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// ══════════════════════════════════════════════════════════════════════════════
// SLIDES
// ══════════════════════════════════════════════════════════════════════════════

// ── SLIDE 1 — Title ─────────────────────────────────────────────────────────
{
  const s = pres.addSlide();
  titleSlide(s,
    "Neuromuscular Junction\nAnatomy, Physiology & Metabolism",
    "Structure • Function • Neurotransmission • Clinical Correlates"
  );
}

// ── SLIDE 2 — Outline ────────────────────────────────────────────────────────
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  contentSlide(s, "Presentation Outline", [
    "1.  Introduction & Overview of the NMJ",
    "2.  Gross Anatomy of the Motor Unit",
    "3.  Microanatomy of the NMJ",
    "4.  Presynaptic Terminal Ultrastructure",
    "5.  Synaptic Cleft & Basal Lamina",
    "6.  Postsynaptic Membrane & Motor Endplate",
    "7.  Acetylcholine: Synthesis & Storage",
    "8.  Vesicle Pools & Mobilization",
    "9.  SNARE Proteins & Exocytosis",
    "10. Role of Calcium in Transmission",
    "11. Nicotinic Acetylcholine Receptor",
    "12. Endplate Potential & Action Potential",
    "13. Acetylcholinesterase & ACh Removal",
    "14. Choline Recycling",
    "15. NMJ Metabolism & Energy",
    "16–18. NMJ Disorders & Clinical Correlates",
    "19–20. Summary & Key Points",
  ]);
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// ── SLIDE 3 — Section: Introduction ─────────────────────────────────────────
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  sectionDivider(s, "Introduction & Overview", "01");
}

// ── SLIDE 4 — What is the NMJ? ───────────────────────────────────────────────
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  contentSlide(s, "What is the Neuromuscular Junction?", [
    "The neuromuscular junction (NMJ) is the specialized synapse between a motor neuron axon terminal and a skeletal muscle fiber.",
    "It is the point at which an electrical nerve impulse is converted into a chemical signal, which then triggers muscle contraction.",
    "Also called the myoneural junction or motor end plate region.",
    "Key components: presynaptic nerve terminal, synaptic cleft, and postsynaptic motor endplate.",
    "The primary neurotransmitter is acetylcholine (ACh), acting on nicotinic cholinergic (NM) receptors.",
    "Critical for all voluntary movement; dysfunction leads to neuromuscular diseases (myasthenia gravis, Lambert-Eaton syndrome).",
  ], "Source: Ganong's Review of Medical Physiology, 26th Ed.");
}

// ── SLIDE 5 — Historical Context ─────────────────────────────────────────────
{
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  contentSlide(s, "Historical Milestones in NMJ Research", [
    "1906 – Sir Charles Sherrington coined 'synapse'; motor unit concept established.",
    "1936 – Otto Loewi & Henry Dale awarded Nobel Prize for chemical neurotransmission (ACh).",
    "1950s – Bernard Katz described quantal release of ACh using microelectrodes.",
    "1960s – Introduction of electron microscopy revealed ultrastructure of the NMJ.",
    "1970s–80s – Nicotinic ACh receptor (nAChR) isolated, sequenced, and crystallized.",
    "1990s–2000s – SNARE protein machinery of exocytosis fully elucidated.",
    "2000s–present – Molecular imaging of vesicle fusion; therapeutic applications of botulinum toxin.",
  ]);
}

// ── SLIDE 6 — Section: Motor Unit ───────────────────────────────────────────
{
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  sectionDivider(s, "Gross Anatomy: The Motor Unit", "02");
}

// ── SLIDE 7 — Motor Unit ─────────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "The Motor Unit", [
    "Definition: A single motor neuron and all the skeletal muscle fibers it innervates.",
    "Motor neuron origin: anterior horn of the spinal cord (alpha motor neurons) or brainstem motor nuclei.",
    "The axon travels in a peripheral nerve and loses its myelin sheath at the muscle entry point.",
    "Each axon branches into multiple terminal boutons, each innervating one muscle fiber.",
    "Each muscle fiber is innervated by only one motor neuron (single innervation).",
    "Small motor units (e.g., extraocular muscles): ~5–10 fibers → fine motor control.",
    "Large motor units (e.g., quadriceps): ~1000–2000 fibers → power generation.",
    "Motor unit recruitment follows Henneman's size principle: small units recruited first.",
  ], "Source: Ganong's Review of Medical Physiology, 26th Ed.");
}

// ── SLIDE 8 — Axon Terminal Approach ─────────────────────────────────────────
{
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  contentSlide(s, "Axon Terminal & Myelination", [
    "Motor neuron axons are myelinated (Aα fibers, conduction velocity 70–120 m/s).",
    "As the axon approaches the muscle fiber, it loses the myelin sheath.",
    "The bare axon terminal divides into multiple branches called terminal boutons (synaptic knobs).",
    "The terminal bouton is ~1–2 µm in diameter and sits within a groove (gutter) in the muscle membrane.",
    "The groove in the muscle fiber membrane is called the primary synaptic cleft / primary gutter.",
    "Schwann cells cover the surface of the terminal bouton (not the release face), providing trophic support.",
    "The axon is positioned to ensure directed release of ACh toward the postsynaptic receptor-dense region.",
  ]);
}

// ── SLIDE 9 — Section: Microanatomy ─────────────────────────────────────────
{
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  sectionDivider(s, "Microanatomy of the NMJ", "03");
}

// ── SLIDE 10 — NMJ Structure Overview ────────────────────────────────────────
{
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  boxedSlide(s, "Three Zones of the NMJ", [
    {
      title: "Presynaptic Terminal",
      text: "Axon terminal (bouton) — contains synaptic vesicles, mitochondria, active zones, calcium channels, SNARE proteins.",
      color: "E3F2FD"
    },
    {
      title: "Synaptic Cleft",
      text: "~50–70 nm wide. Contains basal lamina with acetylcholinesterase (AChE) anchored to ColQ scaffold protein.",
      color: "E8F5E9"
    },
    {
      title: "Postsynaptic Membrane",
      text: "Motor endplate: highly folded junctional folds (0.5–1 µm deep). nAChRs densely packed at fold crests. ~10,000 receptors/µm².",
      color: "FFF8E1"
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}

// ── SLIDE 11 — Presynaptic Terminal in Detail ────────────────────────────────
{
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  contentSlide(s, "Presynaptic Terminal — Ultrastructure", [
    "Mitochondria: abundant, providing ATP for ACh synthesis, vesicle cycling, ion pumping.",
    "Smooth endoplasmic reticulum: minimal; ACh is synthesized locally by cytoplasmic enzymes.",
    "Synaptic vesicles: ~50 nm diameter, spherical, clear (small-molecule transmitter).",
    "Active zones (AZs): electron-dense membrane specializations directly opposite junctional folds.",
    "Voltage-gated calcium channels (VGCC): P/Q-type (Cav2.1) clustered at active zones.",
    "SNARE proteins: syntaxin-1, SNAP-25 on plasma membrane; synaptobrevin/VAMP on vesicles.",
    "Reserve pool vesicles tethered to actin cytoskeleton by synapsin proteins.",
    "Readily releasable pool: vesicles already docked at active zones, ~50–200 vesicles available per stimulus.",
  ], "Source: Miller's Anesthesia 10e, Chapter 11");
}

// ── SLIDE 12 — Active Zones ───────────────────────────────────────────────────
{
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  contentSlide(s, "Active Zones — The Release Sites", [
    "Active zones (AZs) are electron-dense thickenings of the presynaptic membrane.",
    "Each NMJ contains ~200–300 active zones per terminal bouton.",
    "Active zones are precisely aligned opposite the crests of junctional folds in the postsynaptic membrane.",
    "P/Q-type (Cav2.1) calcium channels are clustered within 10–20 nm of vesicle docking sites.",
    "Scaffolding proteins (ELKS, Bassoon, Piccolo, RIM) organize the active zone matrix.",
    "The close proximity of Ca²⁺ channels and docked vesicles ensures rapid, synchronous release (<1 ms).",
    "This tight coupling minimizes latency from membrane depolarization to ACh release.",
    "Spacing between active zones and junctional folds ensures maximal receptor activation per quantum.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 13 — Synaptic Cleft & Basal Lamina ─────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Synaptic Cleft & Basal Lamina", [
    "The synaptic cleft is ~50–70 nm wide — comparable to neuron-to-neuron synaptic clefts.",
    "The cleft is filled with a specialized basal lamina (extracellular matrix).",
    "Key basal lamina components: laminin, agrin, perlecan, nidogen, collagen IV.",
    "Agrin (secreted by motor neuron): instructs clustering of nAChRs via MuSK–LRP4 signaling.",
    "Acetylcholinesterase (AChE): anchored to basal lamina via ColQ collagenic tail — rapidly terminates ACh signaling.",
    "Concentration of AChE in cleft: ~3000 AChE active sites/µm² — extremely high density.",
    "Basal lamina also contains neuregulin-1 (ErbB signaling) for NMJ maintenance and repair.",
    "The basal lamina persists after muscle degeneration and guides reinnervation.",
  ]);
}

// ── SLIDE 14 — Postsynaptic Membrane ─────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Postsynaptic Membrane — The Motor Endplate", [
    "The motor endplate is the thickened, specialized region of the muscle plasma membrane (sarcolemma).",
    "Extensive junctional folds amplify postsynaptic surface area ~10-fold.",
    "Fold crests: dense with nAChRs (~10,000/µm²), facing the active zones directly.",
    "Fold troughs: contain voltage-gated Na⁺ channels (Nav1.4) — generate action potential.",
    "The separation of nAChRs (crests) and Nav channels (troughs) focuses signal amplification.",
    "Rapsyn: scaffold protein that anchors and clusters nAChRs at fold crests.",
    "Dystrophin-glycoprotein complex (DGC): links cytoskeleton to basal lamina, maintaining structural integrity.",
    "MuSK (muscle-specific kinase): critical for NMJ formation, nAChR clustering, and maintenance.",
  ]);
}

// ── SLIDE 15 — Section: ACh Synthesis ────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Acetylcholine: Synthesis & Storage", "04");
}

// ── SLIDE 16 — ACh Synthesis ─────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Acetylcholine Synthesis", [
    "ACh is synthesized in the cytoplasm of the presynaptic nerve terminal.",
    "Reaction: Choline + Acetyl-CoA → Acetylcholine + CoA",
    "Enzyme: Choline acetyltransferase (ChAT) — the rate-limiting enzyme.",
    "ChAT is synthesized in the motor neuron cell body and transported to the terminal by axonal transport.",
    "Choline source: ~50% from hydrolysis of ACh by AChE (recycling), remainder from plasma via high-affinity choline transporter (CHT1).",
    "Acetyl-CoA source: mitochondrial oxidative metabolism (pyruvate decarboxylation).",
    "ACh synthesis is very rapid — capable of sustaining extremely high rates of release.",
    "Rate-limiting step during high-frequency stimulation: availability of choline (not ChAT activity).",
  ], "Source: Ganong's 26e; Katzung Pharmacology 16e");
}

// ── SLIDE 17 — ACh Storage in Vesicles ───────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Acetylcholine Storage — Synaptic Vesicles", [
    "Newly synthesized ACh is packaged into synaptic vesicles.",
    "Vesicular acetylcholine transporter (VAChT): uses H⁺ gradient to actively pump ACh into vesicles.",
    "VAChT is driven by vacuolar H⁺-ATPase (proton pump) maintaining vesicle interior at pH ~5.5.",
    "Each vesicle contains a quantum of ~5,000–10,000 ACh molecules.",
    "At rest (~70–80 mV), spontaneous fusion of single vesicles produces miniature endplate potentials (MEPPs): ~0.5 mV amplitude.",
    "MEPP frequency ~1/sec reflects baseline 'leakage' of vesicles — important indicator of NMJ health.",
    "Storage also co-packs ATP with ACh; ATP may act as cotransmitter on purinergic receptors.",
    "Storage vesicles also contain synaptophysin (glycoprotein marker), synaptotagmin (Ca²⁺ sensor), and synapsin.",
  ], "Source: Miller's Anesthesia 10e; Ganong's 26e");
}

// ── SLIDE 18 — Vesicle Pools ──────────────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Vesicle Pools & Mobilization", "05");
}

// ── SLIDE 19 — VP1 and VP2 Pools ─────────────────────────────────────────────
{
  const s = pres.addSlide();
  twoColSlide(s,
    "Two Vesicle Pools: VP1 (Reserve) & VP2 (Readily Releasable)",
    [
      "VP1 = Reserve pool (majority of vesicles)",
      "Tethered to actin cytoskeleton",
      "Held by synapsin (actin-binding protein)",
      "Also anchored by synaptotagmin and spectrin",
      "Located deep in the nerve terminal",
      "Mobilized during prolonged/intense stimulation",
      "Ca²⁺-dependent phosphorylation of synapsin releases VP1 vesicles",
      "Ensures sustained transmission under fatigue conditions",
    ],
    [
      "VP2 = Readily Releasable Pool (RRP)",
      "Smaller, located adjacent to active zones",
      "Already docked at release sites",
      "Immediately available for Ca²⁺-triggered fusion",
      "~50–200 vesicles per bouton in RRP",
      "Depleted rapidly during tetanic stimulation",
      "Replenished from VP1 (mobilization process)",
      "Mobilization rate determines short-term plasticity",
    ],
    "VP1: Reserve Pool", "VP2: Readily Releasable"
  );
}

// ── SLIDE 20 — Mobilization ───────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Vesicle Mobilization & Replenishment", [
    "Mobilization = all steps maintaining the terminal's capacity to release ACh.",
    "Includes: choline uptake → ACh synthesis → vesicle filling → transport to release sites.",
    "Rate-limiting steps: high-affinity choline uptake (CHT1) and ChAT enzyme activity.",
    "During tetanic stimulation, Ca²⁺ activates calmodulin-dependent kinase II (CaMKII).",
    "CaMKII phosphorylates synapsin → breaks actin linkage → VP1 vesicles mobilized to RRP.",
    "Posttetanic potentiation (PTP): residual Ca²⁺ in terminal causes more ACh release per impulse.",
    "PTP explains temporary reversal of neuromuscular block after tetanic stimulation (posttetanic facilitation).",
    "Hemicholinium-3 blocks CHT1 → depletes ACh stores → progressive neuromuscular weakness.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 21 — Section: SNARE Proteins ───────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "SNARE Proteins & Exocytosis", "06");
}

// ── SLIDE 22 — SNARE Overview ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  boxedSlide(s, "SNARE Protein Complex — Key Players", [
    {
      title: "Synaptobrevin (VAMP)",
      text: "v-SNARE on synaptic vesicle membrane. Coils around t-SNAREs to drive fusion. Cleaved by tetanus & botulinum B toxins.",
      color: "E3F2FD"
    },
    {
      title: "Syntaxin-1",
      text: "t-SNARE on presynaptic plasma membrane. Partner of SNAP-25. Cleaved by botulinum toxins C1 and A (partial).",
      color: "E8F5E9"
    },
    {
      title: "SNAP-25",
      text: "t-SNARE on plasma membrane. Two coiled-coil domains. Cleaved by botulinum toxins A, C1, E. Critical for vesicle docking.",
      color: "FFF8E1"
    },
    {
      title: "Synaptotagmin-1",
      text: "Ca²⁺ sensor on vesicle. Binds Ca²⁺ via C2 domains. Triggers final fusion pore opening. Also recruits vesicles to active zones.",
      color: "FCE4EC"
    },
    {
      title: "NSF / α-SNAP",
      text: "ATPase complex that disassembles SNARE complexes after fusion, recycling SNARE proteins for next round of exocytosis.",
      color: "F3E5F5"
    },
    {
      title: "Munc18 / Munc13",
      text: "Regulatory proteins. Munc13 primes vesicles for release. Munc18 stabilizes syntaxin conformation. Essential for fusion competence.",
      color: "E0F7FA"
    },
  ]);
}

// ── SLIDE 23 — Exocytosis Step by Step ───────────────────────────────────────
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  const s = pres.addSlide();
  contentSlide(s, "Process of Exocytosis — Step by Step", [
    "Step 1 — Tethering: Vesicle moves toward active zone; Rab3A-RIM interactions capture vesicle near release site.",
    "Step 2 — Docking: Synaptobrevin on vesicle makes initial contact with syntaxin/SNAP-25 on plasma membrane.",
    "Step 3 — Priming: SNARE complex (ternary coil) assembles under Munc13 guidance → vesicle becomes fusion-competent.",
    "Step 4 — Ca²⁺ triggering: Synaptotagmin-1 binds 2–5 Ca²⁺ ions → electrostatic barrier removed → fusion pore opens.",
    "Step 5 — Fusion pore: Lipid bilayers merge; ACh flows into synaptic cleft within <1 ms of Ca²⁺ entry.",
    "Step 6 — Endocytosis/recycling: Vesicle membrane retrieved via clathrin-mediated ('compensatory') or 'kiss-and-run' mechanisms.",
    "One nerve impulse triggers release of ~60–100 quanta of ACh simultaneously.",
    "ACh reaches postsynaptic receptors in <0.1 ms given the narrow cleft.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 24 — Botulinum Toxin & SNARE ────────────────────────────────────────
{
  const s = pres.addSlide();
  tableSlide(s,
    "Botulinum Toxin — SNARE Protein Targets",
    ["Toxin Type", "Target SNARE", "Cleavage Site", "Clinical Effect"],
    [
      ["BoNT/A", "SNAP-25", "Gln197-Arg198", "Flaccid paralysis; cosmetic / spasticity use"],
      ["BoNT/B", "Synaptobrevin-2 (VAMP)", "Gln76-Phe77", "Cervical dystonia treatment"],
      ["BoNT/C1", "Syntaxin-1 & SNAP-25", "Lys253-Ala254", "Experimental / rare poisoning"],
      ["BoNT/E", "SNAP-25", "Arg180-Ile181", "Infant botulism; food poisoning"],
      ["Tetanus toxin", "Synaptobrevin-2 (VAMP)", "Same as BoNT/B", "Spastic paralysis (retrograde transport → inhibitory neurons)"],
    ]
  );
}

// ── SLIDE 25 — Section: Calcium ───────────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Role of Calcium in Transmission", "07");
}

// ── SLIDE 26 — Calcium Entry ─────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Calcium Channels & Vesicle Release", [
    "Primary channels: P/Q-type (Cav2.1) — exclusively located at presynaptic active zones.",
    "Action potential → depolarization → Cav2.1 channels open within 0.1–0.2 ms.",
    "Ca²⁺ concentration at release site rises from ~100 nM (resting) to ~100–300 µM (local microdomain).",
    "Quantal content is proportional to [Ca²⁺]⁴ — extremely sensitive to small changes in extracellular Ca²⁺.",
    "Doubling extracellular Ca²⁺ → 16-fold increase in quantal content (cooperative effect).",
    "K⁺ channels (voltage-gated + Ca²⁺-activated) repolarize terminal, limiting Ca²⁺ influx duration.",
    "Mg²⁺ competes with Ca²⁺ at P-channels → neuromuscular block (relevant in Mg²⁺ therapy for preeclampsia).",
    "L-type (Cav1) channels NOT significantly involved in NMJ ACh release (cardiovascular L-channel blockers do not block NMJ transmission).",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 27 — Calcium Pathology ─────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Calcium Abnormalities & NMJ Disease", [
    "Lambert-Eaton Myasthenic Syndrome (LEMS): autoimmune antibodies target Cav2.1 (P/Q-type) channels.",
    "→ Decreased Ca²⁺ entry → reduced ACh release → proximal muscle weakness.",
    "→ Unlike myasthenia gravis: strength improves with repetitive stimulation (Ca²⁺ accumulates).",
    "Hypermagnesemia (Mg²⁺ therapy): competitively blocks Ca²⁺ entry → potentiates NMJ block.",
    "Hypokalemia/hypermagnesemia: amplifies effects of non-depolarizing muscle relaxants (NDMRs).",
    "Posttetanic Potentiation (PTP): rapid stimulation → Ca²⁺ accumulates in terminal → excessive ACh release.",
    "→ Clinically seen as posttetanic facilitation in patients under NDMR blockade.",
    "4-Aminopyridine (4-AP): blocks K⁺ channels → prolongs depolarization → increases Ca²⁺ entry → reverses LEMS weakness.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 28 — Section: nAChR ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Nicotinic Acetylcholine Receptor (nAChR)", "08");
}

// ── SLIDE 29 — nAChR Structure ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "nAChR — Molecular Structure", [
    "Pentameric ligand-gated ion channel: composed of 5 subunits arranged around a central pore.",
    "Adult (mature) NMJ receptor: α1₂β1δε (two α, one β, one δ, one ε subunit).",
    "Fetal/denervated receptor: α1₂β1δγ (γ replaces ε) — broader conductance, longer open time.",
    "Each subunit has 4 transmembrane domains (TM1–TM4); TM2 lines the ion channel pore.",
    "Two ACh binding sites: at the α1/δ and α1/ε subunit interfaces.",
    "Both sites must be occupied by ACh to open the channel ('dual binding' requirement).",
    "Ion channel pore: non-selective cation channel; conducts Na⁺ (in) and K⁺ (out).",
    "Resting conductance: ~40–50 pS; open time ~1 ms at body temperature.",
  ], "Source: Katzung Pharmacology 16e; Goodman & Gilman");
}

// ── SLIDE 30 — nAChR Activation ──────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "nAChR Activation & Ion Flow", [
    "ACh binds both α subunits → conformational change → channel opens.",
    "Channel open state allows simultaneous influx of Na⁺ and efflux of K⁺.",
    "Net effect: predominantly Na⁺ influx → membrane depolarizes.",
    "Single channel opening produces a miniature endplate current (MEPC): ~4 nA.",
    "Endplate potential (EPP): summated response from ~200–300 channel openings.",
    "EPP amplitude: ~40–70 mV above resting membrane potential.",
    "Safety factor of transmission: EPP greatly exceeds threshold (~35 mV above rest) → reliable 1:1 nerve-to-muscle coupling.",
    "The safety factor is the key reason NMJ is so reliable — any drug or disease that lowers EPP risks block.",
  ], "Source: Ganong's 26e");
}

// ── SLIDE 31 — Receptor States ───────────────────────────────────────────────
{
  const s = pres.addSlide();
  boxedSlide(s, "nAChR Functional States", [
    {
      title: "Resting State",
      text: "Channel closed. Low affinity for ACh. Default state at membrane potential of -90 mV.",
      color: "E8F5E9"
    },
    {
      title: "Activated State",
      text: "Both ACh binding sites occupied. Channel open. Duration ~1 ms. Na⁺ influx → EPP.",
      color: "E3F2FD"
    },
    {
      title: "Desensitized State",
      text: "Channel closed despite ACh bound. High ACh affinity. Prolonged agonist exposure causes desensitization. Clinical relevance: succinylcholine phase II block.",
      color: "FCE4EC"
    },
    {
      title: "Blocked State",
      text: "Non-depolarizing agents (tubocurarine, rocuronium) competitively block ACh binding. Depolarizing agents (succinylcholine) cause persistent depolarization → desensitization.",
      color: "FFF8E1"
    },
  ]);
}

// ── SLIDE 32 — Section: EPP & AP ────────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Endplate Potential & Muscle Action Potential", "09");
}

// ── SLIDE 33 — From EPP to AP ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "From Nerve Impulse to Muscle Contraction", [
    "Sequence: Nerve AP → Ca²⁺ entry → ACh release → ACh diffuses across cleft.",
    "ACh binds nAChRs → channel opens → Na⁺ influx → endplate potential (EPP).",
    "EPP is a local, graded depolarization centered at the motor endplate.",
    "EPP spreads electrotonically to adjacent sarcolemma containing Nav1.4 channels.",
    "When EPP depolarization reaches threshold (~-55 mV), Nav1.4 channels open → muscle action potential (MAP).",
    "MAP propagates along T-tubule network → triggers Ca²⁺ release from SR (excitation-contraction coupling).",
    "Ca²⁺ from SR binds troponin C → conformational shift → cross-bridge cycling → muscle contraction.",
    "Latency from nerve AP to muscle twitch: ~3–5 ms (includes all NMJ steps + EC coupling).",
  ], "Source: Ganong's 26e; Miller's Anesthesia 10e");
}

// ── SLIDE 34 — Safety Factor ─────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Safety Factor of Neuromuscular Transmission", [
    "The safety factor is the excess EPP amplitude beyond that required to reach threshold for MAP generation.",
    "Normal EPP (~70 mV) greatly exceeds threshold (~35 mV above resting) → safety factor ~3–4×.",
    "This margin ensures reliable transmission even if ACh release is reduced.",
    "Clinical significance: significant reduction in nAChR number (myasthenia gravis) or ACh release (LEMS) needed before weakness becomes apparent.",
    "In myasthenia gravis: antibodies reduce functional nAChRs by ~70–80% before symptomatic block occurs.",
    "Neuromuscular blocking drugs work by reducing EPP below threshold — 75–80% receptor occupancy needed for clinical paralysis.",
    "Factors that reduce safety factor: disease, temperature (↓ → slower acetylcholinesterase → prolonged channel desensitization), acidosis, antibiotics (aminoglycosides).",
    "Monitoring with train-of-four (TOF) stimulation assesses degree of remaining neuromuscular block.",
  ], "Source: Miller's Anesthesia 10e; Ganong's 26e");
}

// ── SLIDE 35 — MEPPs ────────────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Miniature Endplate Potentials (MEPPs)", [
    "Spontaneous, random fusion of single vesicles at rest produces MEPPs.",
    "Each MEPP = ~0.5 mV, lasting ~5–10 ms.",
    "MEPPs occur at a frequency of ~1–2 per second per endplate.",
    "First described by Bernard Katz (1950s) — key evidence for quantal hypothesis.",
    "MEPP amplitude ∝ number of ACh molecules per vesicle (quantum size).",
    "MEPP frequency reflects presynaptic terminal health and vesicle recycling.",
    "Reduced MEPP frequency: botulinum toxin poisoning, Lambert-Eaton syndrome.",
    "Reduced MEPP amplitude: myasthenia gravis (fewer functional receptors per quantum).",
    "Increased MEPP frequency: anticholinesterase treatment, black widow spider venom (alpha-latrotoxin).",
  ], "Source: Ganong's 26e");
}

// ── SLIDE 36 — Section: AChE ─────────────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Acetylcholinesterase & ACh Removal", "10");
}

// ── SLIDE 37 — AChE Structure ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Acetylcholinesterase — Structure & Location", [
    "AChE is one of the fastest enzymes known — can hydrolyze ~25,000 ACh molecules per second per active site.",
    "At the NMJ, AChE is anchored in the synaptic basal lamina via the ColQ collagen-like protein.",
    "Density: ~3,000 AChE active sites per µm² in the synaptic cleft.",
    "Molecular structure: symmetric tetramer (A12 form) — 12 catalytic subunits anchored by ColQ tail.",
    "Active site: serine esterase — serine 203, histidine 447, glutamate 334 (catalytic triad).",
    "ACh hydrolysis reaction: ACh + H₂O → Choline + Acetate (catalyzed by AChE).",
    "Products: choline (recycled) + acetate (enters metabolic pool).",
    "High density ensures ACh is degraded within ~50 µs of receptor binding — prevents receptor desensitization.",
  ], "Source: Miller's Anesthesia 10e; Goodman & Gilman");
}

// ── SLIDE 38 — AChE Inhibitors ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  tableSlide(s,
    "Acetylcholinesterase Inhibitors — Clinical Overview",
    ["Drug", "Type", "Mechanism", "Clinical Use"],
    [
      ["Neostigmine", "Reversible (carbamate)", "Carbamylates AChE serine; competes with ACh", "Reversal of NDMR block; myasthenia gravis"],
      ["Pyridostigmine", "Reversible (carbamate)", "Similar to neostigmine, longer duration", "Chronic myasthenia gravis treatment"],
      ["Edrophonium", "Reversible (electrostatic)", "Electrostatic/H-bond to AChE; rapid onset/offset", "Tensilon test (MG diagnosis)"],
      ["Physostigmine", "Reversible (carbamate)", "Tertiary amine; crosses BBB", "Atropine toxicity; central anticholinergic syndrome"],
      ["Organophosphates (sarin, VX)", "Irreversible", "Phosphorylate AChE serine permanently", "Nerve agent poisoning; treat with atropine + pralidoxime"],
      ["Suxamethonium (succinylcholine)", "Depolarizing NMB, not AChE inhibitor", "Mimics ACh; persistent depolarization", "Rapid-sequence induction"],
    ]
  );
}

// ── SLIDE 39 — Section: Choline Recycling ─────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Choline Recycling & NMJ Metabolism", "11");
}

// ── SLIDE 40 — Choline Recycling ──────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Choline Recycling — Closing the Loop", [
    "After ACh hydrolysis: choline released into the synaptic cleft.",
    "Choline is recaptured by high-affinity choline transporter (CHT1 / SLC5A7) on the presynaptic membrane.",
    "CHT1 is Na⁺-coupled — uses electrochemical Na⁺ gradient for choline uptake against concentration.",
    "~50% of choline from ACh hydrolysis is recycled back for re-synthesis.",
    "CHT1 is rate-limiting for ACh re-synthesis during high-frequency stimulation.",
    "CHT1 expression is up-regulated during nerve activity (activity-dependent choline transport).",
    "Hemicholinium-3 (HC-3): selective CHT1 blocker → depletes ACh stores → progressive neuromuscular weakness.",
    "Choline can also be obtained from diet (phosphatidylcholine) and delivered via plasma.",
  ], "Source: Ganong's 26e; Miller's Anesthesia 10e");
}

// ── SLIDE 41 — NMJ Energy Metabolism ─────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Energy Metabolism at the NMJ", [
    "The presynaptic terminal has very high metabolic demands — rich in mitochondria.",
    "ATP is required for: vesicle loading (VAChT H⁺-ATPase), choline transport (CHT1), ion pump restoration (Na⁺/K⁺-ATPase), actin dynamics.",
    "ACh synthesis: acetyl-CoA (from mitochondrial pyruvate oxidation) + choline → ACh.",
    "Mitochondria occupy ~50% of terminal volume — underscore metabolic dependency.",
    "Na⁺/K⁺-ATPase restores resting membrane potential after action potentials — ATP-dependent.",
    "Failure of mitochondrial function (e.g., mitochondrial myopathies) impairs NMJ transmission.",
    "Metabolic acidosis: reduces EPP amplitude; hypoxia impairs vesicle recycling and transmitter resynthesis.",
    "Hypothermia: slows AChE activity, ChAT activity, and vesicle recycling — prolongs neuromuscular block.",
  ]);
}

// ── SLIDE 42 — Vesicle Recycling ─────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Synaptic Vesicle Recycling Pathways", [
    "After exocytosis, vesicle membrane must be retrieved to maintain terminal homeostasis.",
    "Three modes of retrieval identified by live imaging:",
    "→ 'Kiss-and-run': pore opens briefly then closes; vesicle retains shape; fast recycling.",
    "→ 'Compensatory endocytosis': full fusion, then clathrin-mediated retrieval at periactive zone.",
    "→ 'Stranded': complete collapse; retrieved only after next stimulus.",
    "Clathrin-mediated endocytosis: AP-2/clathrin coat forms; dynamin pinches off vesicle; ~60–90 sec cycle.",
    "Retrieved membranes are refilled with ACh via VAChT and returned to reserve pool.",
    "Activity-dependent bulk endocytosis (ADBE): observed at high stimulation frequencies; clathrin-independent.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 43 — Section: NMJ Development ──────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "NMJ Development & Maintenance", "12");
}

// ── SLIDE 44 — NMJ Formation ─────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "NMJ Development — Key Molecular Steps", [
    "Step 1 — Innervation: motor axon grows toward muscle; muscle pre-clusters nAChRs (MuSK-dependent, agrin-independent initially).",
    "Step 2 — Agrin secretion: motor nerve releases agrin into synaptic basal lamina.",
    "Step 3 — MuSK activation: agrin binds LRP4 → LRP4–MuSK complex activates → nAChR clustering stabilized.",
    "Step 4 — Retrograde signaling: muscle signals (neuregulin, BDNF) regulate presynaptic differentiation.",
    "Step 5 — Synaptic competition: multiple motor axons initially innervate each fiber; activity-dependent elimination retains one axon.",
    "Step 6 — Maturation: γ→ε subunit switch (AChR); junctional folds deepen; active zones align with folds.",
    "Rapsyn: indispensable scaffold for nAChR clustering; rapsyn mutations → congenital myasthenic syndrome.",
    "MuSK mutations/antibodies (anti-MuSK MG): impair clustering → myasthenia gravis phenotype.",
  ]);
}

// ── SLIDE 45 — NMJ Maintenance & Plasticity ───────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "NMJ Maintenance, Plasticity & Aging", [
    "Adult NMJ requires continuous trophic signals from motor neuron (neuregulin-1/ErbB2/4 signaling) and muscle.",
    "Denervation: muscle produces new nAChRs (γ-type, fetal isoform) across entire sarcolemma (extrajunctional spread).",
    "→ Clinical significance: succinylcholine in denervated/burned/immobilized patients → massive K⁺ efflux → life-threatening hyperkalemia.",
    "Exercise: increases size and complexity of NMJ; more vesicle docking sites; greater safety factor.",
    "Disuse atrophy: NMJ shrinks; fewer active zones and vesicles.",
    "Aging: NMJ fragmentation; reduced active zones; decreased quantal content → contributes to sarcopenia.",
    "Neuromuscular repair: basal lamina guides reinnervation after nerve injury; AChE and laminin marks persist.",
    "BDNF (brain-derived neurotrophic factor): promotes NMJ remodeling and maintains presynaptic terminal structure.",
  ]);
}

// ── SLIDE 46 — Section: Neuromuscular Pharmacology ────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Neuromuscular Blocking Drugs", "13");
}

// ── SLIDE 47 — NMBDs Overview ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  twoColSlide(s,
    "Neuromuscular Blocking Drugs (NMBDs) — Overview",
    [
      "DEPOLARIZING NMBDs",
      "Only drug: Succinylcholine (suxamethonium)",
      "Mimics ACh → persistent depolarization",
      "Phase I block: fasciculations then flaccid paralysis",
      "Phase II: desensitization (>5 mg/kg or infusion)",
      "Reversed by plasma pseudocholinesterase",
      "Not reversed by neostigmine (in Phase I)",
      "Contraindicated: denervation, burns, immobility",
      "Risks: malignant hyperthermia trigger, hyperkalemia",
    ],
    [
      "NON-DEPOLARIZING NMBDs",
      "Competitive antagonists of nAChRs",
      "Examples: rocuronium, vecuronium, atracurium, cisatracurium, pancuronium, mivacurium",
      "No fasciculations; smooth onset of paralysis",
      "Reversed by: neostigmine + glycopyrrolate (traditional) or sugammadex (rocuronium/vecuronium)",
      "Mechanism of reversal: increase ACh (neostigmine) or encapsulate drug (sugammadex)",
      "TOF ratio used to monitor degree of block",
      "Potentiated by: volatile agents, Mg²⁺, acidosis, hypothermia, aminoglycosides",
    ],
    "Depolarizing", "Non-Depolarizing"
  );
}

// ── SLIDE 48 — NMBDs Table ───────────────────────────────────────────────────
{
  const s = pres.addSlide();
  tableSlide(s,
    "Non-Depolarizing NMBDs — Comparison",
    ["Drug", "Onset (min)", "Duration", "Metabolism/Excretion", "Notes"],
    [
      ["Rocuronium", "1–2", "Intermediate (30–60 min)", "Hepatic/biliary", "Fast onset; reversible with sugammadex"],
      ["Vecuronium", "2–3", "Intermediate (25–40 min)", "Hepatic/biliary", "CV stable; accumulates in liver failure"],
      ["Cisatracurium", "3–5", "Intermediate (40–60 min)", "Hofmann elimination", "Organ-independent; ICU use"],
      ["Atracurium", "2–3", "Intermediate (30–45 min)", "Hofmann + ester", "Histamine release possible"],
      ["Pancuronium", "3–4", "Long (60–90 min)", "Renal/hepatic", "Tachycardia; avoid in cardiac disease"],
      ["Mivacurium", "2–3", "Short (15–20 min)", "Plasma cholinesterase", "Short-acting; prolonged in pseudocholinesterase deficiency"],
    ]
  );
}

// ── SLIDE 49 — Monitoring NMJ ────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Monitoring Neuromuscular Blockade", [
    "Peripheral nerve stimulator (PNS) applied over ulnar nerve; adductor pollicis muscle response measured.",
    "Train-of-Four (TOF): 4 stimuli at 2 Hz; TOF ratio = T4/T1.",
    "→ TOF < 0.25: deep block (only 1–2 twitches visible).",
    "→ TOF 0.75–0.9: adequate reversal for extubation (old threshold 0.7).",
    "→ TOF ≥ 0.9: considered full recovery of NMJ function (current threshold).",
    "Double-burst stimulation (DBS): two bursts of 50 Hz — detects residual block more sensitively than TOF.",
    "Post-tetanic count (PTC): assesses deep block when TOF count = 0.",
    "Quantitative TOF (acceleromyography or kinemyography) superior to subjective assessment.",
    "Residual neuromuscular block at extubation increases risk of airway obstruction and aspiration.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 50 — Section: NMJ Disorders ────────────────────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "NMJ Disorders — Clinical Correlates", "14");
}

// ── SLIDE 51 — Myasthenia Gravis ─────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Myasthenia Gravis (MG)", [
    "Autoimmune disorder targeting postsynaptic nAChRs (or MuSK, LRP4 in seronegative MG).",
    "Anti-nAChR IgG antibodies in ~85%: cause receptor degradation, complement-mediated destruction, and functional block.",
    "Pathology: reduced nAChR density; simplification of junctional folds; widened synaptic cleft.",
    "Result: reduced EPP amplitude → falls below threshold for MAP generation → muscle weakness.",
    "Hallmark: fatigable weakness — worsens with activity, improves with rest.",
    "Extraocular muscles frequently affected first (ptosis, diplopia); bulbar and limb involvement later.",
    "Diagnosis: positive Tensilon (edrophonium) test; anti-nAChR antibodies; repetitive nerve stimulation shows decrement.",
    "Treatment: acetylcholinesterase inhibitors (pyridostigmine); immunosuppression; thymectomy; IVIG/plasma exchange for crisis.",
  ], "Source: Ganong's 26e; Bradley & Daroff Neurology");
}

// ── SLIDE 52 — Lambert-Eaton Syndrome ────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Lambert-Eaton Myasthenic Syndrome (LEMS)", [
    "Presynaptic NMJ disorder — autoimmune antibodies target voltage-gated Ca²⁺ channels (Cav2.1).",
    "50–60% associated with small-cell lung carcinoma (paraneoplastic).",
    "Result: reduced Ca²⁺ entry → reduced ACh quantal release per stimulus.",
    "Hallmark: proximal muscle weakness (legs > arms) with IMPROVEMENT on repetitive stimulation.",
    "Autonomic dysfunction: dry mouth, impotence, constipation (Ca²⁺ channels also in autonomic terminals).",
    "Electrophysiology: low-amplitude CMAP at rest; increment on repetitive 50 Hz stimulation (>100%).",
    "Diagnosis: anti-VGCC antibodies (P/Q-type); EMG pattern; tumor workup.",
    "Treatment: 3,4-diaminopyridine (3,4-DAP) → blocks K⁺ channels → prolongs depolarization → more Ca²⁺ entry; IVIg; treat underlying malignancy.",
  ], "Source: Bradley & Daroff Neurology; Miller's Anesthesia 10e");
}

// ── SLIDE 53 — Congenital Myasthenic Syndromes ───────────────────────────────
{
  const s = pres.addSlide();
  tableSlide(s,
    "Congenital Myasthenic Syndromes (CMS) — Key Types",
    ["Type", "Defective Protein", "Mechanism", "Hallmark Feature"],
    [
      ["Presynaptic CMS", "ChAT, VAChT", "Reduced ACh synthesis or vesicle loading", "Episodic apnea; worse with fever/illness"],
      ["Slow-Channel CMS", "nAChR (gain-of-function)", "Prolonged channel opening → Ca²⁺ overload", "Slowly progressive; focal muscle atrophy"],
      ["Fast-Channel CMS", "nAChR (loss-of-function)", "Shortened channel opening → reduced EPP", "Similar to seronegative MG"],
      ["Rapsyn deficiency", "Rapsyn scaffold protein", "Impaired nAChR clustering", "Neonatal hypotonia; ptosis; apnea"],
      ["MuSK CMS", "MuSK kinase", "Impaired agrin signaling → poor nAChR clustering", "Variable; bulbar weakness"],
      ["AChE deficiency (ColQ)", "ColQ collagen tail", "AChE absent from cleft → excessive depolarization", "Worsened by AChEIs"],
    ]
  );
}

// ── SLIDE 54 — Botulism ──────────────────────────────────────────────────────
{
  const s = pres.addSlide();
  contentSlide(s, "Botulism — Presynaptic NMJ Poisoning", [
    "Caused by Clostridium botulinum neurotoxin (BoNT) types A–G.",
    "Mechanism: BoNT heavy chain binds polysialogangliosides on presynaptic membrane → endocytosis.",
    "BoNT light chain escapes vesicle → cleaves SNARE proteins → ACh release blocked.",
    "Result: flaccid descending paralysis, autonomic dysfunction, cranial nerve palsies.",
    "Foodborne botulism: pre-formed toxin ingested. Wound botulism: spores germinate in wound. Infant botulism: spore ingestion in neonates (honey).",
    "Diagnosis: clinical picture + mouse bioassay + ELISA for toxin.",
    "Treatment: antitoxin (equine heptavalent); supportive care; mechanical ventilation if needed.",
    "Therapeutic use: BoNT/A (Botox) — focal injection for spasticity, dystonias, hyperhidrosis, cosmetic wrinkles.",
  ], "Source: Miller's Anesthesia 10e");
}

// ── SLIDE 55 — Section: Clinical Pharmacology Table ──────────────────────────
{
  const s = pres.addSlide();
  sectionDivider(s, "Drugs Acting at the NMJ — Full Summary", "15");
}

// ── SLIDE 56 — Drugs Acting at NMJ ────────────────────────────────────────────
{
  const s = pres.addSlide();
  tableSlide(s,
    "Drug Targets at the NMJ",
    ["Target", "Drug / Toxin", "Effect"],
    [
      ["ChAT (ACh synthesis)", "Hemicholinium-3", "Blocks choline uptake → depletes ACh"],
      ["VAChT (vesicle loading)", "Vesamicol", "Blocks VAChT → prevents ACh storage"],
      ["Ca²⁺ channels (Cav2.1)", "ω-conotoxin, Mg²⁺", "Blocks Ca²⁺ entry → reduces ACh release"],
      ["SNARE proteins", "Botulinum toxins A–G, Tetanus toxin", "Cleaves SNAREs → blocks ACh release"],
      ["Vesicle exocytosis (non-SNARE)", "Alpha-latrotoxin (black widow venom)", "Massive ACh release → depolarization block"],
      ["nAChR (competitive block)", "Rocuronium, curare, tubocurarine", "Competitive antagonism → no EPP"],
      ["nAChR (depolarizing)", "Succinylcholine, nicotine (high)", "Persistent depolarization → desensitization"],
      ["AChE", "Neostigmine, organophosphates", "Inhibit ACh hydrolysis → ↑ ACh in cleft"],
      ["K⁺ channels", "4-Aminopyridine", "Prolongs depolarization → ↑ Ca²⁺ → ↑ ACh release"],
    ]
  );
}

// ── SLIDE 57 — Section: Summary ───────────────────────────────────────────────
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// ── SLIDE 58 — Key Summary Points ────────────────────────────────────────────
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  contentSlide(s, "Key Summary Points — Part 1", [
    "The NMJ converts a nerve action potential into muscle contraction via chemical neurotransmission.",
    "Three structural zones: presynaptic terminal, synaptic cleft (50–70 nm), and postsynaptic motor endplate.",
    "Acetylcholine synthesized from choline + acetyl-CoA by ChAT; stored in vesicles (~10,000 molecules each).",
    "Two vesicle pools: VP1 (reserve, tethered to cytoskeleton) and VP2 (readily releasable, at active zones).",
    "Exocytosis triggered by Ca²⁺ entry via P/Q-type channels; SNARE complex (synaptobrevin/syntaxin/SNAP-25) drives fusion.",
    "Calcium is the critical variable — quantal content ∝ [Ca²⁺]⁴.",
    "nAChR: pentameric (α₁₂β₁δε); dual ACh binding → cation channel opens → Na⁺ influx → EPP.",
    "Normal EPP far exceeds threshold for MAP → high safety factor ensures reliable 1:1 transmission.",
  ]);
}

// ── SLIDE 59 — Key Summary Points 2 ─────────────────────────────────────────
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    "AChE hydrolyzes ACh within the synaptic cleft in ~50 µs — terminating the signal.",
    "Choline recycled by CHT1 back into presynaptic terminal for re-synthesis.",
    "NMJ development requires agrin → LRP4/MuSK signaling for nAChR clustering.",
    "Denervation → extrajunctional γ-nAChRs → hyperkalemia with succinylcholine.",
    "Myasthenia gravis: postsynaptic (anti-nAChR/MuSK antibodies); fatigable weakness; treat with AChEI + immunosuppression.",
    "Lambert-Eaton: presynaptic (anti-Cav2.1 antibodies); strength improves with repetition; treat with 3,4-DAP.",
    "Botulinum toxin: SNARE cleavage → no ACh release; flaccid paralysis; therapeutic and cosmetic uses.",
    "Non-depolarizing NMBDs monitored by TOF; reversed by neostigmine or sugammadex.",
  ]);
}

// ── SLIDE 60 — Thank You ──────────────────────────────────────────────────────
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// ── WRITE FILE ────────────────────────────────────────────────────────────────
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