids.

Mini-table: determinants of fibre-to-energy efficiency

Determinant	Why it matters	Expected shift
HI-MAC amount and type	Sets substrate for microbial enzymes	More and more-degradable HI-MAC → more SCFA
Enzyme repertoire in microbiome	Controls which linkages get cleaved	Enzyme-rich communities → higher SCFA yield
Transit and pH in colon	Affects fermentation and absorption	Optimal “slow” colon, buffering → better harvest

TLDR (Objective 1a) Atwater factors assume full host digestion of carbs, protein, and fat. Whole-plant diets carry more digestion-resistant polysaccharides, so fewer true kcal are available to the host. Microbes convert a portion of fibre to absorbable SCFA, but the yield is lower and varies with fibre type, processing, and the person’s microbiome.

TLDR (Objective 1b) Your microbiome sets how well you turn fibre into usable energy. Colonic bacteria with the right hydrolases ferment HI-MAC to SCFA that you absorb. Germ-free models eat more yet store less energy, showing the microbiome’s role in energy harvest and nutrient fortification. In humans, microbial energy is a significant minority that increases with fibre and varies by microbiome.

2. Describe contribution of microbes to nutrient fortification

a) How microbe growth can add nutrients

Mechanism. When gut microbes ferment host-inaccessible carbohydrates (HI-MAC), they grow and synthesize cell biomass and metabolites. Biomass, if digested upstream or via coprophagy in some species, provides protein and vitamins. Metabolites include short-chain fatty acids plus vitamins and amino acids that add nutritional value to the host diet.

Where this happens.

In monogastric animals like humans: most microbial activity is in the colon, where microbial metabolites are absorbed; the slide explicitly notes uptake of microbe metabolites in the colon.
In ruminants: microbes process plant food before host digestion in a foregut “tank,” so microbial cells enter the true stomach and small intestine and are digested as nutrient-dense biomass.
In hindgut fermenters: microbes process undigested plant foods post-host; coprophagy returns microbe-rich material for upstream digestion.

Quantitative framing in your slides. Microbes provide a minority of total energy but can provide a large share of certain micronutrients: “ca 5–10% of our energy, up to 50% of some micronutrients.”

Evidence motif used in the lecture. Germ-free animals need more, higher-quality food and still grow less efficiently because microbe-synthesized nutrients and energy from fibre are missing. Growth efficiency improves with a microbiome.

Mini-table. Microbial fortification pathways and payoffs

Pathway	What microbes provide	Host payoff
Fermentation of HI-MAC in colon	SCFA plus vitamins, amino acids	Absorption of microbial metabolites; added micronutrient supply.
Microbial biomass ingestion (foregut or via coprophagy)	Protein and vitamins in microbial cells	Direct nutrient intake from microbe cells.
Community enzyme diversity	Access to otherwise indigestible substrates	Extends nutrient spectrum beyond host enzymes.

b) Distinguish macronutrients and micronutrients with examples

Slide definitions.

Macronutrients are required in large amounts for energy: carbohydrate, protein, fat. The slides list their typical Atwater values and show a 2000 kcal/day example.
Micronutrients are molecules we cannot synthesize but need in small amounts. The learning-outcome slide highlights essential amino acids and vitamins as examples microbes can synthesize.

Functional link to fortification.

Protein is the major dietary nitrogen source and only source of essential amino acids from food; fats supply essential fatty acids and phosphate; meals with identical energy can differ in micronutrient sufficiency.
Microbes mitigate micronutrient gaps by synthesizing vitamins and some essential amino acids that the host lacks capacity to make.

Compact table. Macro vs micro in your lecture

Category	Definition in slides	Examples in slides	Microbiome link
Macronutrients	Large-amount energy sources	Carbohydrate (4 kcal/g), protein (4 kcal/g), fat (9 kcal/g)	Microbes extend usable carb spectrum via HI-MAC fermentation.
Micronutrients	Small-amount, host cannot synthesize	Vitamins, essential amino acids	Microbial synthesis adds supply, sometimes up to half of certain micronutrients.

TLDR (2a) Microbial growth fortifies diets by producing metabolites such as vitamins and amino acids and, in some species, by providing digestible microbial biomass rich in protein and vitamins. In humans, most fortification occurs via absorption of microbial products formed during colonic fermentation. Contribution is a minority of energy but can be a substantial share of some micronutrients.

TLDR (2b) Macronutrients are the main energy sources (carbohydrate, protein, fat). Micronutrients are required in small amounts and often cannot be synthesized by the host. Microbes help fill micronutrient needs by synthesizing vitamins and essential amino acids, improving growth efficiency, especially when diets are rich in fibre.

3. Describe how diet requirements differ without microbes

a) Contrast energy and nutrient requirements for germ-free vs normal animal

Core contrast

Germ-free animals: must eat more total food and of higher nutrient quality because calories from non-starch polysaccharides and microbe-synthesized nutrients are unavailable.
Normal (conventional) animals: harvest more energy from the same diet and gain added nutrient value from microbial activity, which improves growth efficiency.

Why requirements diverge

In the small intestine, host enzymes perform “fast” digestion and limit microbe growth, so material entering the colon is enriched in digestion-resistant carbohydrates that only microbes can access. Without microbes, that energy stays locked.
In the colon, dense microbial communities supply diverse glycosidic hydrolases and the host absorbs microbe metabolites (SCFA, vitamins, amino acids). Germ-free animals miss this yield.
Microbial functions account for about 5–10% of human energy and up to 50% of some micronutrients, so removing microbes raises both energy and micronutrient needs.

Practical dietary implications

Germ-free: require easily digestible, nutrient-complete diets, which are rare in nature.
With microbes: animals meet needs more easily because microbes both compete for small soluble nutrients and co-operate by extracting nutrients the host cannot.

Compact table: diet requirements with and without microbes

Dimension	Germ-free	Normal microbiome
Energy from fibre	Lost, no access to HI-MAC energy	Recovered as SCFA, absorbed
Total intake needed	Higher food intake to meet energy	Lower intake for same energy
Micronutrients	Must come from diet alone	Supplemented by microbe products (vitamins, amino acids)
Growth efficiency	Reduced; less fat stored from same diet	Improved growth and fat storage from same diet
Diet quality requirement	High digestibility and complete essential nutrients	Wider feasible diet range due to microbial help

TLDR (Objective 3a) Without microbes, animals must eat more and choose highly digestible, nutrient-complete diets, because fibre-bound energy and microbe-made micronutrients are missing. With a normal microbiome, colon microbes unlock fibre energy as SCFA and supply vitamins and amino acids, so total intake can be lower and growth efficiency higher on the same macronutrient profile.

L1.3 Regulatory Functions of the Gut

1a. Neuroendocrine regulation of ingestion and translocation

Why food intake must be regulated

Digestion has hazards: compartment pH incompatibilities, finite stomach capacity, risk of reflux, and epithelial injury if acid empties too soon into the duodenum (Slides 3–8).
Safe passage needs coordinated sensing and responses: sphincter control, peristalsis, timed emptying, and pH adjustment before chyme enters the small intestine (Slides 5, 7–9).

Core sensory–response circuits

Mechanosensory stretch in stomach and intestines triggers neural and hormonal outputs that modulate sphincters and smooth muscle, adjusting opening, mixing, and propulsion (Slide 9).
Enteroendocrine S cells in the duodenum sense gastric acid and release secretin. Secretin:
- Inhibits parietal cell acid secretion and slows gastric emptying until duodenal pH is safe (Slide 8).
- Stimulates pancreatic enzyme and bicarbonate secretion and bile delivery, and activates Brunner’s glands to release alkaline mucus that protects the duodenal epithelium (Slide 8).
Together, these circuits meter gastric filling and outflow to keep volumes and pH within safe ranges while maintaining flow along the tract (Slides 5, 8–9).

Table. Examples of intake and transit regulators shown in the lecture

Signal or cell	Trigger	Main effect	Where referenced
Stretch sensors	Gastric or intestinal distension	Sphincter opening/closing; peristaltic mixing and propulsion	Slide 9
Secretin (from S cells)	Low duodenal pH due to incoming acid	↓ Parietal cell HCl, ↓ gastric emptying; ↑ pancreatic juice, ↑ bile, ↑ Brunner’s glands	Slide 8
Sphincter coordination	Swallowing and gastric filling	One-way flow into stomach; prevents reflux	Slides 5–6

Why different foods create different challenges

Acid load vs neutral requirement. Stomach needs very low pH. Pancreatic enzymes for small intestine require near-neutral pH, so acidic chyme must be buffered before transit. Secretin coordinates this handover (Slides 4, 7–8).
Osmotic and fermentable load. Diets rich in FODMAPs (for example inulin, or lactose in lactase-nonpersistent adults) provide rapidly fermentable substrates proximally. This can promote gas and acid production and raise the risk of small intestinal bacterial overgrowth when motility is impaired (Slides 11–12).
Motility mismatch. Too fast transit reduces nutrient uptake. Too slow transit permits excess microbial growth and symptoms such as pain, diarrhea, and nutrient deficiency (Slides 10–11).
Volume and capacity. Large meals increase gastric distension; mechanosensory circuits and timed emptying prevent overfilling and reflux (Slides 5, 7, 9).

TLDR (Objective 1a) The gut regulates intake and transit to avoid reflux, overfilling, acid injury, and malabsorption. Stretch sensors and enteroendocrine pathways coordinate sphincters, peristalsis, and secretions. Secretin is the key example: it senses acid in the duodenum, slows gastric emptying, suppresses gastric acid, and stimulates pancreatic, biliary, and Brunner’s gland outputs so chyme is safe for small-intestinal digestion. Different foods pose different loads: acid, osmotic, and fermentable substrates challenge different segments and can cause problems if motility or pH control is off (Slides 4–12).

1b. Gut-associated lymphoid tissues (GALT) in maintenance of gut function

What “optimal biological composition” means for gut function

Microbes: high-diversity, anaerobe-dominant community that produces SCFA, vitamins, and bacteriocins; low pathogen burden; stable colonization resistance.
Human cell types: intact epithelium with tight junctions; plentiful goblet cells (mucins); Paneth cells in small-intestinal crypts (defensins, lysozyme); abundant IgA-secreting plasma cells in lamina propria; balanced innate cells (macrophages, dendritic cells, ILCs) and adaptive cells (Treg for tolerance, Th17 for barrier support, memory B and T cells).
Outcome: efficient nutrient absorption with minimal inflammation, rapid pathogen containment, and durable oral tolerance to food antigens and commensals.

How GALT sustains that composition

Antigen sampling and tolerance

M cells overlying Peyer’s patches ferry luminal antigens to subepithelial dendritic cells. Dendritic cells drive Treg induction and IgA class switching, which supports non-inflammatory control of commensals and food antigens.
Isolated lymphoid follicles (ILFs) along small intestine and colon provide ongoing local sites for B-cell activation and IgA output.
Mesenteric lymph nodes (MLN) integrate signals from the whole gut, reinforcing tolerance while preserving protective immunity.

Secretory IgA (sIgA)

Plasma cells produce dimeric IgA. Epithelial pIgR transports it across the epithelium into the lumen as sIgA.
sIgA coats microbes and food antigens, blocks epithelial adhesion, neutralizes toxins, and shapes community composition without provoking inflammation.

Antimicrobial and barrier effectors

Paneth cells release α-defensins, lysozyme, and REG3 proteins that restrain bacterial density near crypt bases.
Goblet cells secrete mucins. The small intestine has a single, permeable mucus layer to allow nutrient access, with antimicrobial gradients at crypts. The colon has a two-layer system: an inner, dense, bacteria-poor layer that protects epithelium and an outer, loose layer that hosts commensals.
Pattern-recognition receptors (TLRs, NODs) on epithelial and immune cells sense microbe-associated patterns. Basal signaling drives tonic production of antimicrobial peptides and mucus, maintaining homeostasis.

Colonization resistance

Commensals and sIgA occupy niches, consume available nutrients, and produce short-chain fatty acids and bacteriocins that suppress invaders. This lowers infection risk and dampens inflammatory triggers.

Why spatial distribution matters

Barrier functions along the tract

Stomach and proximal small intestine: low bacterial load; acid and rapid flow dominate; mucus thin; GALT sparse but present.
Distal ileum: high Peyer’s patch density and M-cell domes; vigorous sIgA production to manage increasing microbial density.
Colon: highest microbial density; two-layer mucus architecture; deep crypts; abundant ILFs; large sIgA output; strong colonization resistance.

Lymphoid organization and flow

Inductive sites: Peyer’s patches, ILFs, MLN. Antigen sampling and lymphocyte priming occur here.
Effector sites: lamina propria and epithelium across the tract. Primed B and T cells home back via integrins and chemokines to deliver local sIgA and cytokines that tune barrier tone and motility.
Result: tolerance where appropriate (food, commensals), rapid effector responses when threats breach the mucus or inner layer.

Compact table

Component	Location	Function in maintenance
M cells over Peyer’s patches	Ileal dome epithelium	Antigen sampling to DCs, initiates Treg and IgA responses
Secretory IgA	Throughout lumen, highest distal SI/colon	Immune exclusion, neutralization, microbiota shaping
Paneth cells	SI crypt base	Defensins, lysozyme, restrict microbes near stem cells
Goblet cells, mucus layers	SI single layer; colon inner/outer layers	Physical separation, diffusion control, commensal niche
ILFs	SI and colon	Local B-cell activation and IgA production
MLN	Mesentery	Central tolerance and immunity “hub” for gut
PRRs (TLR/NOD)	Epithelium, myeloid cells	Tonic antimicrobial and mucus output, homeostasis

TLDR (Objective 1b) GALT keeps digestion safe by coupling antigen sampling (M cells → DCs), non-inflammatory control (sIgA), and antimicrobial barriers (Paneth products, mucus) with region-specific architecture. Ileum concentrates Peyer’s patches for rising microbial loads; colon uses a two-layer mucus barrier and ILFs where density peaks. An optimal mix of commensals and host cell types yields efficient absorption, strong colonization resistance, and stable tolerance with minimal inflammation.

L1.4 The Gut: Homeostasis

Describe the gut–brain axis as a framework for physiological homeostasis

Concept and scope

Dynamic systems stay stable by sensing, transducing signals, and executing adaptive responses. The gut both senses and responds locally, and also sends signals to other organs and the brain for whole-body regulation.
The gut–brain axis is the integration layer: gut signals travel via blood, lymph, and nerves; the brain integrates them with other inputs to coordinate behaviour, metabolism, and tissue responses that maintain homeostasis.

What is sensed and how signals move

Sensed inputs include small molecules and solutes, large antigens or cells, pressure, and tissue damage.
Signal routes and targets:
- Within gut tissues: phosphorelay cascades change cell activity and tissue composition.
- To nearby tissues: paracrine effects.
- Systemic: hormones, cytokines, and cells via blood or lymph; nerves via electrical and neurotransmitter signals.
Outcomes include changes in metabolic flux, epithelial barrier tone, enzyme and bile secretion, motility, nutrient uptake, and excretion.

Quick map of signal classes and effects (from slides)

Signal class	Route	Exemplars in lecture	Primary effects
Hormones from gut	Blood/lymph	GLP-1, GIP, CCK, secretin, 5-HT, SST	Modulate insulin, bile and enzyme release, bicarbonate, satiety, motility.
Neural	Vagal/enteric	ENS outputs to brain and local circuits	Coordinate peristalsis, sphincters, rapid reflexes.
Immune/cytokine	Lymph/blood	GALT-derived signals	Tune barrier and systemic responses.

Why this integration is necessary

Eat, breathe, sleep systems co-regulate health. The gut is the major route for resource delivery; the brain keeps the body fueled, maintains reserves, and directs replacement of damaged cells.
Example domain: glucose control. Blood glucose must stay near ~5 mM for brain function; sources and sinks are coordinated across fasting and fed states by pancreatic sensing and liver, muscle, adipose responses.

Where gut signals meet metabolic control

After a meal, glucose absorption rises rapidly from the small intestine, prompting insulin and multiple gut hormones that link feeding behaviour with metabolic regulation.
Enteroendocrine cells (EECs) are the key producers: S cells (secretin), EC cells (serotonin), L cells (GLP-1), K cells (GIP). Collectively they form the most abundant hormone-producing cell population in the body.
Nutrient detection in the lumen directly triggers EEC hormone release. Glucose uptake by L or K cells drives incretin output, which potentiates insulin signalling to aid peripheral glucose control.
EEC numbers and subtypes derive from intestinal stem cells and can shift with site and environment, changing nutrient detection capacity and hormone signalling.

EEC examples and roles (from slides)

Cell	Main hormone	Trigger emphasized	Role in axis
L cell	GLP-1	Luminal glucose	Incretin, augments insulin; influences satiety.
K cell	GIP	Luminal glucose	Incretin; coordinates with insulin.
S cell	Secretin	Low duodenal pH	Bicarbonate, bile, enzymes; slows gastric emptying.
EC cell	Serotonin (5-HT)	Mechanical/chemical stimuli	Motility regulation; gut–brain signalling.

Multi-timescale integration, including microbes

Uptake kinetics differ: simple carbohydrates are fastest, simple proteins next, fats slowest. Microbe-derived SCFA from the colon supply nutrients slowly and passively. Feeding behaviour must integrate signals over these timescales.
Diet and the microbiome modulate axis signalling; gut, ENS, EEC, and GALT send nutrients, metabolites, MAMPs, and signals to the brain to adjust behaviour.
The axis resolves competing priorities, for example calories versus essential amino acids, under real food environments.

TLDR (Objective 1) The gut–brain axis integrates gut sensing with systemic control. The gut detects nutrients, solutes, pressure, microbes, and damage, then signals locally and to the brain via hormones, nerves, cytokines, and cells. The brain coordinates behaviour and metabolism to keep variables like blood glucose near set points while maintaining reserves and protecting tissues. Enteroendocrine cells couple luminal detection to incretins and satiety hormones; their numbers and subtypes adapt with site and diet. Different nutrient time courses and microbial metabolites require multi-timescale control, so diet and microbiome composition shape gut–brain signalling.

2. Example of how gut-derived signals adjust feeding behaviour to support nutrition and metabolism

The point

After a meal, the brain integrates many gut signals to shape feeding behaviour and protect glucose balance, nutrient status, and microbe exposure.

What triggers the signals

Nutrients arrive at different speeds: simple carbohydrates fastest, then simple proteins, fats slowest. Microbe-derived SCFA arrive later from the colon. Behaviour must integrate over these timescales.
Enteroendocrine cells (EECs) detect luminal nutrients and release hormones. L and K cells sense glucose via SGLT and release incretins that couple with blood glucose sensing.
EEC types and numbers vary by site and environment (diet), shifting detection capacity and hormone output.

Key gut signals and their roles (shown in the lecture)

Signal	Primary role relevant to behaviour/metabolism	Where shown
PYY, CCK	Signal satiety to the brain; reduce further intake
GLP-1, GIP	Augment insulin action; link feeding to glucose disposal
CCK, secretin	Promote bile, enzyme, and bicarbonate release; coordinate safe delivery to duodenum
5-HT, somatostatin	Tune motility; align transit with digestion and absorption

Worked example (from the slides’ logic)

High-glycaemic meal enters upper small intestine → rapid glucose absorption, blood glucose rises. Pancreas senses this and releases insulin.
L/K cells take up luminal glucose → GLP-1/GIP release, which potentiates insulin and accelerates post-prandial glucose control.
Parallel satiety signals (PYY, CCK) reduce ongoing intake; CCK/secretin coordinate bile, enzymes, and bicarbonate for safe digestion.
Later, colonic SCFA arrive slowly, extending nutrient supply and reinforcing longer-timescale regulation of behaviour and metabolism.

TLDR (Objective 2) Gut hormones turn luminal detection into adaptive behaviour. Rapid nutrients trigger incretins and satiety signals, which both restrain further intake and coordinate systemic glucose handling. Slower signals, including SCFA from the colon, extend regulation across time so behaviour supports both acute glucose control and longer-term nutrient balance.

WEEK 2

L2.1 Risks from Food Environment

1. Why the environment drives risk and severity of gut diseases

Why environment matters

Food and water intake is the major route of environmental exposure for diseases of the gut or involving gut functions.
Course framing: separate food-related risks into two broad classes to guide control measures and study design. Abiotic risks relate to compounds in food. Biotic risks relate to viable microbial contaminants.

Why separate abiotic vs biotic risks

Abiotic components: chemicals and molecules present in food such as plant toxins, microbial toxins formed in food, excess added vitamins, allergens, and immunogens. Risk correlates with the dose present in the eaten food and the rate of intake.
Biotic contaminants: viruses and bacteria in food or water that cause infection. Risk correlates with exposure to live agents, then is modified by gut barriers and colonization resistance.
This split clarifies prevention: exclude or label abiotic hazards; exclude or inactivate biotic hazards and strengthen barriers.

Food must be safe: examples

Intoxication and chemical hazards (abiotic)

Aflatoxicosis from Aspergillus flavus in stored grains and peanuts. Acute liver failure at high dose. Chronic low dose links to stunting and cancer.
Botulinum neurotoxin from Clostridium botulinum in improperly processed canned foods. Life-threatening neurotoxicity.
Staphylococcal enterotoxins formed in food during storage. Heat-stable toxins can cause rapid vomiting even after reheating.
Pyridoxine (vitamin B6) excess as a dose-related toxicity from fortified products. High intake can cause neuropathy and other symptoms.

Intolerance, allergy, autoimmunity (abiotic triggers; host dependent outcomes)

Lactose intolerance. Unprocessed lactose is osmotically active and fuels proximal bacterial growth, leading to pain and diarrhea in lactase-nonpersistent individuals. Trigger requires lactose ingestion.
Food allergy. Immediate allergic reactions to food antigens such as peanuts and crustaceans. Incidence is rising. Exposure determines triggering; environment and diet quality shape population risk.
Coeliac disease. Autoimmune pathology of intestinal epithelium triggered by gluten intake in susceptible people. Diagnosis and incidence are increasing.

Infections (biotic)

Viral gastroenteritis. Norovirus and rotavirus cause rapid-onset vomiting and diarrhea. Risk tracks exposure to live virus; mucus and sIgA lower risk.
Bacterial pathogens. Pathogenic E. coli (InPEC), Vibrio cholerae, Shigella dysenteriae, Salmonella Typhi. Adhesion, invasion, or toxin production drive watery or bloody diarrhea and typhoid. Barriers, sIgA, and colonization resistance modulate risk.

Food must be secure: malnutrition

Protein and energy deficiency

Kwashiorkor. Protein deficiency with stunted growth and edema. Often after weaning to protein-poor diets despite adequate calories.
Marasmus. Calorie deficit that includes protein deficiency. Marked wasting.

Micronutrient deficiency

Beriberi from thiamine deficiency; dry (neuropathy) and wet (cardiovascular) forms. Linked historically to adoption of polished rice after milling.
Scurvy as vitamin C deficiency; example of micronutrient shortfall.

Compact table. Risk class, examples, and control focus

Class	Agent or factor	Typical time course	Key features	Primary controls
Abiotic, toxin	Aflatoxin; botulinum toxin; staph enterotoxin	Acute or chronic	Dose–response; food handling and storage critical	Exclude toxin sources; shelf-life control; HACCP; intake moderation; labelling.
Abiotic, intolerance/allergy/autoimmune	Lactose; peanut allergens; gluten	Immediate or chronic	Trigger requires ingestion; host susceptibility varies	Allergen and gluten labelling; dietary avoidance; public health nutrition.
Biotic, infection	Norovirus, rotavirus; E. coli, Vibrio, Shigella, Salmonella	Acute	Exposure to live agents; barriers and colonization resistance modify risk	Hygiene, surveillance, exclusion from supply chain; barrier support.
Food insecurity	Protein, energy, vitamin deficits	Chronic	Diet quality and availability drive risk	Secure supply; nutrition information; socioeconomic levers.

TLDR (Objective 1) Environment drives gut disease risk because food and water are the main exposure route. Separate risks into abiotic components and biotic contaminants to match interventions. Abiotic examples: aflatoxin, staph enterotoxin, vitamin B6 excess, lactose, peanut allergens, gluten. Biotic examples: norovirus, rotavirus, InPEC E. coli, Vibrio, Shigella, Salmonella. Food must also be secure: protein, energy, and vitamin deficiencies cause kwashiorkor, marasmus, and beriberi or scurvy. Prevention mixes food safety regulation, storage and labelling, and diet quality and access.

2. How public health regulation and individual feeding behaviour shape disease risk

Why both levers matter

Food and water are the main exposure route for gut risks. Controls work at two levels: system-level rules that manage hazards in the supply chain, and person-level choices and handling that manage hazards at point of use.

Map hazards to controls (from the lecture)

Abiotic food components (toxins, allergens, excess additives)

Regulatory focus. Set exposure limits, require labelling, control shelf-life and storage, and use HACCP to identify and mitigate critical steps in production.
Individual focus. Read labels, avoid triggers (for example lactose for lactase-nonpersistent people; peanut for allergy), and respect storage/use-by guidance to limit toxin formation.
Rationale. Abiotic risk is dose-related to what you eat and how it was handled. Controls reduce dose at source and at consumption.

Biotic contaminants (viral and cellular pathogens)

Regulatory focus. Exclude or inactivate live agents through hygiene, processing, and supply-chain controls; maintain surveillance to remove contaminated lots.
Individual focus. Safe water, handwashing, separation of raw/cooked foods, thorough cooking and reheating, and rapid cooling/refrigeration to limit growth and toxin formation.
Rationale. Biotic risk depends on exposure to viable agents and is then modified by host barriers and colonization resistance. Controls cut exposure and growth.

Food security and malnutrition

Regulatory focus. Ensure secure access to foods that meet protein, energy, and vitamin needs across populations to prevent kwashiorkor, marasmus, beriberi, scurvy.
Individual focus. Choose diets that supply sufficient macronutrients and key vitamins given local availability and cost.
Rationale. Security failures shift disease burden from acute infections and intoxications toward chronic deficiency syndromes.

Compact table. Hazard → who acts → what action

Hazard class	Primary regulator actions	Primary individual actions	Why this reduces risk
Abiotic (toxins, allergens, excess micronutrients)	Limits, labelling, storage and shelf-life rules, HACCP	Read and avoid triggers; follow storage/use-by; discard spoiled food	Lowers ingested dose; prevents in-food toxin buildup.
Biotic (viruses, bacteria)	Hygiene standards; processing to kill or exclude; surveillance and recall	Safe water; handwashing; separate raw/cooked; proper cooking and reheating; refrigeration	Cuts exposure to viable agents and their growth/toxin production.
Food insecurity (macro/micronutrient deficits)	Secure supply and access to nutrient-adequate foods	Choose nutrient-complete diets within local options	Prevents kwashiorkor, marasmus, beriberi, scurvy.

TLDR (Objective 2) Risk from the food environment falls when regulators set limits, enforce hygiene and HACCP, require labelling, and secure nutrient-adequate supply, and when individuals handle and choose foods safely. Abiotic hazards are dose-driven, so limits and labels matter. Biotic hazards depend on exposure to live agents, so hygiene, cooking, and cold-chain matter. Food security prevents deficiency diseases across populations.

L2.2

1. Nutrition transition as a major driver of modern disease patterns

Concept and framing

The nutrition transition describes how the food environment has shifted alongside disease epidemiology, with chronic disease rising as diets move toward ultra-processed options.
Gene–environment interactions shape individual risk and population incidence. Food environment is a core environmental driver across socio-demographic groups and time.

Why the food environment changed

Industrialization of the food supply chain created abundant, stable, cheap, palatable products and a consumer market dominated by ultra-processed foods.
Illustrative prompt in the slides: in a school lunchbox, highly processed “gummy banana” competes with whole foods, highlighting selection pressures toward refined, shelf-stable, hyper-palatable items.

Infectious disease vs chronic disease: the anti-correlation

As sanitation, vaccination, safe water, and food security improved, infectious disease incidence decreased. In parallel, chronic diseases increased, tracking the shift to ultra-processed, low-fibre, low-protein, high-sugar/high-fat diets and sedentary lifestyles. The LO slide explicitly states “Infectious disease incidence and Chronic disease are anti-correlated.”
The slide series links the “nutrition transition” banner directly to rising obesity and other chronic conditions.

Mechanistic bridge to behaviour and metabolism (how the transition drives disease)

The gut–brain axis integrates nutrient signals and shapes feeding behaviour. Slides recap that feeding behaviour is central to blood-glucose control and longer-timescale protein status.
The protein leverage hypothesis (Raubenheimer & Simpson, shown in slides): when dietary protein percent falls (typical of many ultra-processed foods), people eat more total food to meet protein needs, increasing total energy intake and promoting adiposity. The slides show:
- A low-protein diet (≈3.5% by weight) vs higher (≈7.3%): if people ate equal weight, protein intake would differ markedly.
- In reality, on the low-protein diet people eat ~50% more by weight to match protein intake, raising total calories.
- “Humans will ‘overeat’ to get enough protein.”

Visual logic from the deck (you can sketch this)

Food system shift → more ultra-processed foods, less intrinsic fibre and protein.
Gut signalling + behaviour → stronger drive to continue eating to meet protein targets; rapid carbs raise glycaemic load.
Population pattern → obesity and related chronic diseases rise, while historical infectious disease burden falls with public health gains and secure food supply.

Compact table. Elements of the nutrition transition

Element in slides	What changed	Health link in slides
Supply chain industrialization	Ultra-processed foods dominate availability and preference	Higher energy density, lower fibre/protein, hyper-palatability → weight gain risk
Diet composition	Lower protein and fibre, higher sugar and fat	Protein leverage → increased intake; glycaemic load and adiposity rise
Disease patterns	↓ Infectious disease, ↑ chronic disease	Anti-correlation stated on LO slide; obesity highlighted under “nutrition transition”
Control systems	Gut–brain axis integrates meal signals	Behaviour links to glucose control and longer-term protein sufficiency

TLDR (Objective 1) The nutrition transition is the shift to an ultra-processed food environment that coincides with falling infectious disease and rising chronic disease. Industrial supply chains produced low-protein, low-fibre, high-sugar/fat foods that drive protein leverage (people eat more to reach protein targets), raising total energy intake and obesity risk. The slides explicitly state the anti-correlation between infectious and chronic disease and tie it to this transition via gut–brain–behaviour mechanisms.

2. How industrialization of the food supply chain improved food security and reduced malnutrition

What changed

Industrialization reshaped the food environment and availability, with ultra-processed products dominating in modern societies.
Consumer preference and economics selected shelf-stable, palatable items that are widely accessible.

Why this improved security and lowered classical malnutrition

The regulated supply chain supports year-round access to food, underpinned by hygiene, surveillance, quality control, shelf-life rules, labelling, nutrition guidelines, and socio-economic levers that keep staples affordable.
These system controls lowered exposure to famine and seasonal shortages, reducing protein-energy malnutrition and classic micronutrient deficiencies at a population level (context provided across Week 2).

Trade-off the lecture highlights

The same industrialization that increased security also fostered an environment dominated by ultra-processed foods, setting the stage for the nutrition transition and rising chronic disease.

TLDR (Objective 2) Industrialization made food consistent, safe, and year-round, which helped suppress classical malnutrition. The cost is an environment dominated by ultra-processed foods that contributes to chronic disease patterns.

3. Why processed-food features (low fibre, low protein, higher fat and sugar) change feeding behaviour

The behavioural mechanism your slides emphasise

Protein leverage: when the percent protein of the diet falls (common in ultra-processed foods), people eat more total food to achieve a similar absolute protein intake, raising total calories. The lecture cites Raubenheimer & Simpson and shows: low-protein diets lead to ~50% more food by weight and “humans will ‘overeat’ to get enough protein.”

The composition shift that enables overeating

Snack/processed foods are presented as low protein and simple-carb heavy, with strong marketing, compared with whole-plant diets richer in digestion-resistant carbohydrates.
Your Week 1/2 reminder slides contrast traditional high-fibre meals with processed, easily digestible carb meals, highlighting how carbohydrate quality shifts absorption speed and satiety dynamics.

How this plays out in the gut–brain axis (from the same deck)

After eating, the brain integrates gut signals to shape feeding behaviour and glucose control; diet quality (protein fraction, fibre type) modulates those signals.
The system-level schema in the lecture links available foods → digestion and hormone/neuro signals → CNS integration → feeding behaviour, tying composition directly to subsequent intake.

Compact table: feature → effect on behaviour (as taught)

Processed-food feature	Immediate physiological effect	Behavioural outcome shown in slides
Lower protein %	Protein target unmet after a normal meal size	Increase meal size/total intake (protein leverage) → higher calories.
Lower fibre, simpler carbs	Faster digestion and absorption	Weaker sustained satiety, easier excess energy intake.
Higher sugar and fat	High palatability and energy density	Reinforces selection toward ultra-processed options; supports overconsumption.

TLDR (Objective 3) Ultra-processed foods lower protein fraction and fibre quality while raising sugar/fat. The slides show this drives protein leverage—people eat more to hit protein needs—and weakens sustained satiety, so total energy intake rises.

L2.3 Environment as a Source of Toxins

1. Common sources of ingestible toxicants

The oral route dominates exposure

People ingest roughly 1–2 kg of food and 1–3 L of fluid daily, so the oral route is a major pathway for xenobiotic exposure. Sources include industrial waste, algal blooms in water supplies, microbial spoilage, the built environment, and food contaminants. Toxic effects can be local (corrosives) or systemic (organ toxicity).

Source overview (with slide examples)

Industrial waste Per- and polyfluoroalkyl substances (PFAS), especially PFOS and PFOA, enter via food, water, dust, and food-contact materials. In rodents they activate PPAR-α and enlarge liver; human relevance remains uncertain.
Water contaminants: algal blooms Rapid growth of cyanobacteria or dinoflagellates in water supplies can produce toxins. Cyanobacteria produce microcystins that injure the liver. Dinoflagellate blooms (e.g., Alexandrium “red tides”) load shellfish with saxitoxin, causing paralytic shellfish poisoning. Climate change expands bloom distribution.
Microbial food spoilage Fungi generate potent toxins in staples.

• Aflatoxin B1 from Aspergillus flavus in grains/nuts; a major global liver-cancer cause.

• Ergot alkaloids from Claviceps purpurea on rye; “ergots” contain ergotamine, ergometrine, lysergic acid.
Food contaminants (processing/fermentation) Methanol can concentrate during distillation of fruit brandies; small volumes can be lethal.
Built environment Lead from aging plumbing (e.g., Flint, Michigan) leached into drinking water, exposing large populations.
Natural toxins in foods Poisonous mushrooms: Death cap (Amanita phalloides) frequently causes fatal poisonings; resembles edible species (paddy straw mushroom).

TLDR (Obj 1): Daily ingestion makes the gut a primary exposure route. Key sources are industrial chemicals (PFAS), water-bloom toxins (microcystin, saxitoxin), fungal food toxins (aflatoxin, ergot alkaloids), process contaminants (methanol), metals from infrastructure (lead), and natural poisons (Amanita). Local corrosive injury exists, but systemic organ toxicity dominates the burden.

2. Examples of ingestible toxicants and their mechanisms

Industrial chemicals

PFOS/PFOA (PFAS) Exposure: food, water, dust; food-contact packaging. Mechanism (rodents): PPAR-α activation → hepatomegaly, liver tumors; human relevance unresolved.

Water-bloom toxins

Microcystin (cyanobacteria) Exposure: drinking water during blooms. Mechanism: hepatotoxic; slides flag liver injury.
Saxitoxin (dinoflagellates → shellfish) Exposure: contaminated shellfish after “red tides.” Mechanism: voltage-gated sodium channel blockade → paralytic shellfish poisoning. Climate change widens risk zones.

Fungal food toxins

Aflatoxin B1 (Aspergillus flavus) Exposure: stored grains, nuts, maize. Mechanism: metabolic activation to aflatoxin B1-8,9-epoxide → DNA adducts and TP53 point mutation → hepatocellular carcinoma; acute aflatoxicosis causes GI/hepatic symptoms.
Ergot alkaloids (Claviceps purpurea) Exposure: ergot-contaminated rye. Mechanisms:

• 5-HT2A agonism → hallucinations (“St Anthony’s fire” features).

• Potent vasoconstriction → ischemia, gangrene.

Processing/fermentation contaminants

Methanol Exposure: fermentation by-product; concentrates in early distillate fractions, especially from high-pectin fruit mashes. Mechanism: metabolic conversion to formic acid → cytochrome oxidase inhibition → mitochondrial toxin with high ocular and CNS toxicity; small amounts may be lethal.

Metals from infrastructure

Lead (Pb2+) Exposure: leaching from pipes (Flint case). Mechanism: mimics divalent cations (Ca, Fe, Mg, Zn) → interferes with neurotransmission, heme synthesis, DNA repair, mitochondrial function.

Natural poisons in foods

Alpha-amanitin (Amanita phalloides, “death cap”) Exposure: misidentification of edible look-alikes. Mechanism: uptake into hepatocytes via OATP1B3 → RNA polymerase II inhibition → halted protein synthesis → hepatic and renal failure; not destroyed by cooking; lethal dose ≈1 mg/kg.

Compact mechanism table

Toxicant	Typical source	Primary mechanism	Key organ effect
PFOS/PFOA	Water, food, packaging	PPAR-α activation (rodents)	Hepatomegaly, tumors (rodent data)
Microcystin	Cyanobacterial blooms	Hepatotoxin	Liver injury
Saxitoxin	Red-tide shellfish	Na⁺ channel blockade	Paralysis, respiratory risk
Aflatoxin B1	Grains, nuts	Epoxide → TP53 mutation	HCC; acute aflatoxicosis
Ergot alkaloids	Rye (ergots)	5-HT2A agonism; vasoconstriction	Hallucinations; ischemia/gangrene
Methanol	Fermentation/distillates	Formic acid → cytochrome oxidase block	Ocular, CNS, systemic mitochondrial toxicity
Lead	Leached pipes	Mimics Ca/Fe/Mg/Zn; enzyme interference	Neuro, hematologic, mitochondrial dysfunction
Alpha-amanitin	Death cap mushroom	RNA Pol II inhibition (via OATP1B3 uptake)	Fulminant hepatic failure, death

TLDR (Obj 2): Slide exemplars map source to mechanism. PFAS activate PPAR-α (rodents). Cyanobacterial microcystin is hepatotoxic. Dinoflagellate saxitoxin blocks Na⁺ channels. Aflatoxin B1 forms an epoxide that mutates TP53. Ergot alkaloids trigger 5-HT2A effects and vasoconstriction. Methanol is converted to formic acid, inhibiting cytochrome oxidase. Lead imitates essential cations, disrupting key pathways. Alpha-amanitin blocks RNA Pol II after OATP1B3 uptake; cooking does not inactivate it.

3. Explain the toxicity and treatment of methanol poisoning

Key facts and mechanism

Sources: by-product of fermentation and a contaminant of poorly made distilled spirits; small volumes can be lethal.
Metabolism: alcohol dehydrogenase converts methanol to formaldehyde, then to formic acid. Formate inhibits mitochondrial cytochrome c oxidase, producing cellular hypoxia with high risk to retina and CNS.

Clinical pattern (what to look for)

Latent period after ingestion, then headache, dizziness, nausea, visual symptoms, metabolic acidosis that may be severe. Ocular toxicity is characteristic.

Treatment priorities

Block further toxic metabolism: give fomepizole to inhibit alcohol dehydrogenase. If unavailable, ethanol can be used as a competitive substrate.
Correct acidosis with intravenous bicarbonate and support ventilation and circulation as needed.
Enhance elimination and remove formate in severe poisoning: hemodialysis when profound acidosis, visual toxicity, renal failure, or high methanol levels are present.

TLDR Methanol itself is not the main toxin. Its metabolite formic acid inhibits cytochrome oxidase, causing severe acidosis and eye–brain injury. Treat by blocking ADH (fomepizole or ethanol), buffering acidosis, and using hemodialysis in severe cases. Small amounts can be lethal.

Describe the toxic sequelae of alpha-amanitin (death cap)

Source and mechanism

Source: Amanita phalloides misidentified as an edible mushroom; cooking does not inactivate the toxin.
Mechanism: alpha-amanitin is taken up into hepatocytes via OATP1B3 and inhibits RNA polymerase II, halting mRNA synthesis and protein production. Result is fulminant hepatic and subsequent renal failure. Lethal dose about 1 mg/kg.

Clinical course (sequelae over time)

Latent phase after ingestion, then abrupt GI phase with severe vomiting and diarrhea.
Apparent improvement for a short interval while hepatocellular injury evolves.
Hepatic failure with coagulopathy, jaundice, hypoglycemia, encephalopathy; renal injury may follow. High mortality without timely care.

TLDR Death cap ingestion delivers alpha-amanitin, which enters hepatocytes and blocks RNA Pol II. Expect GI collapse, a deceptive lull, then fulminant hepatic failure and possible renal failure. Heat does not destroy the toxin; even small doses can be fatal.

L2.4 Environment Effect on Disease Risk

1. How gut signals influence homeostasis (energy balance, glycemic control, immune function)

What changes, changes signals

If the substrates entering the gut change, or the microbe species/abundances or their activity change, then the pools of microbial metabolites and MAMPs in the lumen change. Those are major signals at the epithelial interface.
Barrier status from post-natal development and current tissue health modifies which signals reach tissue, so inputs → responses → outcomes shift.

Energy balance (feeding behaviour and nutrient partitioning)

Altered gut signals change feeding behaviour and thus calorie intake. This sits in the lecture’s list of consequences when the microbiome–gut–brain axis is perturbed.
Mechanism (from the same slide series): differences in metabolite and MAMP pools and in barrier tone → different epithelial and neural–endocrine signalling → changed appetite and motility.

Glycemic control

The lecture names insulin signalling as a key axis outcome: changes in signals from the gut alter post-prandial glycemic control.
Practical link: what and how fast nutrients arrive (diet-dependent) and how tissues sense them (barrier/development-dependent) shape the glycaemic response trajectory.

Immune function and inflammatory tone

The same signal shifts modulate immune signalling; the deck lists chronic inflammation as a hallmark consequence of altered gut signalling.
Rationale in slides: changes in MAMPs exposure and barrier “leakiness” alter immune inputs and downstream tone.

Compact map (from this deck’s logic)

Signal class (from lumen)	What shifts it	Primary host effects highlighted
Microbial metabolites	Diet substrates; microbiome composition/activity	Modulate appetite, motility, energy balance, glycemic control.
MAMPs (cell structures)	Microbe types and abundance distribution	Tune immune signalling; affect inflammatory tone.
Barrier gating of signals	Post-natal development; current tissue state	Changes which signals pass into tissue; alters systemic outcomes.

DOHAD: how post-natal development relates to adult disease risk

Main idea. The gut–microbiome–barrier system assembles after birth and becomes adult-like only after several years. Early exposures alter what signals are produced, how they are gated, and how tissues respond, so developmental differences can shift adult disease risk.

Timeline and phases in the deck.

0–12 months (developmental): very simple communities, dominated by one or two species; tissues are still naïve and developing.
12–30 months (transitional): rising diversity and complexity.
≥30 months to early adulthood (stable): adult-like communities (>100 species) and more even compositions.

Determinants highlighted (three drivers).

Microbe inoculation: family environment; often the same strain as mother seeds infant types.
Microbe nutrients: human milk oligosaccharides (HMO) composition selects Bifidobacterium-type states; brand/formula and HMO genotype differences are noted.
Microbe exclusion: birth mode, antibiotics, host inflammation alter who can colonize (e.g., C-section associates with EF-type communities).

Why this ties to adult risk.

The deck explicitly frames that post-conception and neonatal exposures change microbiomes and have disease associations (Developmental Origins of Health and Disease).
Mechanistic bridge: early-set community states, barrier maturation, and signal profiles calibrate energy balance, glycemic responses, and inflammatory tone, which the earlier slide links to modern chronic diseases.

TLDR (Objective 1 + DOHAD) Change diet or microbes and you change metabolite and MAMP signals at the gut surface. Barrier development and tissue state gate those signals. This shifts feeding behaviour/energy balance, insulin-linked glycemic control, and immune/inflammatory tone. Because the microbiome and barrier assemble post-natally over 3–4 years, early exposures (inoculation, nutrients, exclusion) set long-lived signal profiles, providing a DOHAD path from infancy to adult disease risk.

2. Community states / enterotypes in infants and adults

Definitions and idea

“Community state” and “enterotype” are the same concept, used at different ages. They group gut microbiomes by the driver that best explains between-sample differences. Boundaries are fuzzy but useful for linking exposures to outcomes.

Infant community states are simple: BB, BL, EF

In the first month of life, infant microbiomes cluster into three simple types, each dominated or “best explained” by a single driver species: BB (Bifidobacterium breve), BL (Bifidobacterium longum), or EF (Enterococcus faecalis). Communities are low diversity and often have only 1–2 dominant species.
The slide notes that “community state categorizations are based on which species best explains the differences,” not strictly the most abundant organism.

How infant types arise

Birth mode: Caesarean section significantly increases the probability of an EF-type community. Vaginal birth more often associates with BB or BL types. Mechanism is uncertain; hypotheses include inflammatory exclusion during vaginal delivery or peri-operative antibiotics with C-section.
Family inoculation: Where data exist, the same strain present in the mother is often found in the infant, especially for BL. Family environment seeds early states.
Milk oligosaccharides and ethnicity: Differences in HMO composition and maternal genotype associate with Bifidobacterium-type states. The slides and transcript highlight higher frequency of certain HMO genes in Asian mothers and enrichment of Bifidobacterium types in their infants. Brand of formula can also shift selection.
Three determinants summary: microbe exclusion (antibiotics, inflammation, competition), microbe inoculation (family environment), microbe nutrients (milk oligosaccharides).

Adult communities are complex: ET-B, ET-P, ET-F

Adult microbiomes have >100 species and are typically grouped by higher taxa: ET-P (Prevotellaceae), ET-F (Firmicutes class), ET-B (Bacteroidaceae). The term “enterotype” is used for adults.
Boundaries are gradients, not sharp separations, but the three groups are reproducible and useful for health associations.

How adult types differ with lifestyle

ET-P is more prevalent in societies with traditional food systems and fibre-rich diets.
ET-F and ET-B are more prevalent in industrialised settings and associate with metabolic syndrome, insulin resistance, and diabetes in the transcript commentary.

Compact comparison table

Age band	Label used	Typical drivers	Diversity	Key determinants / correlates
Infants (first months)	Community state	BB (B. breve), BL (B. longum), EF (E. faecalis)	Very low, 1–2 dominant species	Birth mode, family strain seeding, HMO composition and ethnicity, antibiotics and inflammation.
Adults	Enterotype	ET-P (Prevotellaceae), ET-F (Firmicutes), ET-B (Bacteroidaceae)	High, >100 species	Diet pattern and lifestyle. ET-P with traditional, fibre-rich diets; ET-F and ET-B with industrialised diets and metabolic disease associations.

TLDR (Objective 2) Infants show simple community states: BB, BL, EF. They differ by birth mode, family strain seeding, and HMO composition. Adults show complex enterotypes: ET-P, ET-F, ET-B. ET-P aligns with traditional, fibre-rich diets, while ET-F/ET-B are common in industrialised settings and link to metabolic risks in lecture commentary.

3. Make a simple argument for how microbiome development after birth may affect adult health

One-sentence argument

Early-life assembly of the gut–microbiome–barrier system sets the mix of microbial metabolites and MAMP signals that reach tissues; those signals calibrate appetite and energy balance, glycemic responses, and immune tone, which shifts adult disease risk.

The deck’s logic step-by-step

Signals drive homeostasis. Changes in luminal metabolites and MAMPs alter epithelial, neural–endocrine, and immune outputs that control feeding behaviour, glycemic control, and inflammatory tone.
Post-natal gating matures. Barrier properties and tissue responsiveness develop after birth, modifying which signals enter tissue and how they are interpreted.
Assembly takes years. Microbiome complexity progresses from very simple in infancy to adult-like after ~30 months, so early exposures can shift long-term signal profiles.
Determinants of early states. Three drivers shape infant communities:
- Microbe inoculation (family strain seeding),
- Microbe nutrients (HMO composition; feeding mode),
- Microbe exclusion (birth mode, antibiotics, inflammation).
DOHAD link. The slides frame post-conception and neonatal exposures as altering microbiomes with adult disease associations (Developmental Origins of Health and Disease).

Practical illustrations the lecture supports

Energy balance: Early states that bias metabolite output and barrier tone can shift appetite and motility, nudging lifetime energy intake.
Glycemic control: Different nutrient-sensing and incretin landscapes emerge as the gut matures; early programming affects post-prandial glucose handling later.
Immune function: Early differences in MAMP exposure and barrier “leakiness” calibrate inflammatory tone, a listed outcome of altered gut signalling.

Compact table. From early assembly to adult outcomes

Early-life factor (in slides)	Immediate effect on assembly	Long-run signal profile likely	Adult risk lever mentioned
Birth mode, antibiotics, inflammation	Exclusion of key colonizers or overgrowth of others	Different MAMP exposure, barrier gating	Basal inflammatory tone shifts; behaviour/metabolic signals change.
Family strain seeding	Inoculation with maternal strains	Stable early community states	Trajectories toward specific metabolite pools.
HMO composition, feeding	Nutrients selecting Bifidobacterium-type states	SCFA and vitamin output patterns differ	Appetite and glycemic signal integration shifts.

TLDR (Objective 3) The gut’s signals regulate behaviour, metabolism, and immunity. Because the microbiome and barrier assemble after birth, early exposures (who colonizes, which nutrients select them, which factors exclude them) set the signal mix that tissues see. Those signals calibrate energy balance, glycemic control, and inflammation, providing a DOHAD path from infancy to adult disease risk.

WEEK 3

L3.1 Dysbiosis

1) Similarities and key differences: infectious diseases vs dysbiotic diseases

How they differ (etiology, pathology, management)

Etiology (why disease develops)

Infectious disease: caused by one pathogenic species, acquired exogenously (contagious, food/water, zoonotic, nosocomial) or endogenously from the host’s own sites.
Dysbiosis: multifactorial; disease is associated with a distinct community state and altered functions. Microbial changes can be cause, consequence, or contribution, and may occur long before pathology appears.

Pathology (what causes damage)

Infectious disease: pathology tightly linked to the presence/growth of the pathogen, via effectors/toxins or host response damage.
Dysbiosis: pathology often response-driven and amplified by communities with pro-inflammatory activities; positive feedback can sustain inflammation without a single pathogen.

Management logic

Infectious disease: prevent by quarantine/surveillance/vaccination; treat by antibiotics or anti-toxin when relevant.
Dysbiosis: microbe-targeted steps alone seldom cure because underlying physiology/regulatory set-points are altered; microbe presence often potentiates pathology rather than uniquely causing it.

Snapshot table

Feature	Infectious disease	Dysbiosis
Etiology	One pathogen (exo/endogenous)	Multifactorial; community state shift; cause/consequence/contribution debates
Pathology link	Coincident with pathogen; effector or response damage	Sustained by host responses and pro-inflammatory consortia; feedback loops
Prevention	Pathogen-targeted (quarantine, surveillance, vaccines)	Hard to “prevent” by one microbe action; address environment/physiology
Treatment	Kill pathogen; block toxin	Modest benefit from microbe-targeted steps; physiology often key

TLDR (Obj 1) Infectious diseases are single-pathogen problems with pathology tied to that pathogen and amenable to pathogen-targeted prevention/treatment. Dysbioses are multifactorial states where communities and host responses sustain pathology; microbe changes may precede or follow disease, so microbe-only fixes rarely cure.

2) Why microbe-targeted strategies in dysbiosis are used yet rarely curative

The two microbe-targeted goals in the lecture

Restore lost benefits by adding or stimulating beneficial microbes (probiotics, prebiotics; FMT concept).
Remove undesirable microbes/activities that drive pathology (reduce pro-inflammatory or cytotoxic activities).

Why they help

Loss-of-function arm (barrier and tolerance). Depletion of microbes that support epithelial energy (butyrate) and Treg differentiation weakens the barrier and shifts immune tone toward inflammation; restoring these functions lowers risk.
Gain-of-harm arm (inflammatory loops). Expanded sulfate-reducers and organisms with pro-inflammatory MAMPs plus host oxidants create self-reinforcing inflammation; reducing these activities can dampen the loop.

Why they are rarely a lasting cure

Dysbiotic diseases reflect altered regulatory/physiological set-points; once established, the system can sit in a new stable state that persists even if you add “good” microbes or transiently suppress “bad” ones.
The underlying susceptibility (immune and metabolic) remains; microbe targeting often gives symptom relief but not durable resolution.
Fecal microbiota transplant is highly successful only in limited indications (e.g., recurrent C. difficile), moderately helpful in IBD, and not useful for most dysbioses, illustrating the constraint.

What to use, when (from the slides’ logic)

Strategy	Primary target	Works best when	Limitation in dysbiosis
Probiotics / FMT	Restore missing functions (butyrate producers; tolerance cues)	Loss-of-function dominates pathology	New state often persists; engraftment may be transient
Prebiotics / diet	Stimulate resident beneficial taxa (barrier energy, Treg support)	Functions can recover without transplant	Slow; depends on host context
Reduce pro-inflammatory consortia	Lower H₂S producers; dampen inflammatory MAMPs	Feedback loop weakens	Underlying immune set-point still abnormal

TLDR (Obj 2) Dysbiosis management often adds or stimulates beneficial microbes to restore lost functions and reduces pro-inflammatory activities to break loops. These steps help, yet they are rarely curative because dysbioses reflect stable, altered host–microbe set-points; without resetting physiology, communities drift back or benefits remain transient.

3) Why dysbiosis interventions target physiological responses, and how this limits positive feedback loops

Core idea

Dysbiosis is a host–microbe state maintained by physiology. Inflammation, motility, pH, oxygen and bile acids shape which microbes thrive. Those microbes then reinforce the same physiology. This produces self-reinforcing loops, so microbe-only fixes are often transient. Resetting physiological set-points helps break the loops.

Common positive feedback loops outlined in the lecture

Inflammation → oxidants/electron acceptors → pro-inflammatory consortia → more inflammation. Host inflammation increases oxygen/nitrate and favors taxa with inflammatory MAMPs or cytotoxic outputs. These consortia keep inflammation high.
Barrier energy deficit → mucus erosion/permeability → immune activation → deeper deficit. Loss of butyrate-producing allies lowers colonocyte fuel, weakens mucus and tight junctions, and raises immune activation, which further suppresses allies.
Motility/pH/bile mismatch → small-bowel overgrowth or irritant metabolite load → dysmotility and symptoms → further mismatch. Physiology shifts transit, acidity, and bile acids, changing where and how microbes grow. The result feeds back on motility and secretion.

Why target physiology (slides’ logic)

Once a new stable state forms, adding “good” microbes or trimming “bad” ones does not reset set-points. Changing host conditions (inflammatory tone, motility, luminal chemistry) removes the niche that maintains the dysbiotic state.

Levers that act on physiology (with the loop each lever addresses)

Physiological lever	What it changes	Which loop it breaks	Expected effect
Reduce inflammatory tone (e.g., anti-inflammatory therapy; barrier-supportive diet)	Lowers oxidants and nitrate availability	Inflammation→pro-inflammatory consortia loop	Shrinks niches for inflammatory consortia; symptoms fall.
Restore barrier energy and mucus (increase fermentable substrates tolerated by patient; epithelial support)	Raises butyrate at the epithelium, strengthens mucus and tight junctions	Barrier-deficit loop	Reduces antigen/MAMP translocation; dampens immune drive.
Normalize motility (pro- or anti-motility strategies as indicated)	Corrects stasis or hypermotility	SIBO/irritant metabolite loop	Limits overgrowth, reduces symptom triggers.
Rebalance luminal chemistry (acid, bicarbonate, bile acids)	Sets pH and bile delivery to intended segments	Growth-location mismatch	Shifts growth away from sensitive sites; improves digestion.
Lower host-derived electron acceptors (by treating mucosal inflammation)	Reduces oxygen/nitrate in lumen	Inflammation-selected taxa	Decreases selection for pro-inflammatory consortia.

How this complements microbe-targeted steps

Add/stimulate beneficial functions (prebiotics, probiotics, diet) lifts barrier energy and tolerance cues, but effects persist only if physiology supports them.
Remove harmful activities lowers immediate triggers, but physiology must be corrected to prevent re-selection of the same consortia.

TLDR (Objective 3) Dysbiosis persists because physiology and microbes co-stabilize. Inflammation, barrier energy, motility, pH, and bile acids select the community that then feeds back on those same variables. Interventions that reset physiology weaken these loops, allow beneficial functions to re-establish, and make microbe-directed steps more durable.

L3.2 Molecular Pathogenesis: Bacteria

Describe how virulence factors improve pathogen fitness

What virulence factors are

Molecules produced by a pathogen that increase fitness in a pathogenic niche. For bacteria, many are positioned in or on the cell envelope, the principal interface with host tissues. Some are essential for disease; loss renders the strain avirulent.

Fitness problems pathogens must solve and the virulence solutions

Reach and stick to the right surface (colonisation). Adhesins and pili bind host glycoconjugates to secure the niche and resist clearance.
Resist host immunity. Capsules, proteases that cleave antibodies, and LPS features that resist cationic antimicrobial peptides mitigate innate and adaptive attack.
Tolerate harsh environments. Envelope- and enzyme-based systems allow survival across extreme pH, bile, and oxidative stress (for example, gastric colonisers).
Manipulate host cells. Secretory nanomachines (for example, Type III secretion system, T3SS) inject effectors that rewire host pathways for uptake, survival, and immune evasion.
Move within or between cells/tissues. Motility systems, including flagella and actin-based motility (ABM), position bacteria in optimal microenvironments and spread the infection focus.
Acquire limiting nutrients. Siderophores and surface transporters scavenge host-held iron and other nutrients during nutritional immunity.
Transmit to new hosts. Toxins or secreted factors that increase fluid loss (diarrhoea) can enhance shedding and spread.
Resist chemotherapy. Envelope barriers and dedicated resistance determinants reduce antibiotic entry or neutralise drugs, preserving population survival under treatment.

Worked examples from the lecture

Fitness hurdle	Virulence factor (mechanism)	Fitness gain
Breach and colonise the epithelium	T3SS injects effectors that trigger phagocyte death and force epithelial uptake	Creates intracellular niche, avoids extracellular defenses.
Expand the infection focus	IcsA on the Shigella surface recruits host actin machinery to drive actin-based motility and spread cell-to-cell	Local expansion without extracellular exposure; lesion formation.
Withstand host antimicrobials and stress	LPS architecture and other envelope features reduce peptide/drug penetration and tolerate low pH	Persistence in hostile sites; improved colonisation success.

Two take-home rules from the lecture

Location matters. Because the envelope is the host–pathogen interface, many virulence traits are surface-exposed or envelope-embedded.
Essential vs accessory. Some virulence factors are required for disease in a given niche (for example, Shigella T3SS or IcsA for intracellular lifestyle), while others modulate severity or manifestations (for example, toxins that alter stool water content).

TLDR (Objective 1) Virulence factors are pathogen molecules that solve fitness bottlenecks in the host: attachment, immune resistance, environmental tolerance, host manipulation, motility, nutrient capture, transmission, and drug survival. In bacteria these functions are often encoded at the cell envelope, and some are essential for disease in the relevant niche (for example, Shigella T3SS and IcsA), while others tune disease severity or form.

Objective 2. Apply understanding to explain functional benefits of virulence factors, with examples

What “benefit” means

Virulence factors solve fitness bottlenecks in the host: getting to, staying in, exploiting, and leaving a niche, while resisting host defenses and treatment. Many are envelope-associated because the envelope is the host–pathogen interface.

Concrete examples from the lecture

Fitness bottleneck	Virulence factor → mechanism	Functional benefit to the pathogen
Initial epithelial engagement and uptake	Type III secretion system (T3SS) injects effectors that trigger epithelial cytoskeletal changes and phagocyte death	Forces entry into cells, creates a protected intracellular niche, reduces extracellular killing.
Local expansion without extracellular exposure	IcsA recruits host actin for actin-based motility (ABM) and cell-to-cell spread	Spreads through tissue while avoiding antibodies and complement in luminal/extracellular spaces.
Withstand chemical stress and host antimicrobials	LPS architecture and other envelope features reduce penetration of cationic peptides and some antibiotics; envelope systems buffer low pH/bile	Survival in hostile sites, persistence during early innate responses and therapy.
Acquire iron under nutritional immunity	Siderophores and surface transporters scavenge host-bound iron	Restores growth in iron-limited tissues; supports high-titer infection.
Maintain position against shear and clearance	Adhesins/pili bind host glycoconjugates	Lowers the effective ID50 by preventing washout, enabling microcolony formation.
Enhance exit and transmission	Secreted factors that increase fluid loss	Increases shedding to new hosts; preserves transmission chains.

TLDR (Objective 2) Virulence factors are adaptations that remove host-imposed constraints. In this lecture: T3SS forces uptake and disarms phagocytes; IcsA drives cell-to-cell spread; LPS/envelope traits tolerate antimicrobials and acid; siderophores beat iron restriction; adhesins secure the niche; secreted factors can boost transmission. These functions raise within-host survival and between-host spread.

3. Use virulence-factor knowledge to explain how their presence shapes infectious-disease manifestations

Map factor → tissue process → clinical pattern

Virulence factor class	Tissue-level effect	Expected manifestation (how disease “looks”)
Adhesins/pili	Tight binding to intestinal epithelium and microcolony formation	Lower ID50; earlier colonisation; persistent mucosal infection.
T3SS effectors	Trigger epithelial uptake, subvert phagocytes	Inflammatory diarrhea with epithelial damage; invasive foci; systemic symptoms if spread.
Actin-based motility (IcsA)	Cell-to-cell spread without extracellular phase	Confluent mucosal ulcers and intense local inflammation; scant bacteremia because exposure to serum is minimized.
Capsule/LPS traits	Serum and phagocyte resistance	Greater propensity for bacteremia/meningitis in encapsulated strains; higher case severity.
Siderophores/iron uptake	Growth in iron-limited compartments	Higher organism burden; prolonged fever and tissue damage due to high titers.
Envelope-mediated antimicrobial tolerance	Reduced peptide/drug penetration; acid/bile tolerance	Longer carriage, treatment failures, relapse from protected niches.
Secreted factors that alter secretion/ion transport	Increased luminal fluid	Profuse watery stools that favor shedding and transmission.

Two worked lecture examples tying factor to phenotype

Shigella: T3SS establishes intracellular lifestyle and kills phagocytes; IcsA enables lateral spread through epithelium. Result: inflammatory diarrhea with mucosal ulceration, high local cytokines, and limited extracellular exposure.
Envelope-centric survival: strains with LPS/envelope features that resist cationic peptides, acid, and some antibiotics survive early innate attack and therapy, biasing toward persistent or systemic disease when other factors permit invasion.

How this informs prediction and control

Presence of invasion systems predicts tissue-destructive, inflammatory syndromes and a need for rapid source control.
Dominant adhesion and secretion-altering factors predict high-volume shedding and transmission focus.
Envelope and nutrient-capture suites predict persistence, tolerance to first-line therapy, and benefit from strategies that also target host factors (acid, bile, inflammation) to unmask the pathogen.

TLDR (Objective 3) Disease form follows function. Adhesins lower ID50 and prolong mucosal residence; T3SS and IcsA shift disease toward invasive, inflammatory damage; capsule/LPS features push toward bloodstream survival; siderophores and envelope tolerance sustain high titers and relapse. Reading a pathogen’s virulence set lets you anticipate colonisation success, tissue tropism, inflammation level, transmission style, and treatment pitfalls.

L3.3 Viral Pathogens: Infection by obligate Intracellular Parasites

1) Describe what a virus is and how it replicates

What a virus is

An infectious, obligate intracellular parasite that contains a nucleic-acid genome (DNA or RNA, single- or double-stranded), encased in a protein capsid, sometimes with a host-derived lipid envelope.
Viruses infect all cellular life. Most do not impact human health.

Why “obligate intracellular”

Viruses lack ribosomes and cannot synthesize proteins or divide on their own, so they must use host cell machinery.

Core replication steps shown in the lecture

Attachment and entry by receptor binding and membrane fusion or endocytosis.
Production of viral proteins by hijacking host translation.
Genome replication by viral polymerase or host enzymes, depending on the virus.
Assembly and exit by budding or cell lysis, often producing hundreds to thousands of virions per infected cell.

Infection patterns the slides distinguish

Localised infection at the entry site. Disseminated infection that spreads to target organs. Systemic infection affecting many organs.

TLDR (Objective 1) A virus is an obligate intracellular parasite with a DNA or RNA genome in a capsid, sometimes with a lipid envelope. It attaches, enters, uses host translation, replicates its genome, assembles, and exits by budding or lysis. Infections can be localised, disseminated, or systemic.

2) List some common virus infections of the gastrointestinal tract

Categories from the lecture

Gastroenteritis: norovirus and rotavirus are the focus. Adenovirus and astrovirus also cause gastroenteritis.
Hepatitis acquired via the GI route: hepatitis A virus and hepatitis E virus.
Enteroviruses with dissemination: poliovirus and hand-foot-and-mouth disease viruses.

Brief capsule facts (from the deck)

Virus	Key points from slides
Norovirus	Major cause of acute, self-limiting gastroenteritis; outbreaks in close communities; transmission person-to-person, aerosols during vomiting, and fomites; infectious dose as low as ~10 virions; prolonged shedding; non-enveloped, ~40 nm RNA virus; replicates in small intestine, enterocyte death and barrier dysfunction, altered gastric motility.
Rotavirus	Historically >500,000 child deaths annually pre-vaccine; still major issue in low-income countries; person-to-person, heavy stool shedding; oral live-attenuated infant vaccine in use; non-enveloped, segmented RNA, ~80 nm; infects and destroys enterocytes causing malabsorption, plus NSP4 enterotoxin drives secretory diarrhoea and vomiting via 5-HT and vagal pathways.
Adenovirus, Astrovirus	Listed gastroenteritis causes alongside rota and noro.
Hepatitis A, E	Acquired via the GI tract and target the liver.
Enteroviruses (e.g., Polio, HFMD)	GI acquisition with local replication and potential spread via viraemia to nervous system or skin.

TLDR (Objective 2) GI viruses in this lecture: norovirus and rotavirus for gastroenteritis, plus adenovirus and astrovirus; hepatitis A/E acquired via the gut; enteroviruses such as polio and HFMD that disseminate after GI entry. Key norovirus and rotavirus details include high transmissibility, non-enveloped RNA structure, small-intestine replication, and in rotavirus, NSP4-mediated secretion and vomiting pathways.

3) Outline mechanisms by which viruses cause disease in the GI tract

Direct epithelial injury and malabsorption

Enterocyte death and barrier dysfunction in the small intestine lead to malabsorption and watery diarrhoea in norovirus outbreaks. Your slides explicitly note enterocyte death, barrier dysfunction, and altered gastric motility in norovirus infection.

Toxin-like secretory effects

Rotavirus NSP4 functions as a viral enterotoxin. In your deck it is linked to secretory diarrhoea and vomiting via 5-HT and vagal pathways, in addition to enterocyte destruction.

Motility and neuro-enteric signalling changes

Small-intestinal infection perturbs gastric and intestinal motility, contributing to nausea and vomiting (noted for norovirus).

Replication-linked cytolysis and exit

Viral replication uses host translation and produces large numbers of progeny. Assembly and exit by budding or cell lysis damage infected epithelia, worsening absorptive failure.

TLDR (Objective 3) GI viruses damage the gut by killing enterocytes and disrupting barrier function (norovirus), by enterotoxin-like action that drives secretion and emesis (rotavirus NSP4, via 5-HT and vagal pathways), by altering motility, and by lysis during exit, all of which reduce absorption and increase fluid loss.

4) Describe strategies to treat and prevent viral gastroenteritis

What your slides explicitly support

Vaccination

Rotavirus: oral live-attenuated infant vaccine is in use and has reduced severe disease burden; your rotavirus slides state vaccine use alongside high stool shedding and person-to-person spread.

Transmission control themes embedded in the deck’s organism summaries

Norovirus: extremely low infectious dose, prolonged shedding, and spread by person-to-person, aerosols during vomiting, and fomites. These properties in your slides motivate strict outbreak control and hygiene measures in practice; the slide bullets themselves spell out the transmission routes.

Pathogenesis-linked clinical focus

Because disease is driven by fluid loss and absorptive failure (mechanisms above), supportive management is central. Your slides frame gastroenteritis as typically acute and self-limiting (noted within organism summaries and patterns). I cannot confirm that specific clinical protocols (e.g., oral rehydration solution recipes, antiemetics) are enumerated in the deck.

What I cannot confirm from the slides

I cannot confirm slide text that lists named hygiene steps (e.g., hand hygiene formulations, surface disinfectants) or norovirus vaccines. The norovirus section in your deck emphasises transmission routes and biology, not a licensed vaccine.

TLDR (Objective 4) Your deck supports: rotavirus vaccination (oral live-attenuated) as prevention; and, given the mechanisms, supportive care aimed at replacing losses. For norovirus, slides stress high transmissibility and multiple spread routes, implying strict outbreak control and hygiene in applied settings. I cannot confirm slide coverage of specific hygiene protocols or a licensed norovirus vaccine.

WEEK 4

L4.1 Immunity in GIT

1) Describe how the gastrointestinal tract protects against threats

Multilayered barrier and rapid sensing

The gut is the body’s largest interface with the external environment; homeostasis requires balancing nutrient absorption, a resident microbiome, and pathogen defense.
Physical–chemical barrier: a single layer of intestinal epithelial cells (IECs) with tight junctions, rapid turnover, and a mucus layer that limits access to tissue and retains antimicrobial peptides (from Paneth cells) and IgA.
Threat detection: IECs and immune cells sample the lumen. M cells and goblet cells translocate antigens to immune cells; dendritic cells can extend processes into the lumen. Note M cells are also an entry route for some pathogens.
Pattern-recognition receptors (PRRs): widely expressed, enriched on innate cells and strategically distributed on IECs at cell surface, endosomes, cytosol, and nucleus to detect microbial-associated molecular patterns (MAMPs).

Innate effector programs

PRR activation triggers inflammatory cytokines, antiviral programs, programmed cell death, and initiation of adaptive immunity; it also tightens junctions and stimulates mucus and AMP production, strengthening the barrier.
Inflammation: classic rubor, calor, tumor, dolor; delivers circulating cells and proteins to the site.
Antiviral signaling: type I interferons (IFN-α/β) from infected cells induce an antiviral state in neighbors.
Cell extrusion and death: infected/damaged IECs are extruded; PRR signaling can drive apoptosis, necroptosis, or pyroptosis to limit pathogen load and spread, though barrier weakening can result.

Adaptive mucosal immunity

GALT (Peyer’s patches, mesenteric nodes, lymphoid follicles) primes naïve B and T cells; DCs present antigen to drive Tregs or effector CD4/CD8 depending on local cues and PRR context.
Secretory IgA: abundant dimeric IgA from plasma cells regulates microbiome composition, protects against toxins and viruses, and limits viral shedding.

Compact map (from slides)

Layer	Key components	Protective actions
Physical–chemical	IEC monolayer, tight junctions, mucus, AMPs	Blocks access, traps and kills microbes, retains IgA.
Innate sensing/effectors	PRRs, IFN-α/β, inflammation, extrusion/death	Detects MAMPs, restricts pathogens, contains spread.
Adaptive	GALT (DC→T/B), sIgA	Tolerance vs immunity, immune exclusion, antiviral protection.

TLDR (Objective 1) Protection is layered: IEC tight junctions and mucus with AMPs/IgA block entry; PRRs trigger inflammation, antiviral states, and controlled cell death while tightening the barrier; GALT primes T and B cells, and sIgA enforces immune exclusion and shapes the microbiome.

2) Describe how the immune response is balanced in the GIT and discuss consequences of an inappropriate response

How balance is achieved

Signal discrimination at the interface: polarized PRR expression on IECs (apical vs basolateral) helps distinguish commensal cues from invasive threats; PRR signaling can tighten junctions and boost mucus, while frequent IEC turnover terminates responses. Negative regulators limit excessive inflammation.
Regulatory–effector tuning in GALT: local environment and PRR context shape naïve T cells toward Tregs or effector CD4/CD8, coordinating tolerance to food/commensals with readiness for pathogens.
IgA-mediated control: abundant sIgA regulates microbiome composition and neutralizes toxins/viruses without inflammation, supporting steady-state tolerance.
Diet–microbiome–immune crosstalk via AHR: dietary and microbial ligands activate AHR to support ILC3 and T cell functions (IL-22, IL-10), maintaining barrier integrity, AMP production, and restrained inflammation.

What goes wrong if balance fails

Excess PRR/inflammatory drive weakens the barrier and amplifies tissue damage (slide notes “overreactions can drive excessive inflammation”).
AHR deficiency perturbs ILC/T cell balance, promotes a proinflammatory milieu, impairs motility via neuronal effects, and allows bacterial overgrowth.
Barrier breakdown increases microbial translocation, escalating inflammation and creating self-reinforcing loops of dysfunction (integrates with extrusion/cell-death notes).

Balance framework (from slides)

Balancing lever	Mechanism	If dysregulated, consequence
Polarized PRR + IEC turnover	Apical/basolateral sensing, negative regulation, response termination	Over-inflammation, barrier damage.
Treg vs effector programming	DC cues in GALT set T cell fates	Loss of tolerance or failed protection.
sIgA immune exclusion	Non-inflammatory control of microbes/toxins/viruses	Dysbiosis, increased pathogen adherence and shedding.
AHR-dependent ILC/T cell tone	Diet/microbe ligands → IL-22/IL-10, barrier support	Proinflammatory state, impaired motility, overgrowth.

TLDR (Objective 2) Balance comes from how the gut senses (polarized PRRs, response termination), what effectors it deploys (sIgA, IL-22/IL-10), and who the effectors are (Tregs, ILC3), all tuned by diet- and microbe-derived signals via AHR. When these checks fail, inflammation escalates, barriers fail, motility changes, and overgrowth occurs.

3) Interactions between the gut microbiota, diet, and the immune system

Core framework

Diet and microbial metabolites provide ligands and cues that tune mucosal immunity. The slides highlight the aryl hydrocarbon receptor (AHR) as a central sensor linking diet and microbiota to immune tone. AHR ligands come from dietary components and from microbial metabolism. Activation supports ILC3 survival and the function of Th17 and Treg cells, which produce IL-22 and IL-10. These cytokines maintain barrier integrity, stimulate antimicrobial peptide production, and dampen excessive inflammation.
When AHR signalling is deficient, ILC and T-cell balance is perturbed, a pro-inflammatory environment emerges, gut motility is impaired through effects on colonic neurons, and bacterial overgrowth develops.

Where these signals act

Epithelial interface and PRRs. IECs detect microbial-associated molecular patterns (MAMPs) via PRRs located apically, basolaterally, in endosomes, cytosol, and nucleus. PRR engagement tightens junctions, induces mucus and antimicrobial peptide production, and “kicks off” innate and adaptive responses. This provides a mechanistic route by which diet-shaped microbiota composition alters barrier tone.
IgA shaping of the microbiome. Plasma cells produce dimeric sIgA, the most abundant gut antibody. sIgA regulates microbiome composition and function, protects against toxins and viruses, and limits viral shedding, giving a non-inflammatory mechanism for host selection of commensals.

Putting diet, microbes, and immunity together (mechanism map)

Input from diet or microbes	Sensor or pathway in host	Immune/epithelial effect	Functional outcome
Dietary and microbial AHR ligands	AHR in ILC3, T cells, neurons	Supports ILC3 and Th17/Treg; IL-22/IL-10 production; barrier integrity; AMP production; restrained inflammation; normal motility	Balanced immune tone; controlled growth of commensals; protection without over-inflammation.
Microbial MAMPs (surface/lumen)	PRRs on IECs and immune cells	Tighten junctions, increase mucus and AMPs; initiate innate/adaptive responses when thresholds exceeded	Rapid containment with barrier reinforcement; tolerance when signals remain compartmentalised.
Microbiome-modulated antigens in lumen	GALT sampling (DC→T/B) and sIgA output	Tuning toward Tregs or effector cells depending on context; IgA-mediated immune exclusion	Stable coexistence with commensals; targeted responses to threats.

What goes wrong when diet–microbe–immune signalling is perturbed

AHR deficiency: pro-inflammatory milieu, disordered motility, and overgrowth of intestinal bacteria.
Imbalanced PRR signalling: excessive inflammation and barrier weakening if responses are not terminated or polarised correctly at the epithelial surface.
Loss of IgA control: reduced ability to regulate microbiome composition and limit pathogen adherence or viral shedding.

TLDR (Objective 3) Diet and microbiota co-define gut immune tone. AHR senses dietary and microbial ligands to sustain ILC3 and Th17/Treg programs, yielding IL-22/IL-10, barrier integrity, AMPs, and restrained inflammation. PRRs on IECs convert microbial cues into barrier reinforcement or alarms, and sIgA shapes the microbiome without inflammation. Defects in these links cause pro-inflammatory states, motility problems, and microbial overgrowth.

L4.2 Clinical Drug Interventions

1) Physiological role of GLP-1 and the rationale for GLP-1 receptor agonists in T2D and obesity

What GLP-1 does

GLP-1 is an incretin hormone released from the gut in response to glucose and lipids.
Incretins increase insulin secretion and reduce glucagon, lowering circulating glucose.
Oral glucose provokes a larger insulin response than IV glucose because of the incretin effect.
In your Week 1 homeostasis slides, GLP-1 (with GIP) is listed as an insulin-augmenting gut hormone, integrating feeding with metabolic control.

Why drug developers target the GLP-1 pathway

Endogenous GLP-1 is rapidly inactivated by DPP-4; native GLP-1 has a ~2-minute half-life.
Three strategies follow from the slides:
1. Give GLP-1 (parenteral) despite short half-life; 2) give a DPP-4–resistant GLP-1 analogue; 3) inhibit DPP-4 (“gliptins,” e.g., alogliptin) to preserve endogenous incretins.
Structural GLP-1 analogues and later agents extend exposure and practicality; your deck highlights once-weekly semaglutide and dual GIP/GLP-1 agonists (tirzepatide).

TLDR (Objective 1) GLP-1 is a gut incretin that raises insulin and lowers glucagon after meals; the oral > IV “incretin effect” shows its importance. Because DPP-4 rapidly inactivates GLP-1, the rationale is to mimic GLP-1 with resistant analogues or block DPP-4 to sustain signaling, improving post-prandial glucose and supporting weight management.

2) Exenatide: origin, mechanism, and clinical limitations

Origin

Your slide traces exenatide to exendin-4 from the Gila monster; this analogue resists DPP-4 degradation. The slide cites Furman 2012 (Toxicon).

Mechanism of action

Exenatide is a GLP-1 receptor agonist that reproduces incretin actions at the GLP-1 receptor (extracellular domain shown on the slide), enhancing insulin and reducing glucagon in a glucose-dependent manner (mechanistic basis from the incretin section).

Clinical limitations highlighted or implied in the deck

Dosing burden and exposure: native GLP-1’s short half-life and the need for parenteral dosing motivated analogues; the slide shows exenatide extended-release and later long-acting agents to increase convenience and exposure.
Immunogenicity/half-life considerations: the slide states that new GLP-1 analogues avoid immunogenicity and increase half-life, which explains movement beyond early agents toward weekly dosing and dual-agonists. (The slide does not ascribe a specific immunogenicity rate to exenatide; it frames this as a design goal for newer agents.)

TLDR (Objective 2) Exenatide derives from exendin-4 (Gila monster), acts at the GLP-1 receptor, and is DPP-4 resistant. Its development addressed GLP-1’s 2-minute half-life and the need for injections. Limitations that drove newer options were exposure and practicality, leading to extended-release exenatide, once-weekly analogues (e.g., semaglutide), and dual-agonists designed to improve efficacy and reduce immunogenicity concerns.

3) Outline the main pharmacological strategies for management of IBD: 5-ASA, corticosteroids, targeted immunomodulators

What the deck lists (category → examples)

Aminosalicylates (5-ASA): sulfasalazine. (Slide p.11)
Corticosteroids: prednisone, prednisolone, budesonide. (Slide p.11)
Immunomodulators: thiopurine derivatives, methotrexate, cyclosporine. (Slide p.11)
Biologics / targeted therapies: JAK-STAT inhibitors, anti-TNF-α antibodies. (Slide p.11)

Mechanistic notes shown or directly supported in the slides

Corticosteroids: cytokines activate IKKβ → NF-κB; NF-κB recruits HAT to drive pro-inflammatory genes. Corticosteroid-GR translocates to the nucleus, interferes with HAT and increases HDAC2, lowering inflammatory mediators. (Slide p.12)
Biologic/targeted class (overview): the deck groups JAK-STAT inhibitors and anti-TNF-α antibodies under “Biologics (targeted therapies).” (Slide p.11)

Compact table (from the slides)

Strategy	Examples in slides	Slide support
5-ASA (aminosalicylates)	Sulfasalazine	p.11
Corticosteroids	Prednisone, prednisolone, budesonide; NF-κB/HAT/HDAC2 mechanism shown	p.11–12
Immunomodulators	Thiopurines, methotrexate, cyclosporine	p.11
Targeted biologics	JAK-STAT inhibitors, anti-TNF-α antibodies	p.11

TLDR (Obj 3) The slide framework: start with 5-ASA, escalate to corticosteroids, use immunomodulators, and employ targeted biologics including JAK-STAT inhibitors and anti-TNF-α. Corticosteroids down-shift NF-κB–driven transcription via HAT interference and HDAC2 up-regulation. (Slides p.11–12)

4) Explain JAK-STAT signalling and how JAK inhibitors disrupt cytokine signalling in IBD

Pathway pieces shown in the deck

JAKs (Janus kinases): JAK1, JAK2, JAK3, TYK2 located on the cytosolic side of cytokine receptors. (Slide p.13)
STATs: Signal Transducer and Activator of Transcription. (Slide p.13)
Cytokine receptors: example given, IL-6 receptor. (Slide p.13)

Stepwise logic (from the slide content)

Cytokine binds its receptor.
Receptor-associated JAKs signal downstream.
STATs act as transcriptional effectors (“Signal Transducer and Activator of Transcription”). (Slide p.13)

Where JAK inhibitors act (as framed by the slides)

The slides categorise JAK-STAT inhibitors among targeted IBD therapies (p.11) and depict the JAK/STAT nodes (p.13). Putting these together: JAK inhibitors act at the JAK step on cytokine receptors, preventing downstream STAT activation and the cytokine-driven transcriptional program.

TLDR (Obj 4) JAK-STAT in the slides: cytokine receptor with JAK1/2/3/TYK2 → STAT transcription factors. JAK inhibitors block signalling at the receptor-associated JAKs, so STAT-mediated cytokine responses do not proceed, which is why they are grouped under targeted IBD therapies. (Slides p.11, p.13)

L4.3 Antibiotics: Mechanism in Bacteria

1) What bacterial molecules have been successfully targeted by clinically used antibiotic families

Core idea from the deck

Antibiotics treat bacterial infections by targeting critical bacterial molecules/structures needed for viability and growth, and must be specific to avoid human toxicity. Examples of validated targets in current use: LPS, peptidoglycan, and the 70S ribosome.

Validated targets highlighted in the slides

Targeted bacterial component	Why it is a good target	Representative clinical family/mechanism
Peptidoglycan synthesis (PBPs)	Peptidoglycan is unique to bacteria and required for shape and mechanical integrity; disruption → lysis	β-lactams (e.g., penicillin, amoxicillin) bind PBPs and block cross-linking, stopping wall synthesis → lysis.
70S ribosome	Bacterial 70S differs from human 80S, enabling selective inhibition of bacterial translation	Multiple ribosome-targeting classes (slide cites concept and literature) that bind 30S or 50S subunits to block protein synthesis.
LPS / envelope features	The diderm (Gram-negative) envelope with LPS is a distinctive surface; envelope components are drug-addressable and shape access and survival	Polymyxins act at the LPS-rich outer membrane; slide explicitly lists LPS as a target example and frames envelopes as key antibiotic targets.

TLDR (Obj 1) The deck’s validated targets are peptidoglycan/PBPs (β-lactams), the 70S ribosome (ribosome-active classes), and LPS/envelope components (e.g., polymyxins), chosen for bacterial specificity to minimize host toxicity.

2) Example molecules and subcellular structures essential for bacterial survival (from the deck)

Essentials the slides emphasize

Molecule / structure	Essential role stated	What happens when targeted
Peptidoglycan	Holds the cell together, defines cell shape, and directs aspects of cell division	Inhibition of synthesis causes membrane rupture (lysis) and cell death.
Penicillin-binding proteins (PBPs)	Key enzymes that build peptidoglycan	β-lactam binding blocks PBP activity → failed wall synthesis → lysis. (Slide shows E. coli with penicillin vs control.)
70S ribosome	Required for bacterial protein synthesis (bacteria must synthesize proteins to live)	70S-specific inhibitors halt translation without blocking human 80S; growth stops, cells die or fail to replicate.
Cell envelope (Gram-positive monoderm; Gram-negative diderm with LPS)	Defines the interface with the host and environment; governs permeability and resilience	Envelope components (including LPS) are legitimate drug targets and also influence access and resistance.

Resistance context from the slides (why “essential” is not always “fragile”)

Bacteria possess many resistance mechanisms (target-site mutations, expression changes, acquisition of protection/efflux), which can undermine drugs even when the target is essential. Examples shown: PBP site substitutions (β-lactam resistance), pmrA-linked LPS changes (polymyxin resistance), TetM ribosomal protection (tetracycline).

TLDR (Obj 2) The deck’s essential survival systems are peptidoglycan/PBPs, the 70S ribosome, and the cell envelope (including LPS). Blocking wall synthesis lyses cells; blocking the 70S halts translation; targeting the envelope disrupts the bacterial barrier. Clinical effectiveness depends on these essentials and on whether resistance (target modification, expression shifts, acquired protection) is present.

3. Explain the effectiveness of different antibiotics given specific scenarios

First principles from the deck

Antibiotics treat bacteria, not viruses. They target bacterial-specific structures required for viability and growth. The deck calls out peptidoglycan, 70S ribosome, and LPS/envelope as validated targets. Effectiveness depends on the target, the envelope the drug must cross, and resistance mechanisms present.
Gram-positive and Gram-negative envelopes differ. The outer membrane with LPS in Gram-negatives adds a permeability barrier that shapes access and resistance.
Bacteria use many resistance strategies: target-site modification (e.g., PBP substitutions), expression changes that remodel LPS via regulators such as pmrA (polymyxin resistance), and acquired genes such as TetM that protect the ribosome from tetracycline. Choice of drug must account for which mechanism is operating.

Scenario guide linked to slide mechanisms

1) Suspected peptidoglycan synthesis vulnerability

Rationale. Peptidoglycan is unique and essential. Blocking PBPs halts cross-linking and triggers lysis.
Effective choice. A β-lactam that binds PBPs. Expect killing if PBPs are accessible and unmodified.
When it fails. Target-site substitutions in PBPs reduce binding. Consider a different β-lactam with better PBP affinity or move to a non-cell-wall target.

2) Gram-negative with outer-membrane barrier issues

Rationale. The LPS-rich outer membrane blocks some agents yet exposes an LPS target class.
Effective choice. Polymyxins disrupt LPS-containing outer membranes. Use when other options fail and resistance markers are absent.
When it fails. pmrA-linked LPS remodeling reduces polymyxin binding. Switch to a class that does not rely on native LPS.

3) Protein synthesis inhibition needed

Rationale. The 70S ribosome differs from the human 80S, allowing selective translation blockade.
Effective choice. A 30S or 50S-active agent when ribosomal protection is not present.
When it fails. TetM prevents tetracycline from binding the 70S. Choose a different ribosome class or move off-ribosome.

4) Interpreting the deck’s quiz logic for unknown drugs

Observation. Resistance to “Bugsplosin” arises via a substitution in the catalytic site of an essential enzyme. This maps to target modification.
Implication. If the Bugsplosin-resistant isolate remains sensitive to Microbeno, either the two drugs hit different enzymes or Microbeno binds the same enzyme at a site not affected by the mutation. Both interpretations fit the data provided.

Decision table you can apply to cases from the slides

Scenario cue	Likely barrier or mechanism	Better bets	Avoid
Cell-wall synthesis failure suspected; PBPs intact	No PBP substitutions	β-lactam targeting PBPs	β-lactam if PBP mutations present
Gram-negative with LPS barrier; last-line need	Intact LPS favors binding	Polymyxin	Polymyxin if pmrA-type LPS remodeling detected
Protein synthesis target; no TetM	No ribosomal protection	30S or 50S-active agent	Tetracycline in TetM carriers

TLDR (Objective 3) Effectiveness follows three checks in the deck: target present and essential (PBPs, 70S, LPS), envelope access (Gram-negative outer membrane and LPS), and resistance mechanism (PBP substitutions, pmrA-driven LPS change, TetM ribosomal protection). Map the scenario to these checks, then pick a class whose binding site and entry path are still viable.

L4.4 Antibiotics: Pharmacy

1) Identify the three major classes of antibiotics

Three pharmacological classes in this lecture:
1. Drugs interfering with cell wall synthesis.
2. Drugs interfering with nucleic acid synthesis.
3. Drugs interfering with protein synthesis.
Gram-positive vs Gram-negative envelope structure matters for first-line choice and spectrum.

Families under each class (as taught):

Class	Families highlighted in slides
Cell wall synthesis	β-lactams; glycopeptides.
Nucleic acid synthesis	Sulphonamides; quinolones; rifampicin.
Protein synthesis	Tetracyclines; aminoglycosides; macrolides.

TLDR (Obj 1) The lecture groups antibiotics by cell wall, nucleic acid, or protein synthesis targets; common families are β-lactams and glycopeptides, sulphonamides/quinolones/rifampicin, and tetracyclines/aminoglycosides/macrolides. Envelope type guides initial choice.

2) Describe the mechanisms of action of commonly used antibiotics

Cell wall synthesis inhibitors

β-lactams (penicillins, cephalosporins): inhibit transpeptidase (a PBP) that cross-links peptidoglycan peptide chains, causing loss of wall integrity and bactericidal lysis. Many β-lactams are broad spectrum (GP and GN). β-lactamases inactivate some agents; clavulanic acid inhibits β-lactamase.
Glycopeptides (vancomycin): bind the D-Ala-D-Ala terminus of peptidoglycan peptides, sterically blocking transpeptidation; weakened wall leads to bactericidal lysis. Active on Gram-positives; option in β-lactam allergy.

Nucleic acid synthesis inhibitors

Sulphonamides (e.g., sulfamethoxazole): compete for dihydropteroate synthetase to block folate production, thereby inhibiting nucleic acid synthesis; typically bacteriostatic in the summary table.
Quinolones (e.g., ciprofloxacin): inhibit DNA gyrase (topoisomerase) to prevent appropriate DNA supercoiling; bactericidal.
Rifampicin: inhibits bacterial RNA polymerase, blocking transcription from DNA to mRNA; bactericidal.

Protein synthesis inhibitors (70S-selective)

Tetracyclines (e.g., doxycycline): bind 30S subunit and inhibit tRNA association; bacteriostatic.
Aminoglycosides: bind 30S; in this lecture they are grouped with tetracyclines as 30S-acting agents (mechanistic bullet shown under protein synthesis slide).
Macrolides (e.g., erythromycin): bind 50S subunit and inhibit translocation of tRNA/peptide chains; bacteriostatic.

Compact mechanism table from the deck

Family (example)	Primary action	Bactericidal vs static (per summary slide)
β-lactams (amoxicillin, cefalexin)	Inhibit transpeptidase → block peptidoglycan cross-linking	Cidal
Glycopeptides (vancomycin)	Bind D-Ala-D-Ala → prevent transpeptidation	Cidal
Sulphonamides (sulfamethoxazole)	Inhibit folate synthesis (DHPS)	Static
Quinolones (ciprofloxacin)	Inhibit DNA gyrase	Cidal
Rifampicin	Inhibit RNA polymerase	Cidal
Tetracyclines (doxycycline)	30S—block tRNA association	Static
Macrolides (erythromycin)	50S—block translocation	Static

TLDR (Obj 2) Mechanisms in this lecture: β-lactams and glycopeptides stop cell-wall cross-linking (cidal); sulphonamides/quinolones/rifampicin block folate, DNA gyrase, or RNA polymerase (mostly cidal except sulphonamides); tetracyclines/aminoglycosides/macrolides target the 70S ribosome (30S or 50S) to halt translation (tetracyclines/macrolides static).

3) Side effects of antibiotics and their effect on the gut

What the slide set emphasizes overall

Antibiotics are grouped by target class (cell wall, nucleic acids, protein). Across classes, common adverse effects include GI disturbance, microbiome disruption, and risks tied to spectrum and route. Broad-spectrum exposure increases risks for dysbiosis and C. difficile–associated disease; narrow and targeted use reduces these risks.

Class-by-class side-effect map (from the lecture’s families)

Class	Families in deck	Slide-supported adverse effects and gut impact
Cell wall	β-lactams; glycopeptides	β-lactams: allergy/hypersensitivity is the key caution and a common reason to switch to vancomycin; GI upset possible; broader agents disrupt the gut flora more. Glycopeptides (vancomycin): GI disturbance in oral use; used as an alternative in β-lactam allergy.
Nucleic acids	Sulphonamides; quinolones; rifampicin	Sulphonamides: GI upset; classed as bacteriostatic in the summary table (clinical recovery depends on host and site). Quinolones: GI upset; bactericidal; broad activity implies greater microbiome impact. Rifampicin: GI disturbance; drug–drug interaction potential flagged in the family list, so regimens require care.
Protein synthesis	Tetracyclines; aminoglycosides; macrolides	Tetracyclines (e.g., doxycycline): GI upset; bacteriostatic in the deck’s summary. Aminoglycosides: classed among 30S-active agents; systemic use is reserved and monitored (gut effect limited if not given orally). Macrolides: GI disturbance common; bacteriostatic in the summary. Broader or prolonged use across this class family perturbs gut communities.

TLDR (Obj 3) The deck’s families map to predictable adverse-effect patterns: GI disturbance and microbiome disruption are common across classes; β-lactam allergy drives vancomycin use; broad-spectrum agents increase dysbiosis/C. difficile risk; summary slides classify sulphonamides/tetracyclines/macrolides as static and β-lactams/quinolones/rifampicin/glycopeptides as cidal, which shapes clinical recovery and stewardship choices.

4) Purposes of antibiotic stewardship

What stewardship aims to achieve (as framed in the lecture)

Use the right drug, dose, and duration for the organism and site, guided by the three target classes and their mechanisms. This reduces unnecessary exposure and microbiome damage.
Minimize resistance selection by avoiding broad-spectrum agents when narrow options suffice and by avoiding antibiotics for non-bacterial illness.
Reduce adverse events, including C. difficile–associated disease and class-specific toxicities, by curbing unnecessary exposure and choosing narrower agents when possible.
Preserve effectiveness of key classes (β-lactams, glycopeptides, quinolones, protein-synthesis inhibitors) for severe infections by reserving them for clear indications and following local guidance.

Practical stewardship levers reflected in the slides’ structure

Match spectrum to organism/envelope (Gram-positive vs Gram-negative) to limit collateral damage.
Prefer targeted therapy once an organism is identified; avoid antibiotics for viral disease.
Review duration so exposure is long enough for cure but not longer than necessary, limiting gut disruption.

TLDR (Obj 4) Stewardship in this lecture means: select antibiotics by target class and organism, avoid use for non-bacterial illness, narrow spectrum when possible, and limit duration. Goals are to reduce resistance, cut adverse events and C. difficile, preserve gut microbiota, and maintain future efficacy of critical drug classes.

WEEK 5

L5.1 Anatomy of the Respiratory Tract

1) Identify and distinguish the major anatomical structures of the upper and lower respiratory system

Overall organisation

The tract runs from nostrils to alveoli and is divided into upper and lower portions.

Upper respiratory system (conduction and conditioning of air)

External nose with cartilaginous framework and vestibule leading to nasal cavities; nasal septum of cartilage and bone divides right and left cavities.
Nasal cavities lined by highly vascular mucosa to warm, moisten, and clean inspired air; roof contains olfactory neurons. Lateral walls bear 3 nasal conchae with underlying meatuses (paranasal sinus drainage).
Paranasal sinuses (frontal, ethmoidal, sphenoidal, maxillary), air-filled mucosa-lined spaces that drain into meatuses.
Pharynx (naso-, oro-, laryngopharynx): a musculo-fascial tube from skull base to C6, posterior to nasal/oral cavities and larynx.
Larynx: “guardian” of the airway and unit of vocalisation; conducts air between laryngopharynx and trachea via the laryngeal inlet; contains epiglottis, thyroid, cricoid, arytenoid cartilages and vocal folds; strong cough reflex.

Lower respiratory system (airway to exchange surfaces)

Trachea: 10–12 cm fibro-muscular tube from larynx to carina; 16–20 C-shaped cartilages anterolaterally with posterior smooth muscle; air-only conduit.
Bronchial tree: right and left primary bronchi (right is shorter, wider, more vertical), branching to secondary (lobar) bronchi—3 on right, 2 on left—then tertiary (segmental) bronchi, terminal bronchioles (no cartilage), respiratory bronchioles, and finally alveoli/alveolar sacs.
Lungs: occupy lateral pulmonary cavities; have apex, base, costal and mediastinal surfaces. Right lung: 3 lobes (superior, middle, inferior) with oblique and horizontal fissures. Left lung: 2 lobes (superior, inferior) with oblique fissure.
Hilum: doorway for primary bronchus, pulmonary artery, pulmonary veins.
Pleurae: each lung wrapped by visceral and parietal pleura (continuous at hilum) with pleural fluid generating surface tension to oppose elastic recoil and keep lungs expanded.
Respiratory muscles: diaphragm (chief muscle; central tendon descends on inspiration) and intercostals (external, internal, innermost) alter thoracic volume and stabilise the chest wall.

TLDR (Objective 1) Upper tract: nose/vestibule, nasal cavities with conchae/meatuses, paranasal sinuses, pharynx, larynx. Lower tract: trachea, bronchial tree (1°, 2°, 3° bronchi → bronchioles → alveoli), lungs with lobes/fissures, hilum, pleurae, and respiratory muscles.

2) Describe anatomical relationships and the sequential passage of air in and out

Relationships that organise airflow

Nasal cavities → choanae → nasopharynx; the pharynx lies posterior to nasal/oral cavities and larynx and anterior to the vertebral column.
The larynx sits superior to the trachea, guarding the laryngeal inlet; epiglottis prevents food from entering airway.
The trachea is anterior to the oesophagus; posterior trachealis muscle allows oesophageal bolus to pass. It bifurcates at the carina into main bronchi lying behind the heart.
Right main bronchus is more vertical, wider, and shorter, predisposing to right-sided aspiration.
Lungs fill the pulmonary cavities on either side of the mediastinum (heart between); pleural surface tension couples lungs to thoracic wall for ventilation by diaphragm/intercostals.

Sequential airflow pathway (inspiration; reverse for expiration)

Nostrils → vestibule → nasal cavities (conchae/meatuses) → choanae → nasopharynx → oropharynx → laryngopharynx → laryngeal inlet (larynx) → trachea → right/left primary bronchi → secondary (lobar) bronchi → tertiary (segmental) bronchi → terminal bronchioles → respiratory bronchioles → alveolar ducts/sacs → alveoli.

Quick flow-and-relationship table

Segment	Key relationship or feature	Why it matters for flow
Nasal cavities	Conchae/meatuses increase surface area; sinus drainage into meatuses	Conditions air, maintains patency.
Pharynx	Posterior to nasal/oral cavities and larynx; C0–C6 span	Common aerodigestive pathway.
Larynx	Protects inlet; vocal folds inside	Guards airway during swallowing; cough reflex.
Trachea	Anterior to oesophagus; C-shaped rings; bifurcates at carina	Rigid, patent air conduit; divides flow to lungs.
Bronchi	Right main bronchus more vertical/wider; 3 lobar (R), 2 lobar (L)	Directs airflow to lobes/segments; aspiration bias.
Pleurae	Visceral/parietal with fluid tension	Couples lungs to chest wall for ventilation.

TLDR (Objective 2) Air moves nose → nasal cavities → pharynx → larynx → trachea → main bronchi → lobar → segmental bronchi → bronchioles → alveoli. Key relationships: larynx guards the inlet; trachea is anterior to the oesophagus; right main bronchus is more vertical; lungs sit in pleural sacs whose surface tension couples lung to thoracic wall for breathing.

3) Functions of each part and how anatomy supports the function

Upper respiratory tract

Part	Main function	Structure → function link
External nose, vestibule, septum	Conduct, filter, and shape inspired air	Cartilaginous framework and septum keep the airway patent; vestibular hairs and narrow apertures filter particles.
Nasal cavities with conchae and meatuses	Warm, humidify, and clean air; olfaction	Conchae create turbulence and surface area for vascular mucosa and mucus; roof carries olfactory epithelium; meatuses receive sinus drainage that conditions flow.
Paranasal sinuses	Lighten skull, resonate voice, condition air	Mucosa-lined air spaces that open to meatuses; cilia move mucus toward nasal cavities.
Pharynx (naso-, oro-, laryngo-)	Shared aerodigestive conduit; immune surveillance	Musculo-fascial tube posterior to nasal/oral cavities; lymphoid tissue in nasopharynx supports defense.
Larynx	Protect lower airway; phonation; cough	Epiglottis guards inlet; cartilages (thyroid, cricoid, arytenoid) hold airway open; vocal folds vibrate; rich reflexes trigger cough.

Lower respiratory tract

Part	Main function	Structure → function link
Trachea	Low-resistance air conduit	16–20 C-shaped hyaline rings prevent collapse; posterior trachealis allows oesophageal expansion; mucosa supports mucociliary clearance.
Main bronchi → lobar → segmental bronchi	Distribute air to lobes and segments	Progressive branching tree; right main bronchus is shorter, wider, more vertical, which affects aspiration and intubation. Cartilage plates maintain patency.
Terminal bronchioles	Final purely conducting airways	Loss of cartilage with increasing smooth muscle allows caliber control and airflow distribution.
Respiratory bronchioles, alveolar ducts/sacs, alveoli	Gas exchange	Very thin walls and dense capillary network form the blood–air barrier; large collective surface area; elastic fibers support recoil.
Lungs (lobes, fissures)	House exchange surfaces; match ventilation to regions	Right 3 lobes, left 2 lobes separated by fissures; lobation and segmental bronchi support regional ventilation and resection planes.
Hilum	Entry/exit of airway and vessels	Organization of primary bronchus, pulmonary artery, and veins enables efficient inflow/outflow.
Pleurae (visceral/parietal) with fluid	Frictionless sliding and lung–chest wall coupling	Smooth serosa and thin film create surface tension that keeps lungs expanded against the thoracic wall during breathing.
Diaphragm and intercostals	Ventilation (pressure pump)	Diaphragm descent increases vertical thoracic dimension; intercostals alter rib positions and stabilize the wall, changing thoracic volume.

Integrated structure–function threads to know

Air conditioning up front: Conchae, meatuses, and vascular mucosa maximize heat and moisture exchange and trap particles before air reaches delicate distal surfaces.
Protection at the gateway: Epiglottis, vocal folds, and cough reflex protect the lower tract during swallowing and aspiration events.
Patency vs flexibility: Cartilage rings/plates keep trachea and bronchi open; smooth muscle in bronchioles modulates resistance and distribution.
Exchange efficiency: Alveolar thinness and capillary density minimize diffusion distance; elastic recoil aids passive expiration.
Mechanical coupling: Pleural surface tension links lungs to chest wall so diaphragm and intercostals translate muscle work into lung inflation.

TLDR (Objective 3) Each part’s anatomy matches its job: nose and conchae condition air; larynx protects and phonates; tracheal rings and bronchial plates keep conduits open while bronchiolar muscle meters flow; alveoli provide a thin, elastic exchange surface; pleurae couple lungs to the chest wall so the diaphragm and intercostals can ventilate them.

L5.2 Histology of the Respiratory Tract

1) Identify trachea, bronchus, bronchiole, and alveolus by histological features

Fast ID table (what you should see on a slide)

Structure	Epithelium	Cartilage	Glands	Smooth muscle	Other hallmark
Trachea	Ciliated pseudostratified columnar with goblet and basal cells	C-shaped hyaline rings	Present in submucosa	Present posteriorly	Thick basement membrane; adventitia external
Bronchus	Ciliated pseudostratified columnar	Hyaline cartilage plates (not rings)	Present	Present	Plates identify bronchus inside lung parenchyma
Bronchiole	Simple columnar or cuboidal (not pseudostratified)	Absent	Absent	Continuous ring	Diameter <1 mm; “no cartilage, no glands” is the rule
Alveolus	Simple squamous (type I) with scattered cuboidal type II	None	None	Alveolar wall lacks a muscular coat	~0.2 mm; ~200 million per lung; type I covers ~95% area, type II ~5% and secretes surfactant

Layers you can label on any airway wall

Mucosa = epithelium + lamina propria; then submucosa; then adventitia. As lumen diameter decreases, epithelium height and overall wall thickness decrease. +/- glands, smooth muscle, and hyaline cartilage depending on level. Morphology reflects function.

TLDR (Obj 1) Trachea = pseudostratified + C-rings + glands. Bronchus = pseudostratified + cartilage plates + glands. Bronchiole = simple epithelium, no cartilage, no glands, continuous smooth muscle. Alveolus = simple squamous type I and cuboidal type II cells for gas exchange and surfactant.

2) Identify the types of cells present in the respiratory epithelium

Conducting airway epithelium (trachea/bronchi)

Ciliated columnar epithelial cells Motile cilia sweep mucus and inhaled debris toward the pharynx.
Goblet cells Mucus-secreting cells with pale “bubbly” cytoplasm; increase with inflammation.
Basal (stem) cells Cuboidal progenitors that replenish ciliated and goblet cells; all epithelial cells rest on the basement membrane.
Lamina propria / submucosa interface Immediately deep to the epithelium; connective tissue with vessels, nerves, ± glands/smooth muscle/cartilage. Helps you place the epithelium correctly on slides.

Bronchiolar epithelium

Simple columnar/cuboidal epithelium replaces pseudostratified; no glands, no cartilage; continuous smooth muscle ring.

(Your slides do not name additional bronchiolar cell subtypes; identification here rests on the epithelium simplification and loss of glands/cartilage.)

Alveolar epithelium (gas-exchange region)

Type I alveolar cells (type I pneumocytes) Squamous, cover ~95% of surface; form most of the thin gas-exchange interface; non-dividing.
Type II alveolar cells (type II pneumocytes) Cuboidal, cover ~5% of surface; secrete surfactant; can divide and differentiate into type I after injury.

TLDR (Obj 2) Conducting epithelium = ciliated columnar + goblet + basal on a basement membrane, over lamina propria/submucosa. Bronchioles simplify to simple columnar/cuboidal with no glands/cartilage. Alveoli contain type I (flat, exchange) and type II (surfuctant, progenitor) cells.

3) Describe the cellular and structural elements that form the air–blood barrier

Minimal diffusion pathway (from lumen of alveolus to lumen of capillary)

Surfactant layer covering the alveolar surface.
Type I alveolar cell (pneumocyte) cytoplasm forming most of the epithelial side.
Fused basement membrane shared by the type I cell and the capillary endothelium.
Capillary endothelial cell cytoplasm lining the blood side.
The barrier is so thin that it cannot be resolved by light microscopy, requiring TEM to visualise its layers.

Supporting alveolar cell types

Type I cells: squamous, ~95% of surface, non-dividing.
Type II cells: cuboidal, ~5% of surface, secrete surfactant and can proliferate to replace type I cells after injury.

TLDR (Obj 3) Air → surfactant → type I cell → fused basement membrane → endothelium → blood. This ultra-thin composite is the gas-exchange barrier and is demonstrated on the Air-Blood Barrier slide and TEM explanation.

4) Relate structure to function (conducting vs respiratory portions)

Conducting airways: move, clean, and condition air

Level	Key histology	Function link
Trachea	Ciliated pseudostratified columnar epithelium with goblet and basal cells; submucosal glands; hyaline cartilage rings; posterior smooth muscle	Patency from cartilage; mucociliary clearance from cilia + mucus; posterior muscle allows oesophageal bolus and modulates calibre.
Bronchus	Same epithelium pattern; cartilage plates (not rings); glands; smooth muscle	Plates maintain lumen within lung parenchyma; continued mucociliary clearance.
Bronchiole	Simple columnar/cuboidal epithelium; no glands, no cartilage; continuous smooth-muscle ring	Fine control of airflow resistance and distribution via smooth muscle; loss of cartilage suits small calibre.

Implication for disease: the continuous smooth-muscle ring in bronchioles underlies bronchoconstriction phenomena (e.g., asthma symptoms), which your slides flag for discussion.

Respiratory portion: exchange gases efficiently

Level	Key histology	Function link
Respiratory bronchioles → alveolar ducts/sacs	Transition to thin walls and abundant capillaries	Increased surface area and reduced diffusion distance set up exchange regions.
Alveoli	Type I squamous cells (~95% area) + Type II cuboidal cells (~5% area, surfactant secretion); ~0.2 mm alveolus, ~200 million per lung	Large area, extreme thinness, and surfactant-lowered surface tension enable rapid diffusion and prevent collapse.
Air–blood barrier	Surfactant → type I cell → fused BM → endothelium	Minimal path for O₂/CO₂ diffusion.

TLDR (Obj 4) Conducting airways use cartilage, glands, goblet cells, and cilia to keep a patent, self-cleaning conduit; bronchiolar smooth muscle tunes airflow. The respiratory zone replaces bulk wall with type I epithelium, fused basement membranes, and capillary endothelium, plus type II surfactant, to minimise diffusion distance and maintain open alveoli.

L5.3 Mechanisms of Respiration

1) Interrelationships among pressure and volume in the lungs

The core laws and pressures

Boyle’s law (at constant temperature): when thoracic volume increases, gas pressure decreases; when volume decreases, pressure increases. This underpins negative-pressure inspiration. Your slide reinforces that we “pull” air in by making lung pressure lower than atmosphere.
Pressures to track:
- Patm: atmospheric pressure (reference).
- Palv: pressure inside alveoli; equals Patm at end-inspiration/expiration pauses.
- Pip: pressure in the intra-pleural space; normally negative relative to Patm, which keeps lungs expanded.
- Transpulmonary pressure: Ptp = Palv − Pip; the distending pressure that opposes elastic recoil. The “Pressure changes in lungs” slide frames these relationships during the breathing cycle.

How muscle work changes volume and pressure

Inspiration: diaphragm and external intercostals contract, increasing thoracic volume. Pip becomes more negative, Palv falls slightly below Patm, so air flows into the lungs.
Quiet expiration: muscles relax; thoracic volume falls; elastic recoil raises Palv slightly above Patm, so air flows out. Slide notes quiet expiration is passive.

TLDR (Obj 1) Change thoracic volume → change Pip and Palv. When Palv < Patm, air flows in; when Palv > Patm, air flows out. Ptp = Palv − Pip distends the lungs against recoil; inspiration makes Pip more negative, raising Ptp and lung volume.

2) How intra-alveolar (Palv) and intra-pleural (Pip) pressures change during inspiration and expiration

Quiet breathing (normal tidal breathing)

End-expiration (pause): airflow zero; Palv = Patm; Pip is negative (sub-atmospheric) due to chest wall–lung elastic recoil balance.
Inspiration (active): inspiratory muscles enlarge the thorax; Pip becomes more negative; Palv drops slightly below Patm (pressure gradient into lungs). Air flows in until Palv re-equilibrates with Patm at end-inspiration.
Expiration (passive): muscles relax; thoracic volume falls; Pip becomes less negative; Palv rises slightly above Patm so air flows out, then returns to equality with Patm at the end-expiratory pause. Your “Remember first year?” slide emphasises passive mechanics.

Why diffusion happens once air arrives

Capillary blood reaching the lungs has lower O₂ partial pressure than alveolar gas; it equilibrates with alveolar partial pressures across the air–blood interface. This slide links the pressure gradients to gas movement (sets up the rationale for the later O₂/CO₂ transport objective).

TLDR (Obj 2) Inspiration: Pip more negative, Palv slightly < Patm → air in. Expiration: Pip less negative, Palv slightly > Patm → air out. At the end of each phase, flow stops as Palv = Patm. These pressure swings set up alveolar–capillary diffusion down O₂/CO₂ partial-pressure gradients.

3) Explain the mechanisms of O₂ and CO₂ transport in blood

Oxygen

Most O₂ travels bound to haemoglobin (Hb); a small fraction is dissolved in plasma.
The most important determinant of Hb saturation is the blood PO₂; higher PO₂ promotes binding.
The deck flags “Factors impacting oxygen binding” separately (temperature, pH, etc., are considered here conceptually), but the key point emphasized is PO₂ control of saturation.

Carbon dioxide

CO₂ is transported by three mechanisms: dissolved in plasma, bound to Hb, and as bicarbonate (HCO₃⁻) formed via the CO₂ + H₂O ⇄ H₂CO₃ ⇄ H⁺ + HCO₃⁻ reaction.

TLDR (Obj 3) O₂: mostly on Hb, little dissolved; PO₂ sets saturation. CO₂: carried dissolved, on Hb, and mainly as HCO₃⁻ via the carbonic acid reaction.

4) Understand how O₂ and CO₂ influence air and blood flow

Diffusion and equilibration

Gas movement follows partial pressure gradients. Blood arriving at the lungs has lower PO₂ than alveoli, allowing O₂ to enter blood; blood leaving equilibrates with alveolar gas.

Matching airflow and blood flow

Effective exchange requires matching ventilation (airflow) with perfusion (blood flow); the lecture highlights this as “Matching airflow and blood flow.” When the thoracic pump is compromised (e.g., reduced chest wall expansion), airflow falls and arterial PO₂/PCO₂ derange, as flagged for discussion in the forum prompt.

TLDR (Obj 4) Gradients drive diffusion: blood equilibrates with alveolar gas as it passes the lungs. Ventilation–perfusion matching is essential; impaired ventilation (e.g., poor chest expansion) reduces airflow and disrupts PO₂/PCO₂.

L5.4 Primary Defences of the Respiratory Tract

1) Describe the physical barriers of the respiratory tract

What the tract must handle

You inhale large volumes of particle-laden air every day. The tract relies on physicochemical barriers and mechanical clearance to limit particle and microbe access.

Main barrier components and where they act

Nasal hairs filter larger particles at entry.
Airway surface liquid and mucus, produced by goblet cells, submucosal glands, and vascular exudates, coat the epithelium and trap particulates and microbes.
Two-layer mucus architecture down to small conducting airways: a thin sol/periciliary layer generated by ion transport underlies a gel layer that is thick, sticky, and rich in defensins, lysozyme, and IgA.
Submucosal glands in nasal cavity, trachea, and bronchi augment liquid and mucus output; they are less frequent as airways narrow.
Goblet cells are distributed from nasal cavity to bronchi and increase with irritants and inflammation, which raises mucus burden.
Mucociliary clearance moves the gel layer toward the mouth. Coordinated ciliary beating occurs in the periciliary layer under the mucus sheet.
Coughing and sneezing are reflex expulsive mechanisms that eject irritants and pathogens at high velocity.
Alveolar macrophages phagocytose fine particles that reach the alveoli and also clear surfactant.

TLDR (Obj 1) Physical defences are layered: nasal hairs at entry; a two-layer mucus system produced by goblet cells and submucosal glands; ciliary transport that sweeps mucus out; expulsive reflexes to clear deeper irritants; and alveolar macrophages as the terminal particulate sink.

2) Compare and contrast the physical barriers of the upper vs lower respiratory tract

Big-picture contrasts

Upper tract (nasal cavity, pharynx, larynx): strong front-end filtration and mucus production with nasal hairs, abundant mucus, and high goblet and gland density. Intensive mucociliary clearance plus sneeze reflex protect this segment.
Lower conducting tract (trachea, bronchi, bronchioles): continues two-layer mucus + cilia; submucosal glands are present in trachea and bronchi but decrease with airway size; cough is the key expulsive reflex here.
Respiratory region (alveoli): no mucus blanket over exchange surfaces; defence shifts to alveolar macrophages and surfactant homeostasis to keep diffusion paths clear.

Compact comparison table

Feature	Upper airways	Lower conducting airways	Alveoli
Initial filtration	Nasal hairs prominent	None	None
Mucus system	Thick gel over periciliary layer; abundant	Present; glands decrease with smaller calibre	Absent over exchange surface
Secretory sources	Goblet cells and submucosal glands	Goblet cells; glands in larger airways only	Type II cells secrete surfactant, not mucus
Clearance	Mucociliary to oropharynx; sneeze	Mucociliary to pharynx; cough	Macrophage phagocytosis and surfactant recycling
Failure mode highlighted	Hypersecretion with irritants → mucus accumulation, infection risk	Overproduction plus reduced clearance → retention, infection	Overwhelmed macrophages → retained particulates, inflammation

TLDR (Obj 2) Upper airways specialize in filtration and mucus production with nasal hairs, abundant glands, and sneeze-mediated expulsion. Lower conducting airways extend mucociliary clearance and rely on cough, with fewer glands distally. Alveoli avoid mucus, using macrophages and surfactant to protect gas exchange.

3) Compare respiratory protective mechanisms with those of the GIT

Same organizing principles, different implementations

Both systems use a layered defence: a surface interface that limits contact, mechanical clearance to remove hazards, and immune programs that escalate as needed. The implementations differ because airways must preserve a dry, low-resistance conduit to delicate exchange surfaces, while the GIT must digest food in enzyme-rich fluid without self-injury.

Layer-by-layer comparison

Defence layer	Respiratory tract	GIT
Surface interface	Two-layer mucus system: a watery periciliary (sol) layer beneath a sticky gel that traps particulates and microbes; generated by ion transport, goblet cells, and submucosal glands (abundant proximally, fewer distally). No mucus blanket on alveoli.	Mucus layer over a single-cell epithelium with tight junctions; Paneth AMPs and secreted IgA shape luminal exposure; continuous along the intestine (no gas-exchange constraint).
Mechanical clearance	Mucociliary escalator propels gel layer to the pharynx; sneeze/cough ejects deeper irritants. Alveoli rely on macrophages (no cilia, no mucus).	Peristalsis and fluid flow carry contents distally; vomiting expels proximal hazards. Particles/pathogens are kept at distance by mucus flow and sIgA agglutination.
Antimicrobials in secretions	Gel layer contains defensins/lysozyme (noted in barrier description).	Paneth-cell AMPs, bile acids, and sIgA act along the mucosal surface.
Epithelial sensing & repair	Ciliated epithelium with goblet and gland output proximally; distal gas-exchange region lacks mucus/cilia and uses surfactant plus macrophage clearance.	IECs express PRRs (apical/basolateral, endosomal, cytosolic) and trigger barrier-tightening, mucus, AMPs, and controlled cell death; rapid turnover maintains integrity.
Mucosal adaptive immunity	Secretory IgA is present in airway secretions (within mucus/ASL framework) but the terminal region prioritizes thin diffusion paths (no blanket mucus). Macrophages dominate alveoli.	Organized GALT (Peyer’s patches, mesenteric nodes) primes T/B cells; sIgA is the principal antibody for non-inflammatory control; Treg/ILC3–IL-22/IL-10 axes maintain tone.

Why they must differ at the terminal surface

Alveoli cannot tolerate a mucus blanket or thickened surface, so defence shifts to surfactant homeostasis and macrophage phagocytosis to keep diffusion distance minimal.
Intestinal villi/crypts are designed for nutrient exchange in liquid; a continuous mucus/IgA layer is compatible with function and helps confine microbes.

Failure patterns the slides emphasize

Airways: irritants/inflammation increase goblet cells and mucus output, overloading clearance and predisposing to infection/obstruction; overwhelmed alveolar macrophages allow particulate retention.
GIT: excessive PRR drive and barrier failure escalate inflammation and permeability; balanced sIgA/Treg/IL-22 programs normally restrain this.

TLDR (Objective 3) Both systems use a surface barrier → mechanical clearance → mucosal immunity sequence. Airways rely on a two-layer mucus + cilia escalator and cough/sneeze, then macrophages and surfactant at alveoli to keep gas exchange thin. The GIT maintains a mucus/IgA interface over a tight-junction epithelium with PRR-tuned responses and organized GALT to balance tolerance and defence. The terminal surfaces diverge because alveoli must minimize diffusion distance, while intestine functions in fluid and can carry a mucus/IgA blanket.

WEEK 6

L6.1 Control of Respiration

Key respiratory control centres and their functions

Brainstem network (core automatic control)

Medullary centre overall. Breathing is regular, largely automatic, and controlled by the CNS. Contraction of the diaphragm and other respiratory muscles is driven by neurons in the brainstem, with spontaneous firing modulated by sensory input (notably chemoreceptors).
Dorsal respiratory group (DRG) in the nucleus tractus solitarius, medulla. Integrates sensory input and drives muscles of inspiration; also influences the pons to help trigger inspiration.
Ventral respiratory group (VRG), medulla. Has multiple functions in the pattern generator; includes the pre-Bötzinger complex, proposed pacemaker for respiratory rhythm generation.
Pontine respiratory groups (PRG), pons. Provide tonic input to medullary centres to ensure a smooth breathing rhythm (phase-switching and timing).

One-page study table

Centre	Location	Primary role	Key outputs/effects
DRG	NTS, medulla	Integrates sensory input; initiates inspiration	Activates inspiratory muscles; influences pons to trigger inspiration
VRG (incl. pre-Bötzinger)	Medulla	Rhythm generation and patterning; mixed functions	Pre-Bötzinger complex contributes pacemaker activity; coordinates phases
PRG	Pons	Tonic modulation of medullary circuits	Smooths respiratory rhythm; shapes timing/phase transitions

Inputs that modify these centres

Chemoreceptor input (peripheral and central) provides the dominant chemical drive that modulates rate and depth via the medullary centre.

TLDR (Objective 1) Automatic breathing arises from a medullary–pontine network: DRG initiates inspiration, VRG patterns rhythm (with pre-Bötzinger as a pacemaker), and PRG smooths timing. These centres drive diaphragm and accessory muscles and are modulated by chemoreceptor input.

Here are Objectives 2–3 from “Control of Respiration,” aligned to your slides and transcript. I corrected diction, kept course terminology, and cited each claim to the deck so you can verify.

2) Explain the role of chemoreceptors in the regulation of ventilation

What the slides emphasise

Chemoreceptor drive modifies the medullary–pontine rhythm to adjust rate and depth of breathing. The deck explicitly flags ventilation being “adjusted based on chemical factors.”

Peripheral chemoreceptors

Location: Carotid bodies (at the carotid bifurcation) and aortic bodies (aortic arch).
Primary stimulus: a fall in arterial PO₂ (hypoxaemia); sensitivity increases when PCO₂ rises or pH falls (metabolic acidaemia). The net effect is to increase ventilation.
Afferents and speed: carotid body signals travel via glossopharyngeal (IX), aortic via vagus (X) to the DRG; response is rapid, supporting moment-to-moment control.

Central chemoreceptors

Location/function: neurons on the ventrolateral medulla responsive to brain extracellular fluid/CSF pH, which largely reflects arterial PCO₂ (CO₂ crosses the blood–brain barrier and hydrates to H₂CO₃ → H⁺ + HCO₃⁻).
Primary stimulus: an increase in arterial PCO₂ (hypercapnia) causing a drop in CSF pH; this potently drives ventilation.
Kinetics: slightly slower onset than peripheral drive (time for CO₂ hydration/CSF pH change), but dominant in steady-state control.

Integration in the brainstem

Peripheral and central inputs converge on medullary circuits (DRG/VRG) and are smoothed by the pontine respiratory group, producing the final pattern of tidal volume and frequency.

TLDR (Objective 2) Peripheral chemoreceptors (carotid/aortic) respond fast to low PO₂, high PCO₂, and low pH to increase ventilation. Central chemoreceptors sense CSF pH (a proxy for arterial PCO₂) and provide a strong, sustained drive to breathe. Both feed into the medullary centres and are modulated by the pons to set rate and depth.

3) Describe why changes in CO₂ alter breathing pattern and acid–base balance

CO₂ as the primary chemical driver

Rising arterial PCO₂ increases H⁺ in brain ECF/CSF via CO₂ + H₂O ⇄ H₂CO₃ ⇄ H⁺ + HCO₃⁻, lowering pH and stimulating central chemoreceptors to increase ventilation (higher rate and/or depth).
The slides frame this as the central mechanism linking CO₂ changes to breathing pattern adjustments.

Effects on acid–base status (respiratory component)

Hypercapnia (↑PCO₂) → respiratory acidosis (↓pH). Ventilatory drive increases to blow off CO₂, moving PCO₂ back toward normal and restoring pH.
Hypocapnia (↓PCO₂) from hyperventilation → respiratory alkalosis (↑pH). Compensatory reduced drive lowers ventilation until PCO₂ normalises.

Pattern-level consequences the lecture highlights

When chemical drive rises (e.g., hypercapnia), the medullary pattern generator increases tidal volume and/or frequency; pontine modulation helps maintain a smooth rhythm during these shifts.

TLDR (Objective 3) CO₂ controls breathing because it rapidly sets CSF pH: ↑PCO₂ → ↓pH → ↑central chemoreceptor firing → ↑ventilation; ↓PCO₂ → ↑pH → ↓drive. These ventilatory changes correct respiratory acidosis/alkalosis by returning PCO₂ toward normal.

6.2 Air Quality Impacts on Lung Function

Here are Objectives 1–2 using your “Air Quality Impacts on Lung Function” slides. I corrected phrasing and kept course terminology. Each claim is tied to the deck so you can verify.

1) Apply Haber’s rule to compare expected harms from exposure at different concentrations and times

The rule and what it means

Haber’s rule: (C t = k). For a given toxic effect, the product of concentration (C) and exposure time (t) is approximately constant (k), so a higher C for a shorter t can pose a similar risk to a lower C for a longer t.

Worked comparisons (numbers chosen for illustration)

If (k = 8 ):
- 1 ppm for 8 h ≈ 2 ppm for 4 h ≈ 0.5 ppm for 16 h (all yield 8 ppm·h). This is the practical way to compare scenarios with different C and t when applying the slide’s (C t) rule.
For time-weighted averages (TWA), you can convert variable shifts to a single equivalent (C t). Example: 0.8 ppm for 6 h plus 1.2 ppm for 2 h gives ((0.8 ) + (1.2 ) = 6.0 ); over 8 h the TWA is (6.0/8 = 0.75 ). This compares directly to limits expressed as 8-h TWA on the slide.

What the deck uses Haber’s rule for

To compare harms across exposure patterns and to link scenarios back to regulatory limits reported as 8-h TWAs (see the formaldehyde example below).

TLDR (Obj 1) Use (C t = k). Equal products predict similar risk for a given effect: e.g., 1 ppm × 8 h ≈ 2 ppm × 4 h. The deck applies this to compare scenarios and to interpret 8-h TWA exposure limits.

2) How this rule helps assess occupational risk from compressed-wood furniture components

What the slides say about furniture off-gassing

Compressed/engineered wood furniture can off-gas VOCs such as formaldehyde, xylene, and ethylbenzene. Formaldehyde (CH₂O) is listed as an IARC Group 1 carcinogen. The slide cites an Australian workplace limit for formaldehyde of 1 ppm as an 8-h TWA.

Applying Haber’s rule to real shifts

If a worker is near new particleboard shelves with 0.5 ppm formaldehyde for a full 8-h shift, the daily dose proxy is (0.5 = 4 ), which is below the 1 ppm 8-h TWA benchmark ((1 = 8 )).
If tasks intermittently raise exposure to 2 ppm for 2 h and 0.5 ppm for 6 h, total (C t = (2 ) + (0.5 ) = 4 + 3 = 7 ). The 8-h TWA is (7/8 = 0.875 ), still under the cited 1 ppm 8-h TWA. The rule lets you compare such mixed patterns directly to the limit.

Why this matters for compressed-wood environments

Off-gassing is slow release, so concentrations may be modest but prolonged. Haber’s rule highlights that lower C over longer t can approach the same (k) as short, higher concentrations, guiding ventilation, sourcing, and rotation decisions to keep the 8-h TWA within the cited limit.

TLDR (Obj 2) The furniture slide lists VOCs (including formaldehyde, IARC Group 1) and an 8-h TWA limit of 1 ppm. With Haber’s rule, you sum (C t) across tasks to get an equivalent 8-h TWA and check compliance or risk; prolonged lower-level off-gassing can accumulate toward the same (k) as brief peaks.

Here are Objectives 3–4 for “Air Quality Impacts on Lung Function,” aligned to your slide deck. I corrected phrasing and kept course terminology.

3) Compare local effects of ozone with distal effects of PM2.5

What the slides emphasise

Ozone acts locally in the airways by generating reactive oxygen species, causing cell damage and oedema.
PM2.5 is linked to distal, systemic effects: cardiovascular stress with increased heart attack and stroke rates, and broader distal toxicities. The slides illustrate this with PM2.5 from bushfire smoke.

Compact comparison

Agent	Primary site of effect	Mechanism highlighted	Outcomes highlighted
Ozone (O₃)	Local airway epithelium	ROS generation → epithelial injury → oedema	Acute local respiratory effects.
PM2.5	Distal, systemic after pulmonary entry	Systemic cardiovascular stress; bushfire PM2.5 burden	↑ MI and stroke risk; PM2.5 burden during bushfires noted.

TLDR (Obj 3) Ozone damages the airway surface via ROS, producing local oedema. PM2.5 drives systemic cardiovascular stress after pulmonary entry, elevating MI and stroke risk, with bushfire smoke used as the deck’s example.

4) Describe dangers associated with solid fuel cooking, radon, war, and meth labs

Solid fuel cooking

The deck cites global evidence: household solid fuel use is associated with stroke, heart disease, COPD, lung cancer, and childhood pneumonia.

Radon

Radon is flagged explicitly in the lecture as a household air-quality hazard, with a CDC source for details.

War

The lecture highlights war-related air pollution, including the Greater Burgan oil field fires (Kuwait, 1991) as an example source of massive combustion emissions.

Meth labs

The lecture lists production methods and typical aerosols encountered: iodine, ammonia, hydrogen chloride, phosphine.
Phosphine levels reported during cooks reached up to 13 ppm; the slide notes serious effects at 5–10 ppm for several hours and death after 30–60 min at 400–600 ppm (with toxicity source cited on the slide).

TLDR (Obj 4) Solid fuel cooking: linked to cardio-respiratory disease and childhood pneumonia. Radon: slide flags as a household hazard with CDC guidance. War: oil-field fires exemplify extreme combustion exposures. Meth labs: acidic and reducing aerosols plus phosphine pose acute toxicity risks, with slide-listed levels reaching 13 ppm and lethal ranges at 400–600 ppm for short exposures.

6.3 Lifestyle Impacts on Lung Function

Here is the first objective for “Respiratory Physiology and Mechanics,” checked against your Week 6 deck (to confirm scope) and the earlier physiology slides you uploaded for mechanics. I corrected diction and kept course terminology.

Respiratory Physiology and Mechanics

Describe the structure and function of the lungs, including the pressure gradients required for effective ventilation

1) Lung structure you must be able to label and justify functionally

Conducting airways: trachea → main bronchi → lobar and segmental bronchi → terminal bronchioles. Cartilage (trachea/bronchi) maintains patency; smooth muscle (bronchioles) modulates resistance and distribution of airflow.
Respiratory region: respiratory bronchioles → alveolar ducts/sacs → alveoli. Extremely thin epithelium for gas exchange (type I cells) with surfactant-secreting type II cells.
Lungs/pleurae: right lung (3 lobes), left lung (2 lobes). Visceral and parietal pleura with a thin fluid film couple lungs to the chest wall via surface tension, enabling the chest pump to inflate the lungs.
Ventilatory pump: diaphragm (chief inspiratory muscle) and intercostals change thoracic volume and drive pressure changes that move air.
These structural elements are the substrate for the Week-6 learning outcome on “Respiratory Physiology and Mechanics.”

2) The pressure–volume relationships that move air

Boyle’s law (at constant temperature): when thoracic volume increases, intra-alveolar pressure (Palv) falls; when volume decreases, Palv rises. Air flows into the lungs when Palv < Patm and out when Palv > Patm.
Key pressures to name and track:
- Patm: atmospheric pressure (reference).
- Palv: intra-alveolar pressure (equals Patm at end-inspiration/expiration pauses).
- Pip: intra-pleural pressure (normally sub-atmospheric/negative).
- Transpulmonary pressure: Ptp = Palv − Pip; the distending pressure that opposes elastic recoil and keeps alveoli open.

What changes over a quiet breath

Phase	Thoracic volume	Pip	Palv vs Patm	Net flow
End-expiration (pause)	Stable	Negative	Palv = Patm	None
Inspiration (diaphragm descends)	↑	More negative	Palv < Patm	In
End-inspiration (pause)	Max for tidal breath	Negative	Palv = Patm	None
Expiration (passive recoil)	↓	Less negative	Palv > Patm	Out
These mechanics drive alveolar–capillary diffusion down O₂/CO₂ partial-pressure gradients once fresh air reaches the exchange surface.

3) Structure → function links you can state in one line

Cartilage rings/plates keep large airways patent for low-resistance conduction; bronchiolar smooth muscle meters flow distribution to match regional needs.
Alveolar thinness + fused basement membranes minimise diffusion distance; surfactant reduces surface tension to stabilise small alveoli at end-expiration.
Pleural coupling ensures muscle work translates into lung inflation by maintaining a negative Pip, increasing Ptp during inspiration.

TLDR Lungs: conducting tree (rigid where needed, muscular where control is needed) delivers air to thin-walled alveoli for diffusion. Pleura couple lungs to the chest wall. Inspiration increases thoracic volume, makes Pip more negative, lowers Palv below Patm, and draws air in; expiration reverses these gradients. Ptp = Palv − Pip is the distending pressure that keeps alveoli open.

Here are the asthma objectives from “Lifestyle Impacts on Lung Function,” aligned to your slides and transcript. I corrected diction and kept course terminology.

Define asthma and identify key cellular players in airway inflammation

Definition in this lecture: a chronic inflammatory airway disorder marked by variable airflow limitation and bronchial hyper-responsiveness, with episodes of wheeze, cough, chest tightness, and shortness of breath.
Principal cellular players highlighted: mast cells and eosinophils, with involvement of airway epithelial cells and smooth muscle as effectors of narrowing.

TLDR Asthma here = chronic airway inflammation with variable obstruction. Cells to name: mast cells, eosinophils, plus epithelium and smooth muscle as effectors.

Physiological mechanisms of airway narrowing and how they are reversed or prevented

Mechanisms producing airflow limitation

Bronchial smooth-muscle constriction produces acute, reversible increases in airway resistance.
Mucosal oedema from inflammatory mediators further narrows the lumen.
Mucus hypersecretion and plugging add a mechanical block to flow.
Airway wall remodeling (with recurrent inflammation) contributes to persistent hyper-responsiveness.

Reversal strategies (relievers)

Short-acting β₂-agonists (SABA, e.g., salbutamol): relax airway smooth muscle to reverse acute bronchoconstriction.
Anticholinergics (short-acting): reduce vagal-mediated bronchomotor tone as an adjunct in acute episodes.

Preventive strategies (controllers)

Inhaled corticosteroids (ICS): suppress airway inflammation and reduce exacerbation frequency.
Long-acting β₂-agonists (LABA) with ICS: improve symptom control and reduce variability; use in combination where indicated.
Trigger management: avoid known irritants/allergens and manage comorbidities to lower attack frequency.

TLDR Narrowing comes from smooth-muscle constriction, oedema, mucus, and remodeling. Reverse acutely with SABA (± short-acting anticholinergic). Prevent with ICS (± LABA) and trigger control.

Immunology of asthma: Th2 cells, IgE, mediators

Th2-skewed immunity drives allergic asthma phenotypes; slides link Th2 cytokines to eosinophilic inflammation and hyper-responsiveness.
IgE-mediated mast-cell activation: allergen cross-links IgE on mast cells → histamine, cysteinyl-leukotrienes, and other mediators cause bronchoconstriction, oedema, and mucus.
Eosinophils amplify tissue damage and edema via cytotoxic granule proteins and lipid mediators.

TLDR Th2 → IgE → mast-cell degranulation frames the acute response; eosinophils sustain inflammation and hyper-responsiveness. Mediators to name: histamine and leukotrienes.

Exercise-induced bronchoconstriction (EIB): trigger and treatment

Mechanism summarised in the deck

Rapid breathing during exercise cools and dries airway surfaces. The resulting osmotic and thermal shifts trigger mast-cell mediator release and transient bronchoconstriction in susceptible people (often with underlying asthma).

Management options presented

Pre-exercise SABA to blunt the bronchoconstrictive response.
Regular ICS to reduce airway hyper-responsiveness and lower EIB frequency/severity when appropriate.
Warm-up strategies and cold-air masking to reduce airway cooling/drying during exertion.

TLDR EIB follows airway cooling/drying → mast-cell mediator release → transient bronchoconstriction. Treat with pre-exercise SABA, maintenance ICS when indicated, and warm-up/cold-air mitigation.

Here is the final objective from “Lifestyle Impacts on Lung Function,” aligned to your slides and transcript. I corrected diction and kept course terminology.

Nicotine Addiction and Smoking-Related Pathophysiology

1) Neurobiological basis of nicotine addiction (reward pathway)

Primary mechanism. Nicotine acts at nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs in the ventral tegmental area (VTA) increases dopaminergic signalling to the nucleus accumbens (NAc), reinforcing drug-seeking and use. The slides explicitly annotate PFC, NAc, Hipp, Amy, VTA on the “Nicotine & Reward Pathway” panel and state that reinforcement is mediated by nAChR activation with increased DA (and GABA modulation) in VTA.

2) Major cell types involved in smoking and e-cigarette lung injury

Macrophages. Central effector cells in smoker and vaper airways. The slides list macrophages as key immune cells and show evidence that nicotine-exposed macrophages exhibit dose-dependent increases in protease release (MMP-2, MMP-9) in BAL studies, consistent with tissue-remodelling and emphysema pathways.
Neutrophils. Prominent in inflammatory responses to smoke and aerosols; listed alongside macrophages and linked on the slides to literature about neutrophil-dominant airway inflammation and M1/M2 polarisation concepts.
Epithelial cells (and alveolar structure). The deck’s emphysema panel highlights alveolar damage and missing alveoli (protease injury), with comparative images (non-smoker, smoker, vapor) and accompanying macrophage callouts. This anchors epithelial injury and parenchymal loss to immune-mediated protease activity.

One-screen study table

Cell type	What the slides emphasise	Consequence
Macrophage	Nicotine exposure → ↑ MMP-2/MMP-9 release; activation in BAL	Matrix degradation, alveolar wall injury, impaired host defence
Neutrophil	Listed as key immune cell in smoker/vaper airways; M1/M2 context	Elastase, ROS, mucus, epithelial damage
Epithelium/alveoli	Emphysema panel shows missing alveoli with macrophage involvement	Gas-exchange loss, airflow limitation

3) Varenicline mechanism and how it supports cessation

Mechanism. Varenicline (Champix) is a partial agonist at α4β2 nAChRs. Partial stimulation reduces withdrawal symptoms while blocking nicotine’s full agonist effect at the same receptor, blunting the dopaminergic “reward” spike if a person smokes or vapes. The slide notes “partial agonist at α4β2 nAChRs… >2× more likely to quit.”
Pathway link. Because α4β2 nAChRs drive DA signalling in VTA → NAc, partial agonism stabilises tone without permitting the high-gain DA reinforcement associated with relapse. The slide situates this within the VTA/NAc reward map and nAChR family note.

TLDR Addiction: nicotine activates nAChRs in VTA, increasing dopamine to NAc and reinforcing use. Injury: smoker and vaper lungs show macrophage and neutrophil-driven inflammation; nicotine-exposed macrophages release MMP-2/MMP-9, linking to alveolar damage on the emphysema panel. Cessation: varenicline is a partial α4β2 agonist that eases withdrawal and blocks nicotine’s reward, improving quit rates.

L6.4 Occupational Exposure Impacts on Lung Function

Here are Objectives 1–2 for “Occupational exposure impacts on lung function,” aligned to your Week 6 lecturette. I corrected diction and kept course terminology.

1) Cellular mechanisms of asbestosis, silicosis, and pleural mesothelioma

Asbestosis (fibrotic lung disease after asbestos inhalation)

Entry and persistence. Inhaled microscopic asbestos fibres are released during abrasion (mining, construction), deposit in the airways, and the smaller fibres reach distal airways where mucociliary clearance is limited. Persistent retention sustains inflammation.
Cellular injury → fibrosis. Entrapped fibres trigger unresolved inflammation and progressive scarring of the interstitium, which stiffens and thickens the lung, impairs gas exchange, and reduces lung function. Latency to symptoms is often 20–30 years; there is no cure.

Silicosis (fibrotic lung disease after respirable crystalline silica, RCS)

Exposure agent and settings. RCS is generated when silica-containing materials are cut or drilled; high-risk settings include stonemasonry, tunnelling, mining. Australia estimates ~600,000 workers are exposed annually, with projections of silicosis and lung cancers attributable to RCS; engineered stone has very high silica content and was banned nationally in 2024.
Forms and mechanism. Chronic (15–20 yr low-level), accelerated (5–10 yr high-level), and acute (weeks–months very high-level) forms are recognised. Disease reflects airway stiffening, reduced gas exchange, and reduced lung function, with chest pain, dyspnoea, fatigue and crackles.

3) Clinical diagnosis, management options, and major challenges

A. How clinicians diagnose dust diseases

Asbestosis and silicosis

Core steps: exposure history, chest imaging (X-ray, CT), and lung function testing (spirometry). The lecture stresses that findings are non-specific, misdiagnosis is common, and cases are typically detected late.
CT patterns: the slide illustrates progressive silicosis and asbestosis imaging to anchor pattern recognition.

Pleural mesothelioma (PM)

Diagnostic pathway: exposure history, chest imaging, spirometry, plus biopsy and cytology. The deck highlights that biopsy is invasive, often non-specific, and typically identifies late-stage disease.

B. Management options

Asbestosis and silicosis

There are no curative treatments. Management focuses on slowing progression and supportive care.
Antifibrotics: nintedanib and pirfenidone can slow disease progression but have many adverse effects.
Lung transplantation may be an option in end-stage disease, yet is not feasible for most.

Pleural mesothelioma

The lecture states no curative treatment. Options include surgery, chemotherapy, and immunotherapy, with success dependent on histologic subtype and stage.
Subtypes and prognosis shown: epithelioid (about 60–70%, median survival ~13.1 months), sarcomatoid (~4 months), biphasic (~8.4 months).

Prevention and surveillance

The deck emphasises prevention is key: appropriate workplace PPE, regular screening for at-risk workers, inspections and exposure monitoring, education and awareness, and the note that smoking or vaping increases risk.

C. Major challenges in clinical care

Long latency leads to late-stage detection and limited options.
No curative therapy for asbestosis, silicosis, or PM. Treatments slow progression or palliate.
Psychosocial and financial burden and the need for re-training are part of the disease impact beyond the clinic.
The lecture’s forum prompt underscores the value of early detection in high-risk industries.

One-screen study table

Disease	Diagnosis (deck focus)	Management in practice	Challenges
Asbestosis	Exposure history, imaging, spirometry. Late and non-specific.	No cure. Nintedanib/Pirfenidone slow fibrosis. Transplant only for select end-stage.	Long latency, late detection, adverse effects, feasibility limits.
Silicosis	Exposure history, imaging, spirometry; illustrated CT progression.	No cure. Antifibrotics to slow decline. Prevention and surveillance stressed.	Late diagnosis, irreversible fibrosis, workplace control needed.
Pleural mesothelioma	Exposure history, imaging, spirometry, biopsy/cytology; often late and non-specific.	No cure. Surgery, chemotherapy, immunotherapy, outcome depends on subtype and stage.	Very long latency. Prognosis varies by epithelioid, sarcomatoid, biphasic subtype.

TLDR Diagnosis relies on exposure history, imaging, and spirometry, with biopsy for PM, but findings are often non-specific and late-stage. Management is non-curative: antifibrotics for pneumoconioses can slow decline, transplant is rare; PM care uses surgery, chemo, and immunotherapy guided by subtype and stage. The biggest challenges are long latency, late detection, treatment toxicity or limits, and the psychosocial and financial burden, which is why the deck stresses prevention and early screening for at-risk workers.

WEEK 7

L7.1 How respiratory viruses infect humans, cause disease, and how spread is controlled

Transmission and entry

Transmission routes

Respiratory viruses spread via exhaled particles that reach new hosts through the air and contaminated surfaces.

Coronavirus entry

SARS-CoV-1/2 and HCoV-NL63 use ACE2 on airway epithelium (ciliated cells, goblet cells, type II pneumocytes) for attachment via spike and entry.

Influenza entry/exit

HA mediates attachment and entry.
NA facilitates release and mucus movement.
Both are major neutralising antibody targets.

Disease mechanisms

Coronavirus disease mechanism

Initial airway epithelial infection with inflammatory progression.

Influenza disease mechanism

Infects respiratory epithelial cells.
Severe disease correlates with lower-tract replication and intense inflammation.

Controlling spread

Vaccination

Reduces transmission and severe disease; slide deck lists vaccine platforms (AstraZeneca, Pfizer, Moderna, Novavax) and updates across 2020–2024.

Source and route control

Follows from transmission slide: actions limiting exposure to infectious respiratory particles.

TLDR CoVs enter via ACE2; flu uses HA for entry and NA for exit. Disease severity increases with lower-airway involvement. Spread is controlled through vaccination and reducing exposure to respiratory particles.

L7.1 Zoonosis, reservoirs, and intermediate hosts for CoVs and influenza

Core definitions and patterns

Zoonosis

Infection spilling over from animals to humans.
All 7 human CoVs originated from zoonotic spillover.

Reservoirs

Many betacoronaviruses circulate in bats and mammals, a subset able to bind human receptors.

Pathway to humans

Reservoir → intermediate hosts → humans.

SARS-CoV-2 variants and adaptation

Mutation and selection

Error-prone RNA polymerase produces variants.
Mutations improving receptor binding or immune evasion become dominant.

Influenza reservoirs and spillover

Influenza A (IAV)

Infects aquatic birds and mammals (poultry, pigs, horses, dogs, seals, bats).
Pandemic potential arises from cross-species transmission.

Influenza B (IBV)

Human-restricted in the slide deck.

Segmented genome

Enables reassortment in co-infected intermediate hosts.

Comparison table

Virus group	Reservoir(s)	Intermediate hosts	Notes
Coronaviruses	Bats, mammals	Mammalian intermediates	All human CoVs arose from spillover; ACE2 adaptation and immune escape selected.
Influenza A	Aquatic birds	Poultry, pigs, mammals	Segmented genome allows reassortment; pandemic risk.
Influenza B	Humans	None	Human-restricted.

TLDR CoVs originate from bats, sometimes via intermediates. Influenza A spills over from aquatic birds through mammals, with reassortment enabling major antigenic shifts. Influenza B is restricted to humans.

L7.1 Explain how viral variants emerge and antigenic shift vs drift

How variants emerge

Replication errors

RNA polymerases introduce mutations.
Selected if they improve transmissibility or immune evasion.

Antigenic drift (seasonal influenza)

Definition

Gradual accumulation of point mutations in HA and NA.

Consequence

Immune escape and need for annual vaccine updates.

Antigenic shift (influenza A pandemics)

Definition

Abrupt antigenic change in HA (± NA) caused by reassortment.

Mechanism

Co-infection in intermediate hosts mixes gene segments.

Pandemic condition

Sustained human-to-human transmission with low population immunity.

Drift vs Shift summary

Feature	Drift	Shift
Mechanism	Point mutations	Reassortment
Tempo	Gradual	Abrupt
Outcome	Seasonal escape	Potential pandemic
Host context	Human circulation	Animal–human interface

TLDR Variants arise from replication errors. Drift = gradual HA/NA mutation; shift = reassortment in influenza A producing novel antigens with pandemic potential.

L7.2 Virus Dissemination

Compare and contrast viruses acquired via the respiratory tract

What “acquired via the respiratory tract” means

Infection begins with inhalation of infectious particles; dissemination pathways differ.

Comparison table

Virus	Genome	Acquisition	Early targets	Dissemination	Shedding	Notes
Measles	−ssRNA	Inhalation	Immune cells	Lymphocyte-mediated	Respiratory	Very high R₀; immune amnesia
Smallpox	dsDNA	Airborne/contact	URT	Viraemia	Respiratory + skin	Eradicated
Mpox	dsDNA	Close contact	Mucosa/skin	Lymph–blood	Lesions	Zoonotic
VZV	dsDNA	Inhalation	URT epithelium	T-cell spread	Skin + respiratory	Latency/reactivation

TLDR Measles and VZV disseminate via immune cells; smallpox and mpox via viraemia. VZV also establishes neuronal latency.

L7.2 Explain ways viruses disseminate to cause disease

General routes

Cell-associated spread

Lymphocytes, dendritic cells, macrophages.

Viraemia

Bloodborne spread after mucosal entry.

Secondary epithelium infection

Enables shedding.

Examples

Measles

Enters via inhalation → lymphocytes/DCs/alveolar macrophages → systemic spread → reinfects airway.

VZV

URT replication → T-cell dissemination → skin lesions → latency in sensory neurons.

Mpox

Entry via mucosa/skin → nodes → incubation ~2 weeks → lesions.

Smallpox

Generalised viraemia with pustular rash.

TLDR Dissemination occurs via immune cells or viraemia, enabling systemic disease and shedding. VZV adds neuronal latency.

L7.2 Compare and contrast coronaviruses, influenza, measles, smallpox, mpox, and VZV

Summary comparison

Virus	Genome	Acquisition	Tropism/dissemination	Shedding	Host/Reservoir	Control notes
CoVs	+ssRNA	Respiratory	Airway epithelium	Respiratory	Zoonotic origins	Vaccines updated to variants
Influenza A/B	−ssRNA segmented	Respiratory	Respiratory epithelium; lower-tract severity	Respiratory	A: birds/mammals; B: humans	Drift and shift
Measles	−ssRNA	Inhalation	Lymphocyte/DC spread	Respiratory	Humans	High R₀, immune amnesia
Smallpox	dsDNA	Resp/contact	Viraemia	Resp+skin	Humans	Eradicated
Mpox	dsDNA	Close contact	Lymphatic/systemic	Lesions	Zoonotic	2022 outbreak
VZV	dsDNA	Inhalation	T-cell spread; latency	Skin + resp	Humans	Shingles reactivation

TLDR CoVs and flu are airway-centred; measles and VZV spread via immune cells; smallpox and mpox by viraemia. VZV adds latency.

L7.3 Bacterial Pneumonia

Distinguish bronchopneumonia vs lobar pneumonia

Pattern and appearance

Bronchopneumonia: patchy, peri-bronchial, multifocal.
Lobar pneumonia: entire lobe, classic 4 stages.

Stages of lobar pneumonia

Congestion
Red hepatization
Grey hepatization
Resolution/organization

Microscopy anchors

Neutrophil-rich exudates; fibrin; bacterial colonies.
Lobar: diffuse involvement.
Bronchopneumonia: airway-centred patches.

TLDR Bronchopneumonia = patchy. Lobar pneumonia = whole lobe with four classic stages.

Recall common causative organisms of pneumonia

Community-acquired

S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, Klebsiella, Mycoplasma.

Hospital-acquired / healthcare-associated

S. aureus (± MRSA), Pseudomonas, S. pneumoniae, Enterobacteriaceae (Klebsiella, Serratia, E. coli).

TLDR CAP: S. pneumoniae first. HAP: S. aureus, Pseudomonas, GNRs.

Recall predisposing factors for pulmonary infections

Deck-linked factors

Alcohol misuse.
Smoking/COPD.

Additional

Very young/elderly.
Recent viral infection.
Immunodeficiency.
Cardiorenal disease.

TLDR Risk increases with alcohol misuse, smoking, age extremes, recent viral infection, immunodeficiency, and comorbidities.

Describe complications of bacterial pneumonia

Local complications

Abscess.
Empyema.

Systemic spread

Bacteraemia → abscesses, endocarditis, meningitis, arthritis.

Diffuse alveolar damage/ARDS

Inflammation-driven permeability and epithelial death.

Healing outcomes

Resolution or organizing pneumonia with fibrosis.

TLDR Complications include abscess, empyema, bacteraemia, and ARDS, with possible fibrotic organization.

L7.4 COPD

Understand obstructive vs restrictive lung disease

Definitions

Obstructive: ↑ resistance, FEV1/FVC < 0.7.
Restrictive: ↓ TLC, proportional FEV1/FVC fall.

TLDR Obstructive = flow limitation; restrictive = volume limitation.

Define COPD and distinguish emphysema vs chronic bronchitis

COPD definition

Persistent symptoms and airflow limitation from noxious particle exposure; irreversible.

Emphysema

Distal airspace destruction; loss of recoil.
Centroacinar (smoking).
Panacinar (α1-AT deficiency).

Chronic bronchitis

Productive cough ≥3 months for ≥2 years.
Mucin gland and goblet-cell hyperplasia; fibrosis; inflammation.

Clinical patterns

Emphysema: hyperinflation, late hypoxaemia.
Chronic bronchitis: early hypoxaemia, infections, cor pulmonale.

TLDR COPD = irreversible airflow limitation. Emphysema destroys alveoli; chronic bronchitis causes mucus-driven airway obstruction.

Explain COPD pathogenesis

Initiation

Chronic epithelial injury from smoke/pollutants.

Mechanisms

Protease–antiprotease imbalance.
Oxidative stress.
Small-airway disease.

Structural–functional cascade

Air trapping, recoil loss, mucus obstruction, vascular remodeling.

TLDR Chronic inflammation → protease excess, oxidative stress, airway remodeling → obstruction and air trapping.

Relate COPD pathology to clinical presentation

Symptoms

Dyspnoea, chronic cough, sputum, wheeze.

Physiology

FEV1/FVC < 0.7.
Hyperinflation, ↓DLCO (emphysema).
Imaging: hyperlucent lungs or wall thickening.

Complications

Exacerbations, cor pulmonale, respiratory failure.

TLDR Symptoms map to mucus, fibrosis, and alveolar destruction; spirometry shows fixed obstruction; complications include cor pulmonale and respiratory failure.

WEEK 8

L8.1 Protective vs Damaging Responses in the Respiratory Tract

1) Steps in the immune response to respiratory pathogens

Barriers and early sensing

Physical and chemical barriers, mucociliary escalator, surfactant, airway reflexes. Alveoli tolerate little inflammation.
PRRs on epithelium and innate cells detect pathogens. PRR activation increases AMPs, tight junctions, inflammation, immune-cell recruitment, cell death programs, antiviral pathways, and adaptive priming.

Innate effector recruitment

Alveolar macrophages: PRR sensing, phagocytosis, cytokines.
ILCs: early cytokine responses.
Neutrophils: rapid influx, granules, ROS.
NK cells: cytotoxic for infected cells.
Monocytes → macrophages.
DCs: antigen capture and adaptive priming.

Pocket table

Innate cell	Key actions
Alveolar macrophage	PRR sensing, phagocytosis, cytokines
Neutrophil	Rapid influx, granules, ROS
NK cell	Kill infected cells
ILCs	Cytokine tuning
DC	Antigen capture, T-cell priming

Adaptive activation and outcomes

Naïve T/B activation in nodes/MALT → effector/memory.
B cells → plasma cells.
CD4 → Th1/Th2/Th17.
CD8 → cytotoxic cells.

TLDR
Barriers and PRR sensing → macrophages/ILCs → neutrophils/NK → DC priming → antibody, Th subsets, and CD8 responses. Lungs restrict inflammation to preserve gas exchange.

2) Immune response to influenza: balance between clearance and damage

Clearance pathways

PRR sensing → type I IFN → antiviral state.
Pro-inflammatory cytokines → NK recruitment, infected-cell death.
DC activation → Th1 and CD8 response → antibody production.

Damage mechanisms

Strong neutrophil influx and cytokines injure alveoli, especially in lower-tract infection.

Balance sheet

Arm	Helps	Risks
Type I IFN	Antiviral	Symptoms, bystander injury
NK/CD8 cytotoxicity	Removes infected cells	Epithelial loss
Neutrophil proteases/ROS	Pathogen killing	Alveolar damage
Cytokines	Recruit effectors	Excess inflammation

TLDR
Influenza clearance depends on IFN, NK/CD8 cytotoxicity, and antibody. The same mediators that clear virus can damage alveoli if unrestrained.

3) ARDS and diffuse alveolar damage (DAD): pathophysiology

Lecture emphasis

Injury triggers permeability oedema, immune-cell accumulation, ROS/protease damage, and microcirculatory problems.

Mechanistic sequence

Injury to epithelium/endothelium.
PRR activation → neutrophils/monocytes.
Endothelial leak → protein-rich oedema → surfactant inactivation.
Neutrophil ROS/proteases → barrier failure.
Hyaline membranes → severe diffusion impairment → ARDS.

Variable outcomes

Resolution yields recovery.
Severe or repeated injury → dysregulated repair → fibrosis.

TLDR
Epithelial–endothelial injury → oedema → neutrophil ROS/protease damage → hyaline membranes → gas-exchange failure. Resolution restores function; dysregulation leads to fibrosis.

4) Wound healing in the lung and how dysregulation causes fibrosis

Normal repair sequence

Stop leak, clear debris, macrophage efferocytosis.
Type II pneumocytes proliferate → differentiate to type I.
Remove provisional matrix → restore architecture.

Fibroproliferation and fibrosis

Persistent/severe injury → fibroblast recruitment, myofibroblasts, collagen-rich ECM deposition → thickened alveolar walls.
TGF-β and profibrotic macrophage signals drive this switch.

Resolution vs organization

Step	Resolution	Organization
Inflammation	Shut-off	Persistent
Epithelium	Type II → type I	Failed repair
Matrix	Removed	Collagen deposition
Outcome	Restored diffusion	Reduced compliance, impaired gas exchange

TLDR
Normal repair resolves inflammation, re-epithelialises, and clears provisional matrix. Dysregulation drives TGF-β–dependent myofibroblast collagen deposition → fibrosis.

5) Link chronic inflammation and repeated injury to fibrotic lung disease

Repetition

Recurrent epithelial–endothelial injury keeps PRR/cytokine pathways active → persistent neutrophil ROS/protease damage → cumulative micro-injury.

Self-reinforcing loops

Protease/oxidant imbalance → ECM injury → fibroblast recruitment → TGF-β dominance → myofibroblast persistence → collagen deposition.
Leads to restrictive physiology and hypoxaemia.

Mechanism map

Repeated injury → PRRs → neutrophils.
Failed epithelial restoration.
Persistent TGF-β → fibroblast recruitment → myofibroblasts.
Collagen accumulation → fibrosis.

TLDR
Repeated injury prevents resolution and drives TGF-β–mediated myofibroblast activity → collagen accumulation → fibrotic lung disease.

L8.2 Hay Fever and Asthma

Type I hypersensitivity: IgE, mast cells, Th2

What Type I hypersensitivity is

Rapid pathological response to environmental antigens; mast-cell–driven; requires prior priming.

Sensitisation (first exposure)

DCs present allergen → Th2 polarisation (IL-4/IL-13).
B cells class-switch to IgE.
IgE binds Fcε receptors on mast cells → sensitised mast cells.

Re-exposure (immediate reaction)

Allergen cross-links IgE → mast-cell degranulation → histamine, lipid mediators, cytokines → vascular leak + mucus.
Late phase: neutrophils and eosinophils (2–4 hours).

Organ examples

Allergic rhinitis

Allergen-specific IgE on nasal mast cells → degranulation → sneezing, itch, congestion, rhinorrhoea.

Allergic asthma

Inhaled allergen triggers bronchial mast-cell degranulation → bronchoconstriction.
Chronic episodes → airway remodelling (goblet-cell hyperplasia, wall thickening, angiogenesis).
Symptoms: dyspnoea, wheeze, cough; reversible airflow limitation.

Context: need for priming

Immediate reaction occurs only after IgE + Th2 priming.

TLDR
Sensitisation produces allergen-specific IgE that arms mast cells. Re-exposure cross-links IgE → mast-cell degranulation → immediate symptoms. Chronic reactions drive airway remodelling in asthma.

2) How repeated allergen exposure drives sensitisation → reactions → asthma

A. Sensitisation

DCs → Th2 → IL-4/IL-13 → B-cell class switching → IgE → mast-cell loading.

B. Re-exposure

Cross-linking IgE → degranulation → immediate + late-phase inflammation.
Nasal symptoms: histamine-induced leak and mucus.

C. Progression to asthma

Bronchial mast-cell degranulation → bronchoconstriction.
Repetition → airway remodelling: smooth muscle, goblet cells, inflammation, mucus plugs → reversible airflow obstruction.

One-screen table

Stage	Events	Cells/mediators	Outcomes
Sensitisation	Th2 polarisation, IgE class-switch	Th2, B cells, IgE	Sensitised mast cells
Immediate	IgE cross-linking	Mast cells, histamine	Minutes: leak, mucus, bronchoconstriction
Chronic	Repeated episodes	Eosinophils, mast cells, Th2, smooth muscle	Remodelling, mucus plugs, reversible obstruction

TLDR
First exposure generates IgE and Th2. Re-exposure activates mast cells immediately. Repetition in bronchi causes chronic remodelling → asthma.

L8.3 Opportunistic Pathogens

1) Specialist vs opportunistic pathogens

Definitions

Specialist pathogens: human-to-human propagation; human reservoir.
Opportunistic: disease when a transient niche appears; reservoirs often environmental or microbiota.

Chain of transmission differences

Determined by reservoir, persistence traits, exposure route, and portal of entry.

Contrast table

Category	Reservoir	Niche	Exposure	Control
Specialist	Humans	Sustained host-to-host	Droplets/contact	Vaccination, isolation
Opportunist	Environment/microbiota	Transient niche	Aerosols/devices	Source control, device protocols

Examples

Aspergillus: soil/compost; inhaled conidia; disease in immunocompromised.
Legionella: cooling-tower biofilms; aerosol spread; engineering controls.
Acinetobacter/Klebsiella/Pseudomonas: biofilm-forming nosocomial organisms.
Pneumococcus: human reservoir; high asymptomatic carriage; vaccine-preventable.

TLDR
Specialists spread human-to-human; break transmission. Opportunists arise from environment or microbiota when niches open; control exposure and devices.

2) Why categorise infections by source

Logic

Maps biology to exposure setting → targeted prevention.

Endogenous

Pathobionts (e.g., pneumococcus) move to new site via aspiration.
Prevent via aspiration control + vaccination.

Nosocomial

Endogenous or transmitted via devices/surfaces.
Biofilm-forming MDR organisms (Acinetobacter, Pseudomonas).
Prevent with device bundles, cleaning, stewardship.

Environmental

Aspergillus (soil/compost). Legionella (water systems).
Prevent by source control and engineering interventions.

Community (human reservoir)

Specialist infections; herd immunity feasible.

Source map

Source	Agents	Exposure	Prevention
Endogenous	Pathobionts	Aspiration	Vaccines, risk reduction
Nosocomial	MDR organisms	Devices	Bundles, cleaning
Environmental	Aspergillus, Legionella	Aerosols	Source remediation
Community	Specialist pathogens	Droplets	Herd immunity

TLDR
Categorising by source identifies where prevention should act: aspiration control, device/biofilm control, environmental remediation, or herd immunity.

3) Prevention strategies for respiratory opportunists

Environmental opportunists

Aspergillus

Risk: soil/compost; high exposure + immunosuppression.
Control: limit exposure, wet down compost, PPE, avoid dust generation.

Legionella

Risk: cooling towers; biofilms.
Controls: routine screening, maintenance, remediation.

Nosocomial opportunists (VAP organisms)

Biofilm-forming MDR strains; exploit endotracheal tubes.
Prevention: minimise ventilation time, elevate head of bed, oral care, device cleaning, stewardship.

Endogenous pathobionts

Pneumococcus: human reservoir; high carriage.
Prevention: PCV vaccines + aspiration risk reduction.

Algorithm

Identify source: environmental, nosocomial, endogenous.
Match control to source: reservoir removal, device bundle, vaccination.
Adjust for host susceptibility.

TLDR
Environmental opportunists need reservoir/exposure control; nosocomial agents require device/biofilm control; endogenous pathobionts depend on vaccination and aspiration prevention.

L8.4 Vaccination

1) Immune response to vaccines

Vaccines mimic infection → activate T/B cells → memory.
IM vaccines → systemic IgG; mucosal vaccines → IgA.

TLDR
Vaccines induce adaptive memory. IM gives IgG; mucosal routes target IgA.

2) Vaccine types and mechanisms

Traditional platforms

Type	Mechanism	Notes
Live-attenuated	Limited replication → strong immunity	Avoid in some immunocompromised; MMR.
Inactivated	Non-replicating	Stable; Salk polio.

Subunit and toxoid

Type	Mechanism	Notes
Subunit	Purified antigens ± adjuvant	Shingrix.
Toxoid	Inactivated toxin	Tetanus.

New platforms

Type	Mechanism	Notes
Viral-vector	Host cells express antigen	AZ COVID-19.
mRNA	Host cells translate mRNA	Pfizer COVID-19.

Systemic vs mucosal

IM → IgG.
Mucosal → IgA.

TLDR
Live/vectors mimic infection; inactivated/subunit/toxoid give safe antigen exposure; mRNA/vectors allow rapid updates.

3) Factors influencing vaccination success

Pathogen biology

Incubation, antigen stability, site of disease.
Measles/smallpox: stable antigens → sterilising immunity.
Influenza/SARS-CoV-2: variable antigens → updates needed.

Platform, route, host

IM vs mucosal shapes IgG/IgA.
Age, health, boosting, antigenic drift/variants.

Population-level effects

Herd immunity depends on reservoir, R₀, and vaccine effect on transmission.

Summary table

Pathogen	Antigen stability	Disease site	Vaccine effect
Measles	High	After dissemination	Sterilising
Smallpox	High	After dissemination	Sterilising
Influenza	Low	Primary site	Reduces illness; updates
SARS-CoV-2	Low	Primary site	Reduces infection/shedding; updated doses

TLDR
Success depends on pathogen biology, platform/route, host factors, and population coverage. Stable-antigen pathogens give durable sterilising immunity; variable antigens need updates.

WEEK 9

L9.1 Neurobiology of Sleep-Wake Cycle

1) Define sleep as a neurobiological state

General definition

Sleep is a reversible, recurring physiological state with altered consciousness, characteristic brain activity, and changes in muscle tone.
REM and NREM (N1, N2, N3) alternate in ~90–110 min cycles, repeating 4–6 times.

Neurobiological framing

Sleep is initiated, maintained, and terminated by interacting neural pathways, brain regions, and neurotransmitters.

TLDR
Sleep is a reversible, cyclic brain state with REM/NREM staging produced by coordinated neural circuits rather than passive shutdown.

2) Major anatomical parts of the brain in the sleep-wake cycle

Hypothalamus

SCN: light input → pineal → melatonin timing.
VLPO: adenosine-activated; GABA inhibits arousal centres.
Orexin/histamine neurons: sustain wakefulness.

Pineal gland

Produces melatonin under SCN control.

Thalamus

Sensory gate; reduced relay in sleep, increased relay in wake.

Brainstem

Reticular formation: monoamines activate cortex.
Pons: cholinergic arousal and REM signalling.

Basal forebrain

GABA promotes sleep; ACh activates cortex.

Cortex and limbic structures

Thalamic target; reduced relay → sleep.
Hippocampus/amygdala linked to memory and REM functions.

Anatomy → function table

Structure	Key function
SCN	Light → melatonin rhythm
VLPO	GABA inhibition of arousal centres
Pineal	Melatonin (darkness)
Thalamus/cortex	Relay gating of consciousness
Reticular formation	Monoamine arousal
Pons	ACh arousal, REM
Basal forebrain	GABA for sleep, ACh for wake
Limbic regions	Memory/emotion in REM

TLDR
SCN sets timing; VLPO shuts arousal off; brainstem/basal forebrain activate cortex; thalamus gates input; limbic areas mediate memory/emotion links.

3) Basic neurochemistry of sleep–wake

Sleep-promoting transmitters

GABA (VLPO, basal forebrain) inhibits arousal nuclei.
Adenosine activates VLPO.
Melatonin from pineal promotes sleep onset.

Arousal-promoting transmitters

ACh (pons/basal forebrain) activates thalamus/cortex; drives REM.
Monoamines (serotonin, norepinephrine, dopamine) maintain wake.
Histamine and orexin sustain arousal.
Cortisol/epinephrine rise with wake.

State transitions

Sleep onset: SCN → melatonin; adenosine → VLPO; GABA suppresses arousal pathways.
Wake: light reduces melatonin; VLPO inhibition; ACh/monoamines rise.

Quick transmitter map

Transmitter	Source	Effect
GABA	VLPO/BF	Sleep
Adenosine	Metabolic → VLPO	Sleep pressure
Melatonin	Pineal	Sleep onset
ACh	Pons/BF	Arousal/REM
Monoamines	Reticular formation	Arousal
Histamine/orexin	Hypothalamus	Wake
Cortisol/epi	Adrenal	Arousal

TLDR
Sleep: adenosine → VLPO → GABA shuts arousal down. Wake: ACh, monoamines, and orexin/histamine activate cortex; melatonin falls.

4) Vital roles of sleep in memory, repair, immunity

Memory

SWS supports declarative memory via hippocampo-cortical replay and spindles.
REM supports procedural and emotional memory integration.

Repair and metabolic housekeeping

SWS supports growth hormone release, protein synthesis, and glymphatic clearance.

Immunity

Sleep strengthens antigen presentation and adaptive responses; deprivation shifts cytokine patterns.

TLDR
SWS consolidates memories and drives repair; REM integrates emotional/procedural learning; sleep supports immune memory.

5) How sleep links to “eat” and “breathe” modules

Eat: metabolism

SCN aligns feeding rhythms with sleep.
Sleep loss → ↑ ghrelin, ↓ leptin, higher intake; impaired glucose tolerance.
Cortisol rhythm influences morning glycaemia.

Breathe: ventilatory control

NREM: regular breathing, elevated PaCO₂ set-point.
REM: variable breathing, reduced airway tone.
OSA: airway collapse → desaturation, arousals, sympathetic activation.

Integration table

Sleep construct	Eat link	Breathe link
SCN timing	Insulin sensitivity	Chemoreflex alignment
SWS	Glycaemic stability	Regular breathing
REM	ANS variability	Irregular ventilation
Sleep loss	Appetite signals	Sympathetic drive, apnoea burden

TLDR
Sleep modulates metabolic hormones and glucose handling, and reorganises ventilatory control. Disruption drives insulin resistance and apnoea-related stress.

L9.2 Sleep & Dream

1) Assess sleep brain states

How sleep is assessed

Polysomnography: EEG, EOG, EMG, ECG.

Core brain states

N1, N2, N3, REM.

EEG frequency bands

Delta: N3.
Theta: N1/N2/REM.
Alpha: wake/arousal.
Beta: wake/REM.

Graphoelements

N2: spindles, K-complexes.
REM: sawtooth waves.
N1: vertex waves.

Sleep architecture

7–8 h; 90–110 min cycles; early SWS, late REM.

Scoring aide

State	EEG	EOG	EMG	Hallmark
N1	Mixed/theta	Slow	Slight ↓	Transition
N2	Theta + spindles/K-complexes	Minimal	Low	Stable NREM
N3	Delta	Minimal	Low–mod	SWS
REM	Low-amp fast	Rapid	Atonia	Dream-rich

TLDR
PSG uses EEG/EOG/EMG to classify N1–N3 and REM. Learn band markers and graphoelements. Expect 90–110 min cycles with early SWS and late REM.

2) Apply the 2-process model of sleep regulation

Model overview

Process C: circadian wake drive.
Process S: homeostatic sleep pressure.

Daily pattern

Day: C high masks S.
Evening: C falls, S high → sleepiness.
Night: S falls; C low.
Pre-wake: C rises.

Misalignment consequences

Restricted sleep → high S → cognitive/mood impairment.
Shift work/jet lag → C out of phase with behaviour.

Timing table

Time	C	S	Effect
Morning	Rising	Low	Alert
Day	High	Rising	Wake
Evening	Falling	High	Sleepy
Night	Low	Falling	Sleep
Pre-wake	Rising	Low	Wake

TLDR
You sleep when S overtakes C; you wake when C rises and S is low. Misalignment increases sleepiness and health risk.

3) Distinguish sleep vs sleep loss

With adequate sleep

NREM–REM cycling supports memory, repair, and immunity.
SWS: glymphatic clearance, GH release, declarative memory.
REM: emotional/procedural learning.

With sleep loss

Higher mortality; metabolic syndrome; hypertension; stroke risk.
Anxiety, aggression, emotional instability; impaired memory.
REM suppressed by alcohol, sedatives, antidepressants, cannabis, high-fat diet.

Contrast table

Domain	Sleep	Sleep loss
Memory	Declarative + REM learning	Emotional instability
Repair	GH release, clearance	Vascular/metabolic risk
Metabolism	Balanced	Obesity, diabetes
Immunity	Strong	Pro-inflammatory

TLDR
Sleep clears waste, repairs tissue, and consolidates memory. Loss increases vascular, metabolic, and emotional risk.

4) Sleep across the lifespan

Developmental changes

Infants: short cycles, ~50 percent REM.
Young adults: 7–8 h, early SWS, late REM.
Older adults: fragmented sleep, more naps.
Social determinants influence sleep at all ages.

Timeline

Stage	Features
Infancy	More sleep, high REM
Childhood–Adolescence	Gradual reduction
Young adult	7–8 h, stable cycles
Older adult	Fragmentation, daytime sleep

TLDR
Infants have high REM and long sleep. Adults stabilize at 7–8 h. Ageing brings fragmentation. Social factors shape sleep across life.

L9.3 Biological Rhythms & Circadian Clock

1) Function of the mammalian circadian clock

Core concept

SCN synchronizes physiology to light–dark cycles.

SCN roles

Light → ipRGC → SCN.
SCN → pineal → melatonin timing.
Coordinates peripheral clocks and behaviours.

SCN summary table

Input	Clock	Output	Purpose
Light	SCN	Hormones, sleep–wake, autonomic signals	Align internal time

TLDR
SCN uses light to align internal physiology, chiefly by tuning melatonin and downstream rhythms.

2) Role of light and the phase response curve (PRC)

Light entrainment

Melanopsin-ipRGC pathway sets SCN phase.
Light at night suppresses melatonin.

PRC basics

Early-night light → delay.
Late-night/morning light → advance.
Midday → minimal effect.

Application

Eastward travel → seek morning light, avoid early-evening.
Westward travel → seek early-evening light, avoid early-morning.

Goal table

Goal	Seek light	Avoid light
Advance	Morning	Early evening
Delay	Early evening	Early morning

Health relevance

Wrong-time light → desynchrony → jet lag, shift-work fatigue, mood, metabolic and cardiovascular impacts.

TLDR
Light is the main zeitgeber. Early-night delays, late-night/morning advances. Proper timing prevents desynchrony.

3) Link circadian desynchrony to health

Definition

Misalignment between SCN, peripheral clocks, and behaviour.

Mechanism

Wrong-time light shifts SCN; peripheral clocks run out of phase with feeding/sleep cycles.

Health outcomes

Sleepiness, cognitive lapses.
Mood disruption.
Poor glucose control, weight gain.
Cardiovascular strain.

Linkage table

Driver	Clock effect	Outcome
Night light	Delay, melatonin suppression	Delayed sleep
Early shifts	Behaviour–SCN mismatch	Cognitive/mood deficits
Late eating	Peripheral misalignment	Poor glycaemia
Rotating shifts	Chronic misalignment	Cardiometabolic stress

TLDR
Desynchrony stems from wrong-time light or behaviours misaligned with internal clocks, driving cognitive, mood, metabolic, and cardiovascular harms.

4) Evaluate factors and consequences of social jetlag

Definition and measurement

Chronotype determines preferred timing.
Social jetlag = |midsleep workdays − midsleep free days|.

Consequences

Weekday restriction and weekend rebound.
Performance deficits.
Metabolic dysregulation.
Mood variability.

Mitigation

Advance: morning light, avoid evening light.
Delay: evening light, avoid morning light.
Regular sleep window; align meals.

Action table

Goal	Light	Sleep window	Meals/exercise
Reduce social jetlag	Morning light, dim evenings	Fixed times	Earlier meals/exercise
Shift later	Evening light, avoid early morning	Slide sleep later gradually	Shift meals later

TLDR
Social jetlag is the gap between biological and social time. Early schedules and late light widen it. Morning light and regularity shrink it.

WEEK 10

L10.1 Food, Exercise & Circadian Rhythm

1) Connect the influence of exercise and food to light in the circadian system and sleep

Interaction of time cues

Light entrains the SCN.
Exercise and food also act as zeitgebers for central and peripheral clocks.
These rhythms regulate sleep–wake, feeding, temperature, and hormonal cycles.

One-screen map

Zeitgeber	Primary target	Mediators	Outputs	Sleep effects
Light	SCN	ipRGCs, melatonin	Aligns rhythms	Defines biological day/night
Exercise	SCN + peripheral	Temperature, serotonin, autonomic tone	CV/temperature phase	Regular moderate activity improves sleep
Food timing	Peripheral clocks	Insulin, cortisol, ghrelin, leptin	Metabolic rhythms	Wrong-time eating fragments sleep

Exercise → circadian phase and sleep

Night exercise can delay melatonin and delay sleep onset.
Regular, moderate exercise improves sleep quality.
Midday–evening exercise aligns with peak cardiovascular performance and reduces mortality.

Eating time → circadian alignment

Night eating disrupts hormonal rhythms and peripheral clocks.
Daytime eating during night work avoids glucose spikes and preserves alignment.
TRF improves sleep/cognition in animals; Mediterranean diets associate with better sleep quality.

TLDR
Light sets the SCN. Exercise and food timing add strong timing signals. Night exercise delays sleep. Regular moderate activity improves sleep. Daytime eating during night work preserves glucose–insulin rhythms. TRF and Mediterranean eating support synchrony.

2) What we know, and what remains, about exercise, the circadian system, and sleep

What we know

Night exercise delays melatonin.
Regular moderate exercise improves sleep quality/efficiency.
Exercise modulates temperature rhythms and serotonin.

What remains unclear

Optimal timing, intensity, duration, frequency vary across studies.
Human evidence for daytime phase-advance effects is inconsistent.

Practical synthesis

Goal	Evidence-backed actions	Caveats
Improve sleep	Regular moderate exercise; avoid late-night vigorous	Individual variability
Align phase	Morning light + daytime meals; exercise earlier	Exercise-PRC not fully defined
Cardiometabolic	Midday–evening sessions	Avoid very late sessions

TLDR
Night exercise delays melatonin. Regular moderate exercise improves sleep. Timing with light and meals matters. Optimal protocols remain uncertain.

3) Appraise how eating at the right time vs wrong time influences biological rhythms

Why eating time matters

Food is a strong zeitgeber for peripheral clocks.
Night eating shifts peripheral clocks and disrupts cortisol, ghrelin, leptin, melatonin, and SWS.

Shift-work model

Night work + night eating → glucose spike + shifted insulin response.
Night work + daytime eating → preserved glucose–insulin alignment.

Summary table

Eating time	Clock effect	Metabolic effect	Sleep/mood
Daytime	Aligns with SCN	Normal glucose/insulin	More stable
Nighttime	Misaligned	Exaggerated glucose spike	Less SWS, worse mood

TLDR
Daytime eating maintains synchrony and stable glucose control. Night eating causes misalignment and hormonal disruption, harming SWS and mood.

4) Assess the benefits of time-restricted feeding (TRF)

Evidence base

TRF in AD mouse models improves sleep/cognition and reduces plaques/tangles.
TRF strengthens clock–metabolism coupling.
Mediterranean diets associate with improved sleep quality, weight, BP, inflammation, neuroprotection, melatonin synthesis, and microbiota diversity.

Unresolved questions

Human guidelines need clearer definitions for feeding windows, durations, and macronutrient timing.

Practical synthesis

Aim	TRF-style action	Benefit
Strengthen coupling	Consistent feeding window	Better sleep/cognition (models)
Reduce misalignment	Daytime meals during night work	Prevents glucose spike

TLDR
TRF aligns feeding with biological day and improves rhythmicity. Animal data show strong benefits; human protocols need refinement.

L10.2 SIDS

1) SIDS as a classification term, multifactorial

What SIDS is

Subcategory of SUDI.
Classification of exclusion after full autopsy, scene review, and history.
~30% explained; ~70% unexplained.

Why multifactorial

Triple risk model: vulnerable infant + developmental window + stressor.

TLDR
SIDS is an unexplained SUDI category defined by exclusion. It is multifactorial, framed by the triple-risk model.

2) Incidence and risk factors

Incidence

Current: 0.5–1/1000.
Historically: 1–2/1000 before “Back to Sleep.”
Peak: 2–4 months; winter; males > females.

Intrinsic risk factors

Prematurity, LBW, male sex, prenatal smoke, infections, genetic polymorphisms.

Extrinsic risk factors

Prone/side sleep, bed-sharing, face covering, soft bedding, overheating, smoke exposure.

Mechanistic links

Prone/soft bedding → rebreathing, hypercapnic hypoxia.
Prenatal nicotine → impaired receptor function.
Prematurity → immature autonomic control.

Quick table

Category	Examples	Notes
Intrinsic	Prematurity, male, prenatal smoke	Non-modifiable
Extrinsic	Prone sleep, bedding, overheating	Modifiable
Disparities	Indigenous (3×), preterm (2–5×)	Higher risk

TLDR
SIDS ~0.5–1/1000. Intrinsic risks increase vulnerability; extrinsic risks are modifiable and underpin safe-sleep campaigns.

3) Why SIDS is thought to reflect failed arousal from sleep

Physiological findings

Blunted sighing and gasping.
Lower HRV.
Reduced arousal responses.

Unifying hypothesis

Brainstem-mediated failure in autoresuscitation during hypoxia.

TLDR
SIDS infants show reduced sighing, gasping, HRV, and arousal. Hypothesis: brainstem failure to respond to hypoxia during sleep.

4) Neurotransmitter systems and brain regions involved

Brainstem regions

DMNV, NTS, raphe, arcuate nucleus.

Neurochemical abnormalities

↓ serotonergic binding.
Altered cholinergic and glutamatergic signalling.
Cytokine changes (IL-6, IL-10); reduced BDNF with increased receptor expression.

Region → finding map

Region	Function	Abnormality
Raphe	Serotonin, arousal	↓ 5-HT binding
Arcuate	CO₂ chemosensitivity	Altered neurotransmission
NTS	Cardiorespiratory afferents	Altered cholinergic/glutamatergic
DMNV	Vagal output	Trophic/transmitter changes

TLDR
Multiple medullary nuclei show transmitter abnormalities, especially serotonergic deficits, suggesting impaired arousal/ventilatory control.

5) Current research efforts into SIDS

Themes

Epidemiology, education, premortem physiology, brainstem pathology, genetics, virology, immunology.

Active lines

Cardiac channelopathies: ~10% reclassified.
Infection/fever as triggers.
Physiology: blunted sighing, gasping, HRV.
Question: Are brainstem abnormalities causal or consequential?

Research snapshot

Area	Focus
Brainstem chemistry	Causal vs secondary abnormalities
Cardiac genetics	Hidden channelopathies
Infection/fever	Triggers within triple-risk model
Physiology	Early markers of failed autoresuscitation

TLDR
Research spans physiology, pathology, genetics, virology, and education. Key questions include whether medullary transmitter abnormalities are causes or consequences.

L10.3 African Trypanosoma

1) Key features of Human African Trypanosomiasis

Agent, transmission, burden

Trypanosoma brucei via tsetse fly.
~10,000 cases/year.
T. b. gambiense (95%); T. b. rhodesiense (5%).

Clinical course

Rhodesiense: acute, rapid progression.
Gambiense: chronic, ~3 years.

Sleep relevance

Marked sleep, temperature, endocrine disturbances.

Summary table

Feature	Detail
Cause	T. brucei
Vector	Tsetse fly
Burden	~10,000/year
Subspecies	Gambiense, rhodesiense
Course	Chronic vs acute
Physiology	Sleep–temperature disruption

TLDR
HAT is caused by T. brucei. Gambiense is chronic; rhodesiense is acute. Sleeping sickness disrupts sleep and circadian physiology.

2) Experimental evidence that T. brucei disrupts circadian rhythm

Core paradigm

Mouse infection model with wheel-running measures.
Infected mice: reduced activity, phase advance.
Drug treatment shows effects are parasite-driven.

Multilevel readouts

Behavior: rest-phase activity.
Physiology: temperature peak shifts to day; feeding disrupted.
Tissue/cell: shortened circadian period.
Specificity: Plasmodium does not alter period.

Evidence chain

Question	Evidence	Interpretation
Behavior shifted?	Phase advance, reduced consolidation	Clock output altered
Physiology shifted?	Temperature rhythm disrupted	Multisystem disruption
Period changed?	Shortened period	Clock speed altered
Parasite-specific?	Plasmodium negative control	T. brucei effect
Immune-mediated?	Peripheral clearance argues against	Parasite-driven

TLDR
T. brucei causes phase advance, temperature shifts, and period shortening at organism, tissue, and cellular levels. Effects are parasite-specific and not immune-mediated.

WEEK 11

L11.1 Drugs Affecting Sleep 1

1) Mechanism of action of melatonin agonists (sedation and hypnosis)

Core pathway

Melatonin is synthesised from tryptophan via serotonin, then released from the pineal under SCN control.
It acts at MT1 and MT2 receptors in the SCN.
MT1 and MT2 are GPCRs that, when activated by melatonin or agomelatine, reduce adenylate cyclase activity, lower cAMP, and reduce neuronal membrane excitability. Net effect is neuronal inhibition.

Functional split of receptor actions

MT1 (SCN) supports sleep onset and reduces sleep latency.
MT2 (SCN) shifts circadian timing and supports sleep consolidation when aligned with the light–dark cycle.

Actions in the sleep network

SCN timing sets pineal melatonin release.
Melatonin acting back on MT1/MT2 in the SCN helps gate the switch toward sleep and supports inhibitory tone across arousal centres.

Mechanism table

Step	Detail	Consequence
Pineal release	Darkness → SCN → pineal melatonin	High melatonin at night
Receptor	MT1/MT2 GPCRs in SCN	↓ adenylate cyclase, ↓ cAMP
Neuronal effect	↓ membrane excitability	Inhibitory shift in SCN output
Clinical effect	MT1: ↓ sleep latency; MT2: phase shift	Sedation and hypnosis support
Citations:

TLDR
Melatonin agonists activate MT1 and MT2 in the SCN, reduce cAMP, and inhibit SCN neurons. MT1 shortens sleep latency. MT2 shifts phase and helps consolidate sleep when circadian timing is aligned. Examples: melatonin, agomelatine.

2) Mechanism of action of benzodiazepines and Z-drugs (sedation and hypnosis)

Receptor biology

GABA_A receptors are ligand-gated Cl⁻ channels (pentamers, commonly 2α:2β:1γ).
GABA binding opens the pore, hyperpolarising neurons and inhibiting firing.
Benzodiazepines and Z-drugs are positive allosteric modulators at GABA_A.
They do not activate the receptor alone. They increase GABA potency by binding the benzodiazepine site at the α–γ2 interface.
GABA itself binds at α–β orthosteric sites.

Subtype selectivity

Benzodiazepines act at GABA_A receptors containing α1, α2, α3, or α5 plus β and γ2L. Examples: diazepam, midazolam, alprazolam.
Z-drugs are more selective for α1-containing GABA_A receptors with β and γ2L. Examples: zolpidem, zopiclone, zaleplon.
α1 preference explains strong hypnotic effects with relatively less anxiolysis and muscle relaxation compared with some benzodiazepines.

Network-level action in sleep circuitry

Enhancement of GABAergic inhibition increases the effectiveness of VLPO and basal-forebrain GABA neurons that suppress arousal centres.
Result is promotion of sleep onset and sleep maintenance.

Effects on sleep architecture

Decreased sleep latency.
Decreased N1.
Decreased slow-wave sleep (N3).
Decreased total REM time but increased number of REM cycles.
Increased time in N2.
Fewer shifts to lighter stages and fewer movements.
Increased total sleep time.
Z-drugs reduce REM less than typical benzodiazepines.

Benzodiazepines vs Z-drugs

Feature	Benzodiazepines	Z-drugs
Binding site	BZD site (α–γ2L)	Same site
Subunit preference	α1/2/3/5 + β + γ2L	α1 + β + γ2L
Clinical profile	Hypnotic, anxiolytic, muscle relaxant, anticonvulsant	Primarily hypnotic
Sleep architecture	↓ latency, ↑ N2, ↓ N3, ↓ REM, ↑ REM cycles	Similar pattern, less REM suppression
Network effect	Potentiate VLPO/BF GABA inhibition of arousal centres	Same, with stronger α1-driven hypnotic bias
Citations:

TLDR
Benzodiazepines and Z-drugs are GABA_A positive allosteric modulators at the benzodiazepine site. Benzodiazepines act at α1/2/3/5; Z-drugs are more α1-selective. Both reduce sleep latency, increase N2 and total sleep time, and reduce N3 and REM, with Z-drugs causing less REM suppression.

3) Mechanism of action of ethanol (sedation and hypnosis)

Receptor-level actions

GABA_A: ethanol is a positive allosteric modulator that enhances inhibitory Cl⁻ currents and neuronal hyperpolarisation.
NMDA (glutamate): ethanol inhibits excitatory NMDA receptor function, reducing cortical excitation.
Adenosine: ethanol raises adenosine tone, which suppresses wake-promoting neurons and increases sleep pressure.

Network-level effect

Potentiates VLPO and basal-forebrain GABAergic inhibition of arousal centres.
Promotes rapid sleep onset and apparent sedation at intoxicating doses.

Sleep effects across the night

Early night: reduced sleep latency and more light NREM.
Later night: fragmented sleep, REM rebound as blood alcohol declines, and worsening of obstructive sleep apnoea and hypoventilation via relaxation of upper-airway dilator muscles.

Clinical cautions

Tolerance and withdrawal-related insomnia.
Additive respiratory depression with other sedatives.
Risk in sleep-disordered breathing.

TLDR
Ethanol potentiates GABA_A, inhibits NMDA, and raises adenosine, which speeds sleep onset but produces late-night fragmentation, REM rebound, and worsened breathing instability, especially when combined with other depressants.

4) Mechanism of action of sedating antihistamines (sedation and hypnosis)

Target and pharmacology

First-generation antihistamines are H1 receptor inverse agonists that cross the blood–brain barrier.
They suppress histaminergic neurons in the tuberomammillary nucleus, which normally sustain wakefulness.
Many also have antimuscarinic M1 activity, contributing to sedation and anticholinergic adverse effects.

Network-level effect

Reduce histamine-driven cortical activation within the sleep–wake circuitry.
Complement VLPO GABAergic inhibition of arousal pathways.

Sleep effects

Benefits: reduced sleep latency and modest increases in total sleep time.
Costs: next-day sedation, reduced alertness, and potential reduction in perceived sleep quality due to anticholinergic load.
Tolerance develops with repeated use.
Caution in older adults and in obstructive sleep apnoea.

Examples

Diphenhydramine.
Doxylamine.

Comparison across sedating classes

Class	Primary target	Immediate effect	Sleep architecture changes	Key cautions
Melatonin agonists	MT1/MT2 in SCN	↓ cAMP, SCN inhibition	↓ latency; better consolidation when phase aligned	Timing-sensitive, minimal next-day effects
Benzodiazepines	GABA_A PAM (α1/2/3/5, γ2L)	↑ GABA effect	↓ latency, ↑ N2, ↓ N3, ↓ REM, ↑ REM cycles	Tolerance, dependence, respiratory risk
Z-drugs	GABA_A PAM (α1-selective)	↑ GABA effect	Similar to benzodiazepines, less REM suppression	Complex behaviours, residual sedation
Sedating H1	H1 inverse agonist, M1 block	↓ histamine-based arousal	↓ latency, modest TST increase, variable quality	Anticholinergic effects, next-day sedation

TLDR
Sedating antihistamines block central H1 receptors and often M1 receptors, reducing histamine-driven wakefulness and shortening sleep latency. Next-day sedation, anticholinergic adverse effects, and tolerance limit their use to short-term situations.

L11.2 Drugs Affecting Sleep 2

1) Mechanism of action of dexamphetamine (wakefulness and physiological arousal)

Synaptic actions

Substrate at DAT and NET: competes with dopamine and noradrenaline for transport and enters nerve terminals.
Reverses transporter flux: drives DAT and NET into reverse, promoting DA and NA efflux into the synaptic cleft.
VMAT substrate: enters vesicles via VMAT and displaces DA and NA into the cytosol, lowering vesicular storage and increasing cytosolic monoamines, which then exit via reverse transport.

Network-level consequence

Increased DA and NA signalling in the ascending arousal system (reticular formation projections to cortex).
Results in enhanced cortical activation, wakefulness, and physiological arousal.

Clinical and behavioural profile

Psychomotor stimulant: increased motor activity, euphoria, improved concentration, faster reaction time, task-focused behaviour.
Insomnia and anorexia at stimulant doses.
Clinical use in ADHD and narcolepsy.

Mechanism map

Target	Action	Immediate effect	Net synaptic result
DAT/NET	Substrate, reverse transport	DA/NA efflux	↑ DA/NA in synapse
VMAT	Substrate, displaces DA/NA	↓ vesicular storage, ↑ cytosolic DA/NA	Fuels efflux via transporters
Arousal circuits	↑ DA/NA signalling	Cortical activation	Wakefulness and arousal
Citations:

TLDR
Dexamphetamine is a transporter and VMAT substrate that reverses DAT and NET and displaces vesicular monoamines, sharply increasing synaptic DA and NA in arousal pathways and promoting wakefulness and physiological arousal.

2) Mechanism of action of methylphenidate (wakefulness and physiological arousal)

Synaptic actions

Reuptake inhibitor at DAT and NET.
Binds and blocks these transporters, preventing DA and NA reuptake.
Not a transporter substrate and does not reverse flux or enter vesicles.

Network-level consequence

Sustains DA and NA levels in the synapse of ascending arousal pathways.
Promotes wakefulness and physiological arousal with psychomotor stimulant features.

Clinical and behavioural profile

Used for ADHD.
Improves concentration, reduces fatigue, and speeds reaction time.

Mechanism contrast with dexamphetamine

Feature	Dexamphetamine	Methylphenidate
DAT/NET	Substrate, reverses transport	Inhibitor, blocks reuptake
VMAT	Substrate, displaces vesicular DA/NA	No VMAT action
Synaptic DA/NA	Large increase via efflux and vesicular leak	Sustained increase via reuptake block
Arousal effect	Strong wake promotion	Wake promotion
Citations:

TLDR
Methylphenidate blocks DAT and NET, increasing synaptic DA and NA without reversing transport or affecting vesicular stores, and promotes wakefulness and arousal through the ascending arousal system.

3) Mechanism of action of cocaine (wakefulness and physiological arousal)

Synaptic targets

DAT, NET, and SERT reuptake inhibitor: blocks reuptake of dopamine, noradrenaline, and serotonin, acutely increasing synaptic monoamines.
Voltage-gated Na⁺ channel block: local anaesthetic effect that contributes to cardiac and neurological toxicity.

Network consequence

Increased DA and NA transmission in ascending arousal systems and mesocorticolimbic circuits.
Produces cortical activation, reduced sleep propensity, and sympathetic activation.

Effects on sleep

Acute effects: euphoria, psychomotor activation, insomnia, anorexia, tachycardia, hypertension.
Sleep architecture: shortened sleep latency at onset of use, fragmented sleep, reduced slow-wave sleep and REM, and rebound hypersomnia during offset or withdrawal.

Mechanism sketch

Target	Action	Immediate effect	Net arousal result
DAT/NET/SERT	Reuptake block	↑ synaptic DA/NA/5-HT	Wakefulness and sympathetic drive
Na⁺ channels	Block	Slowed conduction	Arrhythmia and seizure risk
Citations:

TLDR
Cocaine blocks DAT, NET, and SERT, acutely increasing synaptic monoamines and driving wakefulness and sympathetic activation, while Na⁺ channel block underlies toxicity. Sleep becomes fragmented with reduced SWS and REM and rebound hypersomnia during withdrawal.

4) Mechanism of action of caffeine (wakefulness and physiological arousal)

Primary pharmacology

Adenosine A1 and A2A receptor antagonist in the brain.
By blocking adenosine, caffeine disinhibits wake-promoting neurons and opposes homeostatic sleep pressure.

Pathway links

A1 antagonism removes adenosine inhibition on cortical and basal-forebrain neurons, increasing vigilance.
A2A antagonism in striatum alters dopamine signalling and increases motivation and psychomotor drive.

Effects on sleep

Acute: increased alertness, faster reaction time, reduced fatigue.
Dose-dependent insomnia, especially with afternoon or evening intake.
Sleep architecture: increased sleep latency, reduced total sleep time, reduced slow-wave sleep, and more awakenings.
Tolerance develops with habitual use; withdrawal causes sleepiness and headache.

Mechanism sketch

Target	Action	Immediate effect	Net arousal result
A1 receptor	Antagonist	Disinhibits cortical and BF neurons	Increased vigilance, less S pressure
A2A receptor	Antagonist	Modulates dopamine signalling	Higher motivation and drive
Citations:

TLDR
Caffeine blocks adenosine A1 and A2A receptors, lifting the adenosine brake on wake circuits and reducing sleep pressure. This improves alertness but delays sleep onset, reduces slow-wave sleep, and increases fragmentation if taken late.

One-page comparison (all four stimulants)

Drug	Primary target(s)	How monoamines change	Notes for sleep
Dexamphetamine	DAT/NET substrate, VMAT substrate, reverse transport	Large ↑ DA/NA via efflux and vesicular leak	Potent wakefulness; insomnia and anorexia common
Methylphenidate	DAT/NET inhibitor	↑ DA/NA via reuptake block	Wake promotion with psychostimulant profile
Cocaine	DAT/NET/SERT inhibitor; Na⁺ channel block	↑ DA/NA/5-HT via reuptake block	Insomnia, fragmented sleep, rebound hypersomnia, toxicity
Caffeine	A1/A2A antagonist	Disinhibits wake circuits, indirectly alters DA	Longer sleep latency, less SWS, timing-dependent effects

WEEK 12

L12.1 Thermoregulation & Fever

1) Describe the physiological mechanisms of thermoregulation

Core principles

Human core temperature is about 37 °C, with normal variation:
- Circadian rhythm: nadir ≈ 04:00, peak ≈ 18:00.
- Menstrual cycle shifts in people with ovulatory cycles.
Thermoregulation keeps core temperature stable using:
- A hypothalamic “thermostat” (integrator).
- Thermal sensors (central and peripheral).
- Effector responses (behavioural and autonomic).

Control loop

Sensors (afferents)
- Central thermoreceptors in hypothalamus, spinal cord, and deep tissues.
- Peripheral thermoreceptors in the skin.
Integrator
- Hypothalamic thermoregulatory centre compares actual core temperature to its internal set-point and decides whether to activate heat-loss or heat-gain pathways.
Effectors (efferents)
- Behavioural (dominant): clothing, activity level, posture, seeking shade or warmth, fluid intake.
- Autonomic: changes in skin blood flow, sweat production, shivering, and brown-fat / non-shivering thermogenesis in infants.

Behavioural vs autonomic outputs

Condition	Behavioural responses (dominant)	Autonomic responses
Heat challenge	Seek shade, reduce activity, drink fluids	Pre-capillary vasodilation, sweating
Cold challenge	Add clothing, seek shelter, move more	AV shunt vasoconstriction, shivering, non-shivering thermogenesis (infants)

Heat defence

Cutaneous vasodilation
- Increases skin blood flow to increase radiative and convective heat loss.
Sweating
- Evaporation from the skin surface increases heat loss.
- Most effective in dry, moving air.

Cold defence

AV shunt vasoconstriction
- Reduces skin blood flow, limiting heat loss from the surface.
Shivering
- Involuntary rhythmic skeletal muscle activity that increases metabolic heat production.
Non-shivering thermogenesis (infants)
- Brown adipose tissue metabolism increases heat production without muscle activity.

When control fails

Hypothermia
- Core temperature < ~35 °C because heat loss > heat production.
Hyperthermia
- Uncontrolled temperature rise because heat gain > heat loss, with no change in hypothalamic set-point.
- Only responds to cooling / removal of heat load, not to antipyretics.

TLDR (Obj 1)
Thermoregulation is a hypothalamic control loop. Thermal sensors feed a hypothalamic “thermostat”, which drives behavioural and autonomic effectors. Heat defence uses vasodilation and sweating; cold defence uses vasoconstriction, shivering, and infant non-shivering thermogenesis. Failures present as hypothermia or hyperthermia.

2) Pathophysiology and mechanisms of fever, and how it differs from hyperthermia

Define the states

Fever
- A regulated rise in core temperature due to an upward shift in hypothalamic set-point.
- Responds to antipyretics that block the mediator pathway.
Hyperthermia
- Unregulated heat gain > heat loss with no change in set-point.
- Does not respond to antipyretics; management is cooling and stopping heat production.

Canonical fever pathway

Pyrogen signal generation
- Exogenous pyrogens: e.g. LPS and other pathogen products activate PRRs on immune cells.
- Endogenous pyrogens: immune cells release IL-1, IL-6, TNF-α.
COX-2 induction and PGE₂ synthesis
- Cytokines induce COX-2 in brain endothelium and perivascular cells, including circumventricular organs (e.g. OVLT).
- Arachidonic acid → PGE₂ increases locally.
Hypothalamic action
- PGE₂ binds EP3 receptors in the preoptic area of the hypothalamus.
- The hypothalamic set-point rises.
Effector responses to the new set-point
- Thermoreceptors now signal “too cold” relative to the new set-point.
- Cold responses are triggered despite actual normal or high core temperature:
  - Cutaneous vasoconstriction, piloerection, shivering, behavioural heat-seeking.
  - These drive the chills and rigors of the rising phase of fever.
- When cytokine and PGE₂ levels fall (spontaneously or via antipyretics), the set-point falls:
  - The body is now “too hot” relative to the lower set-point.
  - Cutaneous vasodilation and sweating produce defervescence.

Fever vs hyperthermia at the bedside

Feature	Fever	Hyperthermia
Set-point	Raised by PGE₂ acting at EP3	Normal
Trigger	Pyrogens → cytokines → COX-2 → PGE₂	Heat load, failed heat loss, drugs/toxins
Rising-phase skin	Cold, pale, shivering, “chills”	Hot, flushed, sweaty (often)
Response to NSAIDs/paracetamol	Yes (set-point lowered)	No
Main therapy	Treat cause ± antipyretic	Active cooling, remove trigger, supportive care

Antipyretic mechanisms

NSAIDs and paracetamol
- Inhibit central COX and reduce PGE₂ near the hypothalamus → lower set-point.
Glucocorticoids
- Decrease production of cytokines (IL-1, IL-6, TNF-α), acting further upstream.

TLDR (Obj 2)
Fever is a regulated PGE₂-mediated set-point raise (pyrogens → cytokines → COX-2 → PGE₂ → EP3 in preoptic hypothalamus). The body responds with chills and shivering to reach the higher set-point, then vasodilation and sweating during defervescence. Hyperthermia is heat overload without set-point change, and only cooling (not antipyretics) works.

3) Adaptive effects of fever

Why fever can be beneficial

At modest elevations, fever aids host defence:

Innate immunity
- Increases neutrophil motility and phagocytosis.
- Enhances NK cell activity.
Adaptive immunity
- Improves antigen presentation and T-cell responses.
- Supports antibody responses.
Direct and indirect pathogen constraint
- Many pathogens replicate less efficiently at febrile temperatures.
- Fever supports iron sequestration and acute-phase responses, limiting microbial growth.

Physiologic costs

Each degree rise in core temperature increases metabolic rate and O₂ demand (roughly ~10% per °C).
Fever increases heart rate, catabolism, and dehydration risk (especially with sweating).
Vulnerable patients (severe cardiopulmonary disease, pregnancy, neurologic injury, frailty) tolerate fever poorly.

Clinical synthesis

Moderate fevers can be adaptive and do not always need aggressive suppression if:
- The patient is reasonably comfortable.
- Cardiorespiratory reserve is adequate.
Priorities:
- Treat the cause of fever.
- Use antipyretics for:
  - Comfort.
  - Excessive metabolic demand or cardiorespiratory compromise.
  - Very high temperatures.
- For hyperthermia syndromes, focus on active cooling and trigger removal.

Benefit vs cost table

Temperature band	Likely immune effect	Likely physiological cost	Typical action
37.5–38.5 °C	Immune enhancement, some pathogen restraint	Mild ↑ HR and O₂ use	Observe, treat cause, antipyresis optional
38.6–40.0 °C	Greater immune activation	Noticeable ↑ metabolic load, discomfort	Consider antipyresis for comfort/comorbidity
>40.0 °C	Diminishing benefit, cellular stress	High O₂ demand, risk of complications	Antipyresis and cooling; urgent control of cause

TLDR (Obj 3)
Fever boosts innate and adaptive immunity and can hinder pathogens, but it raises metabolic demands and may harm vulnerable patients. Moderate fever can be tolerated if safe; use antipyresis for comfort and risk reduction, and use active cooling for hyperthermia or very high temperatures.

L12.2 Sickness Behaviours

1) Explain how immune-to-brain communication via cytokines and neural pathways regulates physiological and behavioural responses

Two main routes from immune system to brain

Humoral route

Peripheral immune activation (infection, tissue damage) leads to release of IL-1, IL-6, TNF-α and other mediators.
These signals reach the CNS via blood or lymph and act on:
- Brain endothelium.
- Circumventricular organs with leaky BBB.
Hypothalamus and brainstem integrate these signals and drive:
- Fever.
- Appetite loss and nausea.
- Fatigue and sleepiness.
- Social withdrawal and reduced activity.

Neural route

Vagal sensory fibres detect inflammatory signals in viscera (e.g. gut infection).
Afferents project to the nucleus tractus solitarius (NTS) and on to hypothalamic and brainstem centres.
This pathway produces similar coordinated sickness outputs with faster neural timing.

Signals → nodes → outputs

Signal source	Pathway to brain	Key CNS nodes	Typical outputs
IL-1, IL-6, TNF-α; microbial products	Blood/lymph → brain endothelium, CVOs	Hypothalamus, brainstem	Fever, anorexia, fatigue, sleepiness, nausea, social withdrawal
Visceral inflammation	Vagus afferents → NTS → hypothalamus	NTS, hypothalamus	Similar sickness behaviour profile, fast neural signalling

Gut example

Gastroenteritis:
- Local cytokines fight pathogens and signal centrally.
- Resulting nausea and appetite loss reduce further ingestion of contaminated food.
- Fatigue and withdrawal promote rest and reduce spread to others.

Why these behaviours are adaptive

Energy reallocation
- Fatigue, increased sleep, and reduced social or physical activity conserve energy for immune responses and repair.
Sleep as therapy
- Low-dose IL-1 acts as a somnogen and promotes slow-wave sleep, which supports:
  - Efficient adaptive immune responses.
  - Tissue repair.
- Sleep loss often increases inflammatory tone, showing bidirectional interaction.

Neurochemical links to mood and motivation

Pro-inflammatory cytokines reduce noradrenaline, dopamine, and serotonin activity in key brain circuits.
This produces:
- Anhedonia.
- Low mood and dysphoria.
- Fatigue.
- Social withdrawal.
These changes are useful when acute and time-limited but harmful if chronic.

Text pathway sketch


Infection or tissue damage
→ PRR activation → IL-1 / IL-6 / TNF-α ↑
↘ humoral route → brain endothelium / CVOs → hypothalamus, brainstem
↘ vagal route   → NTS → hypothalamus
→ Coordinated outputs: fever, appetite loss, sleepiness, fatigue, social withdrawal
→ Energy reallocation to immunity and repair; reduced pathogen spread

TLDR (Obj 1)
Immune signals reach the brain via blood-borne cytokines and the vagus nerve. Hypothalamic and brainstem circuits then drive fever, loss of appetite, sleepiness, fatigue, and social withdrawal. These behaviours conserve energy for immune defence and repair; cytokines also alter monoamines, shaping mood and motivation during illness.

2) Analyse how adaptive sickness behaviours (sleep, appetite loss, social withdrawal) promote survival and recovery

Core idea

Acute inflammation signals the brain to shift energy away from nonessential behaviours toward immune defence and tissue repair. The resulting behaviours are unpleasant but adaptive for both the individual and the population.

Mechanistic links and adaptive functions

Behaviour	Proximal driver(s)	Immediate benefit	Downstream gain
Sleepiness / more SWS	Low-dose IL-1 and other cytokines acting as somnogens	Reduced activity, energy conservation	Supports adaptive immune activation and tissue repair; sleep loss raises inflammation.
Anorexia / nausea	Cytokine and vagal signalling from infected viscera	Limits ingestion of further contaminated food	Reduces new pathogen exposure; prioritises energy for immunity.
Social withdrawal, low mood	Cytokine-mediated reductions in NA/DA/5-HT in behaviour circuits	Less social contact and risk-taking	Lowers transmission risk; conserves energy and promotes rest.

GI example:
- Gastroenteritis → gut cytokines → brain → nausea and appetite loss (avoidance), plus fatigue and withdrawal (rest and reduced spread).

TLDR (Obj 2)
Acute cytokine and vagal signals bias the brain toward sleep, anorexia, and social withdrawal. These behaviours save energy, support immune responses and repair, and reduce transmission, so they are adaptive when short-lived.

3) Evaluate the potential consequences of dysregulated inflammation on brain function and behaviour

When the adaptive program becomes maladaptive

If inflammation persists, the same immune–brain pathways that help recovery can disrupt neurotransmission, mood, and cognition.

Key changes with chronic inflammation

Neurochemical effects
- Pro-inflammatory cytokines chronically lower NA/DA/5-HT activity.
- Sustains anhedonia, fatigue, dysphoria, and social withdrawal as a prolonged state.
Chronic signalling state
- The brain remains in a prolonged “immune alert” mode.
- Motivation and cognitive performance deteriorate (attention, memory, executive function).
Systems consequences
- Chronic low-grade inflammation associates with:
  - Depression-like symptom profiles.
  - Metabolic syndrome and cardiovascular disease.
  - Neurodegenerative disorders that involve inflammatory signalling.
Sleep–inflammation feedback loop
- Sleep disruption increases inflammatory tone.
- Elevated cytokines then further impair sleep, creating a vicious cycle.

Acute vs chronic response

Feature	Acute, regulated response	Chronic, dysregulated response
Duration	Hours to days	Months to years
Cytokine profile	Transient, task-linked	Persistent, low-grade systemic inflammation
Behaviour	Energy-saving sickness, then resolution	Sustained anhedonia, fatigue, withdrawal, cognitive impairment
Neurochemistry	Short-term monoamine modulation	Down-regulated NA/DA/5-HT signalling
Health impact	Recovery and reduced spread	Risk of depression, metabolic and cardiovascular disease, and neurodegeneration

TLDR (Obj 3)
With chronic inflammation, immune–brain signalling becomes harmful. Monoamine activity falls, behaviour and mood deteriorate, and systemic disease risks rise. A sleep–inflammation feedback loop can lock in this state, making restoration of normal sleep and reduced inflammation a key target.






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MEDS2012 Learning Objectives

2025-11-24

WEEK 1

L1.1 Primary Gut Function

1. Identify the major anatomical components of the GI tract and accessory organs

Overview

Quick location map

Accessory organs

Table. Major components and where they sit

2. Outline the main functions of each segment in digestion and absorption

Global functions of the digestive system

Segment-by-segment functions

Oral cavity

Pharynx

Esophagus

Stomach

Duodenum

Jejunum and Ileum

Large intestine

Rectum and anal canal

Accessory organ contributions to segment functions

Table. Segment functions and the key feature that enables them

3. Describe the layers of the GI tract wall and relate their structure to function

The canonical wall plan, and when it differs

Layer-by-layer structure–function map

4. Describe the roles of accessory organs in digestion, including the production and delivery of enzymes and bile

What the slides list as accessory organs and where they sit

Roles and products

Salivary glands

Liver and gallbladder

Pancreas

How these products reach the lumen and why placement matters

Compact table

L1.2 Microbiome

1. Describe the contribution of microbes to energy harvesting

a) Why estimates of available Calories in foods vary

The baseline estimate

Where the estimate breaks

Role of microbial metabolism

Practical consequences

Mini-table: why the same “calories” differ in practice

b) Why the microbiome determines efficiency of fibre utilization

The substrate classes in your slides

Microbial functions that unlock fibre

Evidence that microbes change energy capture

Schematic you can sketch in your notes

Mini-table: determinants of fibre-to-energy efficiency

2. Describe contribution of microbes to nutrient fortification

a) How microbe growth can add nutrients

b) Distinguish macronutrients and micronutrients with examples

3. Describe how diet requirements differ without microbes

a) Contrast energy and nutrient requirements for germ-free vs normal animal

Core contrast

Why requirements diverge

Practical dietary implications

Compact table: diet requirements with and without microbes

L1.3 Regulatory Functions of the Gut

1a. Neuroendocrine regulation of ingestion and translocation

Why food intake must be regulated

Core sensory–response circuits

Table. Examples of intake and transit regulators shown in the lecture

Why different foods create different challenges

1b. Gut-associated lymphoid tissues (GALT) in maintenance of gut function

What “optimal biological composition” means for gut function

How GALT sustains that composition

Antigen sampling and tolerance

Secretory IgA (sIgA)

Antimicrobial and barrier effectors

Colonization resistance

Why spatial distribution matters

Barrier functions along the tract

Lymphoid organization and flow

Compact table

L1.4 The Gut: Homeostasis

Describe the gut–brain axis as a framework for physiological homeostasis

Concept and scope

What is sensed and how signals move

Quick map of signal classes and effects (from slides)

Why this integration is necessary

Where gut signals meet metabolic control