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// ─── Helpers ─────────────────────────────────────────────────

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

// --- SLIDE 1: TITLE ---
titleSlide(
  "Neuromuscular Junction (NMJ)",
  "Anatomy • Physiology • Metabolism\nA Comprehensive Overview for Medical Education"
);

// --- SLIDE 2: TABLE OF CONTENTS ---
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  const sections = [
    ["01", "Introduction & Overview", "Slides 3–6"],
    ["02", "Gross Anatomy of the NMJ", "Slides 7–12"],
    ["03", "Ultrastructure (Electron Microscopy)", "Slides 13–18"],
    ["04", "Acetylcholine: Synthesis & Storage", "Slides 19–24"],
    ["05", "Neuromuscular Transmission", "Slides 25–32"],
    ["06", "Acetylcholinesterase & Termination", "Slides 33–37"],
    ["07", "Nicotinic ACh Receptor Biology", "Slides 38–43"],
    ["08", "Excitation–Contraction Coupling", "Slides 44–48"],
    ["09", "Safety Factor & Modulation", "Slides 49–52"],
    ["10", "Diseases & Pharmacology", "Slides 53–58"],
    ["11", "Clinical Applications & Summary", "Slides 59–60"],
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// ── SECTION 1: INTRODUCTION ──────────────────────────────────
sectionSlide(1, "Introduction & Overview", C.teal);

// SLIDE 4
contentSlide("What is the Neuromuscular Junction?", [
  {text:"Definition: A specialized chemical synapse between a motor neuron axon terminal and a skeletal muscle fiber", bold:true},
  "Also called the myoneural junction or motor endplate region",
  "Site where electrical nerve signals are converted into mechanical muscle contraction",
  "One of the most studied synapses in mammalian physiology",
  {text:"Three key components:", bold:true, color:C.navy},
  {text:"Presynaptic (nerve) terminal — houses synaptic vesicles with acetylcholine (ACh)", sub:true},
  {text:"Synaptic cleft (~50–70 nm wide) — contains acetylcholinesterase (AChE) in basal lamina", sub:true},
  {text:"Postsynaptic (muscle) membrane — motor endplate with nicotinic ACh receptors (nAChR)", sub:true},
]);

// SLIDE 5
contentSlide("Historical Milestones", [
  {text:"1857 – Claude Bernard: Curare blocks NMJ (not muscle/nerve)", bold:true},
  "1900s – Paul Ehrlich, John Langley: Concept of chemoreceptors",
  {text:"1921 – Otto Loewi: Chemical neurotransmission (Vagusstoff = ACh)", bold:true},
  "1936 – Henry Dale: ACh identified as motor nerve transmitter; Nobel Prize shared with Loewi",
  "1950s – Bernard Katz: Quantal hypothesis of transmitter release; miniature end-plate potentials (MEPPs)",
  "1960s – Electron microscopy reveals ultrastructure of active zones and junctional folds",
  {text:"1970s–80s – Molecular cloning of nAChR subunits (Torpedo electric fish)", bold:true},
  "Modern era – SNARE proteins, MuSK signaling, channelopathies fully characterized",
]);

// SLIDE 6
contentSlide("Clinical Relevance of the NMJ", [
  {text:"Pharmacology target site:", bold:true, color:C.navy},
  {text:"Neuromuscular blocking agents (succinylcholine, rocuronium, vecuronium) used in anaesthesia", sub:true},
  {text:"Cholinesterase inhibitors (neostigmine, pyridostigmine) used for reversal and myasthenia gravis", sub:true},
  {text:"Botulinum toxin blocks ACh release; therapeutic use in dystonia, spasticity, cosmetics", sub:true},
  {text:"Disease target:", bold:true, color:C.navy},
  {text:"Myasthenia Gravis — autoantibodies against postsynaptic nAChR", sub:true},
  {text:"Lambert-Eaton Syndrome — autoantibodies against presynaptic Ca²⁺ channels", sub:true},
  {text:"Congenital Myasthenic Syndromes — genetic defects in NMJ proteins", sub:true},
  "Understanding NMJ mechanisms is fundamental to safe perioperative management",
]);

// ── SECTION 2: GROSS ANATOMY ─────────────────────────────────
sectionSlide(2, "Gross Anatomy of the NMJ", C.blue);

// SLIDE 8
contentSlide("The Motor Unit", [
  {text:"Motor unit = one alpha motor neuron + ALL muscle fibers it innervates", bold:true},
  "Motor neuron cell body located in anterior horn of spinal cord (or brainstem motor nuclei)",
  "Axon travels via peripheral nerve, enters muscle and branches",
  {text:"Innervation ratio varies by function:", bold:true},
  {text:"Extraocular muscles: 1 neuron : 3–5 fibers (fine control)", sub:true},
  {text:"Large limb muscles: 1 neuron : 1000+ fibers (power)", sub:true},
  "Each muscle fiber receives only ONE NMJ (monoinnervation in adults)",
  "Graded force is achieved by recruiting different numbers of motor units",
]);

// SLIDE 9
contentSlide("Gross Structure: The Motor Nerve Terminal", [
  {text:"As the axon approaches the muscle it loses its myelin sheath", bold:true},
  "Terminal arbor: the unmyelinated axon branches into multiple terminal boutons",
  "Each terminal bouton lies in a groove on the muscle surface — the 'synaptic gutter'",
  "The area of the muscle membrane beneath the nerve terminal = motor endplate",
  {text:"Schwann cell cap:", bold:true},
  {text:"Perisynaptic Schwann cells cap the nerve terminal from above", sub:true},
  {text:"Provide trophic support, phagocytose debris, sense synaptic activity", sub:true},
  {text:"Play roles in NMJ maintenance and repair after injury", sub:true},
]);

// SLIDE 10
contentSlide("The Motor Endplate Region", [
  {text:"Motor endplate: thickened specialized region of sarcolemma beneath the nerve terminal", bold:true},
  "Located roughly at the midpoint of each muscle fiber (en grappe vs. en plaque innervation)",
  {text:"En plaque (fast twitch fibers): focal single endplate — rapid, precise activation", sub:true},
  {text:"En grappe (slow/tonic fibers): multiple diffuse contacts — graded tonic response", sub:true},
  "The endplate region shows characteristic folds — 'junctional folds' — that amplify surface area",
  "Richly supplied with capillaries and endomysium for support",
  "Can be visualized histologically with AChE stain (Karnovsky–Roots method) or Gömöri stain",
]);

// SLIDE 11
contentSlide("Innervation Pattern & Plasticity", [
  {text:"Development: muscle fibers are transiently polyinnervated, then refined to monoinnervation", bold:true},
  "Synapse elimination in postnatal period driven by activity-dependent competition",
  {text:"Denervation effects:", bold:true},
  {text:"Loss of trophic factor influence → muscle atrophy", sub:true},
  {text:"Extrajunctional spread of nAChR across entire sarcolemma (immature/fetal type)", sub:true},
  {text:"Hypersensitivity to acetylcholine and depolarizing agents like succinylcholine", sub:true},
  {text:"Reinnervation:", bold:true},
  {text:"Nerve sprouts guided by Schwann cells and laminin channels", sub:true},
  {text:"New NMJ forms at or near original site using preserved basal lamina scaffold", sub:true},
]);

// SLIDE 12
twoColSlide(
  "Comparison: Central Synapse vs. NMJ",
  "Central (CNS) Synapse",
  [
    "Gap: ~20 nm synaptic cleft",
    "Many boutons per neuron",
    "Sub-threshold EPSPs: summation needed",
    "Modulated by inhibitory inputs",
    "Transmitters: glutamate, GABA, DA, etc.",
    "No AChE in cleft (diffusion-limited)",
    "Plasticity: LTP/LTD common",
  ],
  "NMJ (Peripheral)",
  [
    "Gap: ~50–70 nm junctional cleft",
    "Each muscle fiber: 1 NMJ",
    "Suprathreshold EPP: 1 nerve impulse = 1 muscle AP",
    "No direct inhibitory input (inhibition via interneurons)",
    "Single transmitter: Acetylcholine",
    "Rich AChE in basal lamina — rapid hydrolysis",
    "Substantial safety factor (>3×)",
  ]
);

// ── SECTION 3: ULTRASTRUCTURE ────────────────────────────────
sectionSlide(3, "Ultrastructure: Electron Microscopy", C.sky);

// SLIDE 14
contentSlide("Presynaptic Terminal: Key Structures", [
  {text:"Axon terminal (bouton) — unmyelinated, 1–3 µm diameter knob", bold:true},
  "Mitochondria — numerous; supply ATP for vesicle cycling and ion pumps",
  "Synaptic vesicles — spherical, ~50 nm diameter; concentrated near active zones",
  {text:"Active zones (release sites):", bold:true},
  {text:"Electron-dense bands running across width of synaptic surface", sub:true},
  {text:"Voltage-gated Ca²⁺ channels (P/Q-type) flanking active zones", sub:true},
  {text:"Cytoskeletal scaffold: bassoon, piccolo, RIM proteins", sub:true},
  "Periactive zone — surrounds active zone; site of endocytosis and recycling",
  "Neurexins — presynaptic adhesion proteins anchoring trans-synaptic scaffold",
]);

// SLIDE 15
contentSlide("Synaptic Vesicles in Detail", [
  {text:"Each vesicle contains ~5,000–10,000 molecules of ACh (one 'quantum')", bold:true},
  "Vesicles clustered in 3 functional pools:",
  {text:"Readily Releasable Pool (RRP): ~100–200 vesicles docked at active zone, immediately available", sub:true},
  {text:"Recycling Pool: ~400–500 vesicles; replenish RRP during moderate stimulation", sub:true},
  {text:"Reserve Pool: thousands of vesicles; mobilized only during intense activity", sub:true},
  {text:"SNARE proteins mediate vesicle docking and fusion:", bold:true},
  {text:"v-SNARE: Synaptobrevin/VAMP (on vesicle membrane)", sub:true},
  {text:"t-SNAREs: Syntaxin-1 and SNAP-25 (on plasma membrane)", sub:true},
  {text:"Ca²⁺ sensor: Synaptotagmin-1/2 triggers fast synchronous fusion", sub:true},
]);

// SLIDE 16
contentSlide("The Synaptic Cleft", [
  {text:"Width: ~50–70 nm (3× wider than CNS synapse)", bold:true},
  "Filled with basal lamina (extracellular matrix)",
  {text:"Basal lamina components:", bold:true},
  {text:"Collagen IV — structural scaffold", sub:true},
  {text:"Laminin α4/α5 — organizes active zones; binds AChE", sub:true},
  {text:"Agrin — secreted by motor nerve; activates MuSK to cluster nAChRs", sub:true},
  {text:"Acetylcholinesterase (AChE) — asymmetric A12 form anchored by ColQ to basal lamina", sub:true},
  "Agrin-MuSK-rapsyn signaling axis is essential for postsynaptic differentiation",
  "Perlecan and nidogen link structural components together",
]);

// SLIDE 17
contentSlide("Postsynaptic Membrane: Junctional Folds", [
  {text:"Junctional folds (secondary synaptic clefts) increase postsynaptic surface area ~10×", bold:true},
  "Fold crests: high density of nAChR (~10,000–20,000 receptors/µm²)",
  "Fold troughs: concentrated voltage-gated Na⁺ channels (Nav1.4) — focus AP initiation",
  {text:"Rapsyn (43 kDa protein):", bold:true},
  {text:"Anchors nAChR to postsynaptic cytoskeleton at 1:1 stoichiometry", sub:true},
  {text:"Connects to dystrophin-associated protein complex", sub:true},
  "MuSK (muscle-specific kinase) — transmembrane RTK, phosphorylated by Agrin signal",
  "Dok-7 — cytoplasmic activator of MuSK; mutations cause congenital myasthenia",
  {text:"β-dystroglycan and utrophin maintain fold architecture", sub:true},
]);

// SLIDE 18
contentSlide("Perisynaptic Schwann Cells (PSCs)", [
  {text:"PSCs (terminal Schwann cells) cap the NMJ from above, outside the cleft", bold:true},
  "Not myelinating — specialized for synaptic support",
  {text:"Functions:", bold:true},
  {text:"Phagocytose excess ACh and synaptic debris", sub:true},
  {text:"Detect ACh release via muscarinic receptors → Ca²⁺ response", sub:true},
  {text:"Provide CNTF, GDNF trophic factors to nerve terminal", sub:true},
  {text:"Guide nerve sprouting during reinnervation", sub:true},
  {text:"After axon removal, PSC processes bridge muscle surface guiding new axons", sub:true},
  "Mast cells and macrophages also reside in perisynaptic space — immune surveillance",
]);

// ── SECTION 4: ACh SYNTHESIS & STORAGE ──────────────────────
sectionSlide(4, "Acetylcholine: Synthesis & Storage", C.teal);

// SLIDE 20
definitionSlide(
  "Acetylcholine (ACh): Chemical Nature",
  "Acetylcholine",
  "Ester of acetic acid and choline; smallest classical neurotransmitter; MW ~146 Da",
  [
    {text:"Chemical formula: CH₃CO-O-CH₂CH₂-N⁺(CH₃)₃", bold:true},
    "Quaternary ammonium compound → positively charged, does not cross blood-brain barrier",
    "Labile — hydrolyzed by AChE within <1 ms at the NMJ",
    "Both muscarinic (GPCR) and nicotinic (ligand-gated ion channel) receptors",
    {text:"At NMJ: acts exclusively on nicotinic NM receptors", bold:true},
    "First neurotransmitter to be identified (Otto Loewi, 1921; Henry Dale, 1936)",
  ]
);

// SLIDE 21
contentSlide("ACh Biosynthesis: Choline Acetyltransferase (ChAT)", [
  {text:"Reaction: Choline + Acetyl-CoA → ACh + CoA-SH", bold:true, color:C.navy},
  "Catalyzed by Choline Acetyltransferase (ChAT) — soluble cytoplasmic enzyme",
  "ChAT is synthesized in motor neuron cell body → transported to terminal by fast anterograde axonal transport",
  {text:"Substrates:", bold:true},
  {text:"Choline: transported from extracellular space by high-affinity Na⁺-dependent choline transporter (CHT1/SLC5A7) in presynaptic membrane — rate-limiting step", sub:true},
  {text:"Acetyl-CoA: derived from mitochondrial metabolism (pyruvate dehydrogenase), exported via citrate shuttle", sub:true},
  "Newly synthesized ACh appears in cytoplasm → packaged into vesicles",
  {text:"CHT1 activity increases with nerve stimulation (activity-dependent upregulation)", bold:true},
]);

// SLIDE 22
contentSlide("ACh Vesicular Storage", [
  {text:"Vesicular ACh Transporter (VAChT):", bold:true, color:C.navy},
  "Encoded by SLC18A3 gene; located in vesicle membrane",
  {text:"Mechanism: Proton gradient (V-type H⁺-ATPase acidifies vesicle lumen pH ~5.5)", sub:true},
  {text:"VAChT exchanges 2 H⁺ out for 1 ACh in — secondary active transport", sub:true},
  "Each vesicle packages 5,000–10,000 ACh molecules",
  {text:"Vesicle membrane proteins:", bold:true},
  {text:"Synaptobrevin/VAMP-2: v-SNARE for exocytosis", sub:true},
  {text:"Synaptotagmin-1: Ca²⁺ sensor", sub:true},
  {text:"Synaptophysin: major vesicle membrane protein; cholesterol-enriched lipid raft", sub:true},
  {text:"Rab3A: GTPase regulating vesicle docking/undocking", sub:true},
]);

// SLIDE 23
contentSlide("Choline Recycling After Hydrolysis", [
  {text:"Choline is the major recycled component after ACh hydrolysis:", bold:true},
  "AChE cleaves ACh → Choline + Acetate in the cleft",
  "~50% of released choline is recaptured by high-affinity CHT1 (Km ~1–5 µM)",
  "Remaining choline diffuses away or is taken up by muscle",
  {text:"Hemicholinium-3 (HC-3):", bold:true},
  {text:"Competitive inhibitor of CHT1 → blocks choline reuptake", sub:true},
  {text:"Depletes ACh stores with repeated stimulation — causes progressive weakness", sub:true},
  "Energy cost: synthesis of ACh requires 1 Acetyl-CoA (from glucose/fatty acid metabolism) + CHT1-mediated active transport",
  {text:"Mitochondria are abundant in terminals to meet high ATP demands", bold:true},
]);

// SLIDE 24
tableSlide("Summary: ACh Metabolism at a Glance",
  ["Step", "Molecule/Enzyme", "Location", "Key Feature"],
  [
    ["Choline uptake", "CHT1 (SLC5A7)", "Presynaptic membrane", "Na⁺-dependent, rate-limiting"],
    ["Acetyl-CoA supply", "Mitochondria / citrate shuttle", "Nerve terminal cytoplasm", "From glucose oxidation"],
    ["Synthesis", "Choline Acetyltransferase (ChAT)", "Cytoplasm", "Choline + Acetyl-CoA → ACh"],
    ["Vesicle packaging", "VAChT (SLC18A3)", "Vesicle membrane", "H⁺ gradient driven"],
    ["Release", "SNARE complex + Synaptotagmin", "Active zone", "Ca²⁺-triggered exocytosis"],
    ["Hydrolysis", "Acetylcholinesterase (AChE)", "Synaptic cleft (basal lamina)", "<1 ms; choline + acetate"],
    ["Choline recycling", "CHT1", "Presynaptic membrane", "~50% recaptured"],
  ],
  { colW:[2.2, 2.1, 2.5, 2.6] }
);

// ── SECTION 5: NEUROMUSCULAR TRANSMISSION ───────────────────
sectionSlide(5, "Neuromuscular Transmission", C.blue);

// SLIDE 26
contentSlide("Overview: Steps of Neuromuscular Transmission", [
  {text:"Step 1: Action potential propagates down motor axon to terminal", bold:true},
  {text:"Step 2: Depolarization opens voltage-gated Ca²⁺ channels at active zones", bold:true},
  {text:"Step 3: Ca²⁺ influx triggers SNARE-mediated vesicle fusion → ACh exocytosis", bold:true},
  {text:"Step 4: ACh diffuses across 50–70 nm cleft", bold:true},
  {text:"Step 5: ACh binds nicotinic nAChR → ion channel opens → Na⁺ influx", bold:true},
  {text:"Step 6: Endplate potential (EPP) generated at motor endplate", bold:true},
  {text:"Step 7: EPP spreads → triggers muscle action potential (AP)", bold:true},
  {text:"Step 8: Muscle AP propagates along sarcolemma and into T-tubules", bold:true},
  {text:"Step 9: Excitation-contraction coupling → Ca²⁺ release from SR → contraction", bold:true},
  {text:"Step 10: AChE hydrolyzes ACh → cleft cleared; membrane repolarizes", bold:true},
]);

// SLIDE 27
contentSlide("Calcium Entry & Quantal Release", [
  {text:"Calcium is the critical trigger for neurotransmitter release", bold:true, color:C.navy},
  "Presynaptic terminal contains P/Q-type (Cav2.1) and L-type (Cav1) Ca²⁺ channels",
  "P/Q-type channels are the primary Ca²⁺ entry pathway for fast synchronous ACh release",
  {text:"Quantal content (m) = mean quanta released per impulse:", bold:true},
  {text:"Normal NMJ: m ≈ 50–300 quanta/impulse", sub:true},
  {text:"m = n × p (n = number of available vesicles; p = release probability)", sub:true},
  "Relationship: Ca²⁺ entry → release scales as 4th power of [Ca²⁺]i",
  "Posttetanic potentiation (PTP): residual Ca²⁺ accumulation after tetanic stimulation → increased m → temporary reversal of NMB",
  {text:"Eaton-Lambert Syndrome: autoantibodies against P/Q-type Ca²⁺ channels → ↓ quantal content", bold:true},
]);

// SLIDE 28
contentSlide("SNARE Complex & Exocytosis", [
  {text:"SNARE hypothesis: core membrane fusion machinery at all secretory synapses", bold:true},
  {text:"v-SNARE — Synaptobrevin/VAMP (vesicle-associated membrane protein):", sub:true},
  {text:"t-SNAREs — Syntaxin-1 (plasma membrane) and SNAP-25 (plasma membrane):", sub:true},
  {text:"Zipper together to form tight 4-helix bundle → brings membranes within 1 nm", sub:true},
  {text:"Ca²⁺ sensor: Synaptotagmin-1/2 — binds Ca²⁺ (Kd ~10–100 µM)", bold:true},
  {text:"Drives final membrane fusion in <1 ms", sub:true},
  "NSF (N-ethylmaleimide-sensitive factor) and α-SNAP disassemble SNARE complex post-fusion",
  {text:"Botulinum toxins (A–G) cleave SNARE proteins → block ACh release:", bold:true},
  {text:"BoNT/A, E: cleave SNAP-25 | BoNT/C: cleaves Syntaxin-1 | BoNT/B, D, F, G: cleave VAMP", sub:true},
]);

// SLIDE 29
contentSlide("Miniature Endplate Potentials (MEPPs)", [
  {text:"MEPPs = small spontaneous depolarizations at the endplate, ~0.4–1 mV", bold:true},
  "Occur at ~1/sec at rest; each MEPP = discharge of ONE quantum of ACh",
  "First described by Fatt & Katz (1952) — foundational evidence for quantal hypothesis",
  {text:"Properties:", bold:true},
  {text:"Same time course as evoked EPP but ~1/100 amplitude", sub:true},
  {text:"Blocked by curare (nAChR antagonist) — confirms ACh-mediated", sub:true},
  {text:"Frequency increased by: Ca²⁺, Black widow spider venom (α-latrotoxin)", sub:true},
  {text:"Frequency decreased by: Mg²⁺, Botulinum toxin", sub:true},
  "MEPPs reflect spontaneous ('leaky') vesicle fusion at active zones",
  {text:"Clinically: reduced MEPP amplitude in myasthenia gravis (fewer functional nAChRs)", bold:true},
]);

// SLIDE 30
contentSlide("The Endplate Potential (EPP)", [
  {text:"EPP = graded depolarization of the motor endplate caused by synchronous quantal ACh release", bold:true},
  "Amplitude: ~70–80 mV above resting potential (normally suprathreshold)",
  "Generated by Na⁺ (and some Ca²⁺) influx through open nAChRs",
  {text:"Ionic basis:", bold:true},
  {text:"nAChR is non-selective cation channel — reversal potential ≈ 0 mV", sub:true},
  {text:"At resting Vm (−80 mV), Na⁺ influx dominant → depolarization", sub:true},
  {text:"EPP amplitude = sum of ≥300 MEPPs occurring simultaneously", sub:true},
  "EPP is NOT an action potential — local, graded response confined to endplate",
  "Current sink created by EPP depolarizes adjacent sarcolemma to threshold",
  {text:"Two APs propagate away from endplate in opposite directions along muscle fiber", bold:true},
]);

// SLIDE 31
contentSlide("Vesicle Recycling: Endocytosis Pathways", [
  {text:"After exocytosis, vesicle membrane must be retrieved to sustain release", bold:true},
  {text:"Clathrin-mediated endocytosis (CME) — main slow pathway:", bold:true},
  {text:"Clathrin coat assembles at periactive zone; adaptor protein AP-2", sub:true},
  {text:"Dynamin-1 GTPase pinches off vesicle neck; requires ~10–20 sec", sub:true},
  {text:"Kiss-and-run (K&R) — fast pathway:", bold:true},
  {text:"Vesicle forms transient fusion pore, releases ACh, then reseals intact", sub:true},
  {text:"Very fast (<1 sec); preserves vesicle identity", sub:true},
  {text:"Bulk endocytosis — during intense stimulation:", bold:true},
  {text:"Large membrane infoldings retrieved then sorted into vesicles via endosome", sub:true},
  "Retrieved vesicle → acidified by V-ATPase → re-loaded with ACh by VAChT → reuse",
]);

// SLIDE 32
contentSlide("Frequency Dependence: Tetanic Stimulation", [
  {text:"Low-frequency stimulation (<5 Hz): reliable 1:1 coupling, stable quantal content", bold:true},
  {text:"High-frequency tetanic stimulation (50–100 Hz):", bold:true},
  {text:"Initial facilitation: residual Ca²⁺ accumulates → ↑ quantal content briefly", sub:true},
  {text:"Then depression: RRP depletion > replenishment rate → ↓ EPP amplitude", sub:true},
  "Post-tetanic potentiation (PTP): 10–60 sec after tetanus — enhanced quantal content due to residual Ca²⁺ and PKC activation",
  "Clinical use: Tetanus of Train-of-Four (TOF) monitoring in anaesthesia",
  {text:"TOF ratio <0.9 = residual neuromuscular blockade", bold:true},
  "5-second tetanus at 50 Hz followed by single twitch — post-tetanic count (PTC) used for deep NMB monitoring",
  {text:"Double-burst stimulation (DBS): two short tetanic bursts — sensitive for fade detection", bold:true},
]);

// ── SECTION 6: AChE & TERMINATION ───────────────────────────
sectionSlide(6, "Acetylcholinesterase & Signal Termination", C.teal);

// SLIDE 34
contentSlide("Acetylcholinesterase (AChE): Structure & Location", [
  {text:"AChE (EC 3.1.1.7): serine hydrolase; one of fastest enzymes known", bold:true},
  "Catalytic rate: ~25,000 ACh molecules hydrolyzed per enzyme molecule per second",
  "Produces choline + acetate from ACh",
  {text:"Forms at NMJ:", bold:true},
  {text:"Asymmetric (A12) form: 3 tetramers of catalytic subunits attached to ColQ collagen strand", sub:true},
  {text:"ColQ anchors AChE to laminin in basal lamina of synaptic cleft", sub:true},
  {text:"A12 form remains in cleft even after nerve degeneration — basal lamina scaffold", sub:true},
  "Globular (G4) form: predominant in brain and muscle cytoplasm",
  "Active site: 'gorge' — ~20 Å deep; contains esteratic site (Ser203-His447-Glu334 triad) and anionic (choline-binding) site",
]);

// SLIDE 35
contentSlide("AChE Catalytic Mechanism", [
  {text:"Two-step ping-pong mechanism:", bold:true, color:C.navy},
  {text:"Step 1 — Acylation: Ser203 attacks ACh carbonyl → tetrahedral intermediate → acetyl-enzyme + choline released (Km ~0.1 mM; very fast)", sub:true},
  {text:"Step 2 — Deacylation: H₂O hydrolyzes acetyl-enzyme → Ser203 regenerated + acetate released", sub:true},
  "Rate-limiting step: deacylation (still extremely fast)",
  {text:"Inhibitors:", bold:true},
  {text:"Reversible: edrophonium (ionic, very short acting), neostigmine, pyridostigmine (carbamylation)", sub:true},
  {text:"Irreversible: organophosphates (DFP, sarin, VX) — phosphorylate Ser → 'aged' enzyme", sub:true},
  {text:"Aging: time-dependent loss of one alkyl group → permanent inactivation; treatment window limited", sub:true},
  "Pralidoxime (2-PAM): reactivates phosphorylated AChE if given before aging",
]);

// SLIDE 36
contentSlide("Termination of ACh Signal", [
  {text:"Three mechanisms clear ACh from the cleft:", bold:true, color:C.navy},
  {text:"1. Enzymatic hydrolysis by AChE — dominant and fastest pathway (<1 ms)", bold:true},
  {text:"AChE is so efficient that most ACh is hydrolyzed before reaching extrajunctional areas", sub:true},
  {text:"2. Diffusion out of the cleft — secondary role", bold:true},
  {text:"Some ACh escapes to extrajunctional space; concentration falls rapidly with distance", sub:true},
  {text:"3. Choline reuptake by CHT1 — after hydrolysis", bold:true},
  {text:"Choline is transported back into nerve terminal for re-synthesis", sub:true},
  "Under AChE inhibition: ACh persists → repeated receptor activation → prolonged EPP → depolarization block",
  {text:"This is the therapeutic basis for neostigmine reversal of NMB and treatment of myasthenia gravis", bold:true},
]);

// SLIDE 37
contentSlide("Drugs Acting on AChE: Clinical Pharmacology", [
  {text:"Cholinesterase inhibitors (anticholinesterases):", bold:true, color:C.navy},
  {text:"Mechanism: inhibit AChE → ACh accumulates → competitive overcomes NMB", sub:true},
  {text:"Neostigmine (Prostigmin): quaternary; 20–45 min duration; reversal + myasthenia gravis", sub:true},
  {text:"Pyridostigmine (Mestinon): longer duration (3–6 h); oral; preferred for MG", sub:true},
  {text:"Edrophonium (Tensilon): very short acting (5–10 min); diagnostic test for MG", sub:true},
  {text:"Physostigmine: tertiary amine; crosses BBB; antidote for antimuscarinic toxicity", sub:true},
  {text:"Must co-administer anticholinergic (atropine/glycopyrrolate) to prevent muscarinic side effects", bold:true},
  "Organophosphate poisoning: SLUDGE syndrome (Salivation, Lacrimation, Urination, Defecation, GI, Emesis)",
  "Treatment: atropine (muscarinic block) + pralidoxime (AChE reactivation) + benzodiazepines (seizures)",
]);

// ── SECTION 7: nAChR BIOLOGY ─────────────────────────────────
sectionSlide(7, "Nicotinic ACh Receptor (nAChR) Biology", C.blue);

// SLIDE 39
contentSlide("nAChR Structure: Subunits & Assembly", [
  {text:"nAChR is a ligand-gated ion channel (Cys-loop superfamily)", bold:true},
  "Pentameric: five subunits arranged symmetrically around central ion-conducting pore",
  {text:"Adult (junctional) NMJ receptor: α₁₂β₁δε (α1, α1, β1, δ, ε)", bold:true},
  {text:"Fetal/extrajunctional receptor: α₁₂β₁δγ (γ instead of ε)", bold:true},
  "Each subunit: 4 transmembrane helices (M1–M4); M2 lines the pore",
  {text:"ACh binding sites:", bold:true},
  {text:"Two sites at α–δ and α–ε interfaces (two α subunits = two ACh molecules required for channel opening)", sub:true},
  {text:"Occupied by ACh, nicotine, succinylcholine, and competitive blockers (e.g., d-tubocurarine, rocuronium)", sub:true},
  "Molecular weight: ~290 kDa per pentamer",
]);

// SLIDE 40
contentSlide("nAChR Gating & Ion Selectivity", [
  {text:"Gating states: Resting (closed) → Active (open) → Desensitized (closed)", bold:true},
  "Activation: 2 ACh bound → conformational change → channel opens within microseconds",
  {text:"Channel properties:", bold:true},
  {text:"Non-selective cation channel — permeable to Na⁺, K⁺, and Ca²⁺", sub:true},
  {text:"Reversal potential (Erev) ≈ 0 mV (between ENa and EK)", sub:true},
  {text:"Single channel conductance: ~40–60 pS; open time ~1–2 ms", sub:true},
  {text:"Selectivity: Na⁺ >> K⁺ > Ca²⁺ under physiological conditions", sub:true},
  {text:"Desensitization:", bold:true},
  {text:"Prolonged/repeated agonist exposure → channel closes despite agonist bound", sub:true},
  {text:"Clinically relevant with succinylcholine (Phase I → Phase II block)", sub:true},
  "Open channel block: some drugs (QX-222, some local anesthetics) enter and plug the open pore",
]);

// SLIDE 41
contentSlide("Fetal vs Adult nAChR: Functional Differences", [
  {text:"Fetal receptor (α₁₂β₁δγ):", bold:true, color:C.blue},
  "Predominant prenatally and in extrajunctional areas of adult denervated muscle",
  "Longer open time (~6 ms), smaller conductance (~35 pS)",
  "Distributed across entire sarcolemma (not clustered at endplate)",
  "Activated by lower concentrations of ACh",
  {text:"Adult receptor (α₁₂β₁δε):", bold:true, color:C.teal},
  "Concentrated at junctional folds at very high density",
  "Shorter open time (~1 ms), larger conductance (~55 pS)",
  "Rapid channel kinetics suited for fast, precise signaling",
  {text:"Clinical significance of fetal receptor spread:", bold:true},
  {text:"Denervation, burns, prolonged immobility, critical illness → succinylcholine causes massive K⁺ efflux → life-threatening hyperkalemia", sub:true},
]);

// SLIDE 42
contentSlide("Competitive Neuromuscular Blocking Drugs (NMBDs)", [
  {text:"Non-depolarizing (competitive) NMBDs:", bold:true, color:C.navy},
  "Compete with ACh for nAChR binding sites; do NOT activate the channel",
  "Structurally: benzylisoquinoliniums (atracurium, cisatracurium, mivacurium) and aminosteroids (rocuronium, vecuronium, pancuronium)",
  {text:"Block is reversible — increasing ACh (via AChE inhibitors) overcomes block", sub:true},
  {text:"Train-of-Four monitoring: progressive fade with successive twitches (receptor reserve depleted)", sub:true},
  {text:"Depolarizing NMBD — Succinylcholine (suxamethonium):", bold:true, color:C.red},
  "Structural analog of 2×ACh; activates nAChR → sustained depolarization → desensitization",
  "Fastest onset (<60 sec); used for rapid sequence intubation",
  {text:"Phase I: depolarization block (fasciculations) | Phase II: desensitization block at high doses", sub:true},
  {text:"Reversed by sugammadex (aminosteroids) or spontaneous recovery (succinylcholine)", sub:true},
]);

// SLIDE 43
contentSlide("Postsynaptic Receptor Regulation", [
  {text:"AChR density at NMJ: ~10,000–20,000 receptors/µm²", bold:true},
  "Maintained by Agrin-LRP4-MuSK signaling pathway:",
  {text:"Motor nerve secretes Agrin → binds LRP4 co-receptor → activates MuSK kinase", sub:true},
  {text:"Phospho-MuSK recruits Dok-7 → activates rapsyn → clusters nAChRs", sub:true},
  "Receptor turnover: adult junctional nAChR half-life ~14 days (fetal: ~1 day)",
  {text:"Regulation:", bold:true},
  {text:"Upregulation: denervation, NMB exposure, immobilization (spread of extrajunctional receptors)", sub:true},
  {text:"Downregulation: excess ACh (cholinergic crisis), autoantibody-mediated internalization (MG)", sub:true},
  "Neuregulin (NRG1) via ErbB2/ErbB4 promotes AChR subunit synthesis",
  "HDAC4 is a transcriptional repressor of synaptic genes; regulated by innervation status",
]);

// ── SECTION 8: EXCITATION-CONTRACTION COUPLING ───────────────
sectionSlide(8, "Excitation-Contraction Coupling", C.sky);

// SLIDE 45
contentSlide("From EPP to Muscle Action Potential", [
  {text:"Muscle action potential (AP) is triggered when EPP depolarizes adjacent membrane above threshold", bold:true},
  "Voltage-gated Na⁺ channels (Nav1.4) at troughs of junctional folds are responsible",
  "Threshold: approx. −55 mV (from resting −80 mV) → large safety margin with normal EPP",
  "Muscle AP propagates bidirectionally along sarcolemma at ~3–5 m/sec",
  {text:"T-tubule (transverse tubule) system:", bold:true},
  {text:"Deep invaginations of sarcolemma at A-I band junction (in mammalian muscle: two per sarcomere)", sub:true},
  {text:"Conduct action potential into muscle interior rapidly and simultaneously", sub:true},
  {text:"L-type Ca²⁺ channels (Cav1.1, dihydropyridine receptor, DHPR) located in T-tubule membrane", sub:true},
  "DHPR acts as voltage sensor — conformational change during AP detected by RyR1",
]);

// SLIDE 46
contentSlide("Triad & Calcium Release from SR", [
  {text:"Triad structure: T-tubule flanked by two terminal cisternae of sarcoplasmic reticulum (SR)", bold:true},
  {text:"DHPR (T-tubule) ↔ RyR1 (SR junctional face membrane) — direct protein-protein coupling", bold:true},
  {text:"Mechanism of skeletal muscle EC coupling (mechanical coupling):", bold:true},
  {text:"AP in T-tubule → conformational change in DHPR (voltage sensor)", sub:true},
  {text:"DHPR physically pulls on RyR1 → opens RyR1 Ca²⁺ release channel in SR", sub:true},
  {text:"SR Ca²⁺ floods into cytoplasm (free [Ca²⁺] rises from ~100 nM to ~10 µM)", sub:true},
  "Ca²⁺ binds Troponin-C → conformational change in troponin-tropomyosin complex",
  "Tropomyosin shifts → exposes myosin binding sites on actin",
  {text:"Cross-bridge cycling begins: ATP hydrolysis powers sliding filament mechanism → sarcomere shortening → force generation", bold:true},
]);

// SLIDE 47
contentSlide("Calcium Removal & Relaxation", [
  {text:"Muscle relaxation requires rapid Ca²⁺ removal from cytoplasm:", bold:true},
  {text:"SERCA pump (SR Ca²⁺-ATPase, ATP2A1): returns Ca²⁺ into SR lumen against concentration gradient", bold:true},
  {text:"Rate: 2 Ca²⁺ per ATP; Vmax determines relaxation speed", sub:true},
  {text:"SERCA1a (fast-twitch) vs SERCA2a (slow-twitch/cardiac) isoforms", sub:true},
  "Phospholamban (in cardiac muscle) regulates SERCA — phosphorylation by PKA relieves inhibition",
  {text:"Plasma membrane Ca²⁺-ATPase (PMCA): exports small fraction to extracellular space", sub:true},
  {text:"Calsequestrin (CASQ1/2): Ca²⁺-binding protein in SR lumen; buffers free [Ca²⁺] in SR", bold:true},
  "Parvalbumin: cytoplasmic Ca²⁺ buffer in fast-twitch muscle; speeds initial relaxation",
  {text:"Malignant hyperthermia: RYR1 or DHPR mutations → uncontrolled Ca²⁺ release → hyperthermia, rigidity, acidosis", bold:true},
]);

// SLIDE 48
tableSlide("EC Coupling: Molecular Players Summary",
  ["Protein", "Location", "Function", "Clinical Link"],
  [
    ["DHPR (Cav1.1)", "T-tubule membrane", "Voltage sensor → activates RyR1", "Hypokalemic periodic paralysis"],
    ["RyR1", "SR junctional face", "Ca²⁺ release channel", "Malignant hyperthermia, CCD"],
    ["SERCA1a", "SR membrane", "Ca²⁺ reuptake pump", "Brody disease"],
    ["Calsequestrin-1", "SR lumen", "Ca²⁺ buffer / RyR1 regulator", "MH susceptibility"],
    ["Calmodulin", "Cytoplasm / T-tubule", "Ca²⁺ sensor; regulates RyR1", "Arrhythmia syndromes"],
    ["Triadin / Junctin", "SR junctional face", "Links CASQ to RyR1", "Inherited arrhythmias"],
  ],
  { colW:[2.0, 2.2, 2.8, 2.4] }
);

// ── SECTION 9: SAFETY FACTOR & MODULATION ───────────────────
sectionSlide(9, "Safety Factor & Modulatory Mechanisms", C.teal);

// SLIDE 50
contentSlide("The NMJ Safety Factor", [
  {text:"Safety factor: ratio of EPP amplitude to the threshold required to fire a muscle AP", bold:true},
  "At normal NMJ: EPP is ~3–5× larger than needed → very wide safety margin",
  {text:"Components of safety factor:", bold:true},
  {text:"High quantal content (m ≈ 200–300 quanta per impulse)", sub:true},
  {text:"High density of postsynaptic nAChRs (~10,000–20,000/µm²)", sub:true},
  {text:"AChR reserve — only ~10–15% of receptors need activation to fire AP", sub:true},
  {text:"High Nav1.4 density at junctional fold troughs amplifies EPP threshold crossing", sub:true},
  "Safety factor is reduced in disease (MG) and restored by AChE inhibitors",
  {text:"Even >70% nAChR loss (as in MG) may not cause weakness at rest — only on exertion", bold:true},
]);

// SLIDE 51
contentSlide("Presynaptic Modulation & Autoreceptors", [
  {text:"The NMJ is not a simple relay — presynaptic modulation fine-tunes output:", bold:true},
  {text:"Presynaptic nAChRs (α3β2 neuronal type):", bold:true},
  {text:"Activated by ACh → positive feedback → increase quantal release at high frequencies", sub:true},
  {text:"Clinical: non-depolarizing NMBDs block these → reduce ACh mobilization (one mechanism of fade)", sub:true},
  {text:"Presynaptic muscarinic M1 receptors:", sub:true},
  {text:"Tonically facilitate ACh release", sub:true},
  {text:"Adenosine A1 receptors: inhibit Ca²⁺ entry → reduce release", sub:true},
  {text:"PKC and PKA pathways regulate vesicle mobilization from reserve to RRP", bold:true},
  "Calcitonin gene-related peptide (CGRP): released with ACh from motor nerve → upregulates nAChR expression",
  "Agrin (motor nerve) + Neuregulin (perisynaptic): maintain postsynaptic differentiation",
]);

// SLIDE 52
contentSlide("Trophic Interactions & Long-term Maintenance", [
  {text:"NMJ integrity requires bidirectional trophic signaling:", bold:true},
  {text:"Anterograde (nerve → muscle):", bold:true},
  {text:"Agrin — clustering nAChR", sub:true},
  {text:"CGRP — upregulating nAChR gene expression", sub:true},
  {text:"NT-4, BDNF, NT-3 — via TrkB/C receptors on muscle", sub:true},
  {text:"Retrograde (muscle → nerve):", bold:true},
  {text:"GDNF, CNTF, BDNF — support motor neuron survival and terminal maintenance", sub:true},
  {text:"Muscle-derived Agrin activates presynaptic ErbB2 on Schwann cells", sub:true},
  "Activity-dependent regulation: exercise upregulates mitochondrial biogenesis, AChR density, and CHT1",
  {text:"Aging: NMJ fragmentation, reduced quantal content, partial denervation — contributes to sarcopenia", bold:true},
  "Aerobic exercise training counters age-related NMJ decline",
]);

// ── SECTION 10: DISEASES & PHARMACOLOGY ─────────────────────
sectionSlide(10, "NMJ Diseases & Pharmacology", C.red);

// SLIDE 54
contentSlide("Myasthenia Gravis (MG)", [
  {text:"Autoimmune disease of the postsynaptic NMJ; prevalence ~150–200/million", bold:true},
  {text:"AChR-antibody MG (85% generalized):", bold:true},
  {text:"Antibodies: binding (complement-mediated destruction), blocking (ACh competition), modulating (cross-link → internalization)", sub:true},
  {text:"Junctional fold simplification, ↓ nAChR density, widened cleft", sub:true},
  {text:"Anti-MuSK MG (5–8%):", bold:true},
  {text:"Antibodies disrupt rapsyn-mediated nAChR clustering; bulbar/respiratory predominant", sub:true},
  {text:"Clinical:", bold:true},
  {text:"Fatigable weakness; ocular (ptosis, diplopia) → bulbar → limb → respiratory crisis", sub:true},
  {text:"Characteristic repetitive nerve stimulation decremental response at 3 Hz", sub:true},
  {text:"SFEMG: increased jitter (most sensitive test)", sub:true},
  "Treatment: pyridostigmine, steroids, IVIG, plasmapheresis, rituximab, complement inhibitors (eculizumab), thymectomy",
]);

// SLIDE 55
contentSlide("Lambert-Eaton Myasthenic Syndrome (LEMS)", [
  {text:"Autoimmune presynaptic NMJ disorder", bold:true},
  "Autoantibodies against voltage-gated P/Q-type Ca²⁺ channels (Cav2.1) → ↓ ACh quantal release",
  {text:"Paraneoplastic in ~60% — especially small cell lung cancer (SCLC)", bold:true},
  "Pure autoimmune in ~40% (often HLA-B8 associated)",
  {text:"Clinical features:", bold:true},
  {text:"Proximal limb weakness (legs > arms), autonomic dysfunction (dry mouth, impotence)", sub:true},
  {text:"Paradoxical improvement with brief exercise or repeated contraction (unlike MG)", sub:true},
  {text:"Repetitive nerve stimulation: INCREMENTAL response at 50 Hz (>100% increase)", sub:true},
  {text:"Treatment:", bold:true},
  {text:"Amifampridine (3,4-diaminopyridine): blocks presynaptic K⁺ channels → prolonged depolarization → ↑ Ca²⁺ entry → ↑ ACh release", sub:true},
  {text:"Treat underlying malignancy; IVIG, immunosuppression", sub:true},
]);

// SLIDE 56
contentSlide("Congenital Myasthenic Syndromes (CMS)", [
  {text:"Genetic (not autoimmune) NMJ disorders — >30 genes identified", bold:true},
  {text:"Presynaptic CMS:", bold:true},
  {text:"ChAT mutations → episodic apnea; CHT1 mutations → severe congenital myasthenia", sub:true},
  {text:"SNAP25 mutations (rare) — reduced quantal content", sub:true},
  {text:"Synaptic basal lamina CMS:", bold:true},
  {text:"COLQ mutations → AChE deficiency; prolonged EPP → depolarization block", sub:true},
  {text:"LAMB2 mutations → laminin β2 deficiency; presynaptic structure disorganized", sub:true},
  {text:"Postsynaptic CMS (most common):", bold:true},
  {text:"CHRNA1, CHRNB1, CHRND, CHRNE mutations → slow or fast channel syndromes", sub:true},
  {text:"RAPSN, MUSK, DOK7 mutations → endplate AChR deficiency", sub:true},
  "Treatment depends on type: AChE inhibitors, amifampridine, quinidine, fluoxetine, ephedrine",
]);

// SLIDE 57
twoColSlide(
  "Botulinum Toxin vs Organophosphates",
  "Botulinum Toxin (BoNT)",
  [
    "Produced by Clostridium botulinum",
    "Serotypes A–G; BoNT/A most potent",
    "Mechanism: cleaves SNARE proteins (SNAP-25, VAMP, Syntaxin)",
    "→ Blocks ACh exocytosis",
    "→ Flaccid paralysis; descending pattern",
    "Therapeutic uses: dystonia, spasticity, hyperhidrosis, cosmetics",
    "Treatment: trivalent antitoxin (A, B, E) if given early",
    "Recovery: weeks–months via nerve sprouting",
  ],
  "Organophosphate Poisoning",
  [
    "Irreversible AChE inhibition → ACh accumulation",
    "Muscarinic: SLUDGE syndrome",
    "Nicotinic: muscle fasciculations → paralysis",
    "CNS: anxiety, seizures, coma",
    "Treatment:",
    "  Atropine (muscarinic block)",
    "  Pralidoxime/2-PAM (AChE reactivation)",
    "  Benzodiazepines (seizures)",
    "  Supportive: ventilatory support",
  ]
);

// SLIDE 58
tableSlide("Drugs Acting on the NMJ: Summary Table",
  ["Drug/Agent", "Target", "Mechanism", "Clinical Use"],
  [
    ["Succinylcholine", "nAChR (postjunctional)", "Depolarizing block → desensitization", "RSI, laryngospasm"],
    ["Rocuronium/Vecuronium", "nAChR (postjunctional)", "Competitive non-depolarizing block", "Surgical relaxation"],
    ["Neostigmine", "AChE", "Reversible carbamylation; ↑ ACh", "Reversal of NMB; MG"],
    ["Sugammadex", "Rocuronium/Vecuronium (free)", "Encapsulates aminosteroid NMBDs", "Rapid NMB reversal"],
    ["Amifampridine", "K⁺ channels (presynaptic)", "Blocks K⁺ efflux → ↑ Ca²⁺ entry → ↑ ACh release", "LEMS, CMS"],
    ["BoNT/A", "SNAP-25 (presynaptic)", "Cleaves SNARE protein → blocks exocytosis", "Spasticity, cosmetics"],
    ["Eculizumab", "Complement C5", "Inhibits complement cascade", "AChR-MG"],
    ["Pyridostigmine", "AChE", "Reversible inhibition; ↑ ACh at endplate", "Myasthenia gravis"],
  ],
  { colW:[2.0, 2.0, 3.2, 2.2] }
);

// ── SECTION 11: CLINICAL APPLICATIONS & SUMMARY ─────────────
sectionSlide(11, "Clinical Applications & Summary", C.blue);

// SLIDE 60: Summary
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  const msgs = [
    ["ANATOMY", "NMJ = presynaptic terminal + synaptic cleft + postsynaptic endplate; junctional folds amplify signal", C.teal],
    ["SYNTHESIS", "ACh synthesized from choline + Acetyl-CoA by ChAT; stored in vesicles via VAChT; choline uptake rate-limiting", C.blue],
    ["RELEASE", "Ca²⁺-triggered SNARE exocytosis; quantal release; ~300 quanta/impulse; large safety factor", C.sky],
    ["RECEPTOR", "Pentameric nAChR; 2 ACh required; non-selective cation channel; concentrated at fold crests", C.navy],
    ["TERMINATION", "AChE cleaves ACh in <1 ms; choline recycled via CHT1; signal precisely terminated", C.teal],
    ["EC COUPLING", "AP → T-tubule → DHPR → RyR1 → SR Ca²⁺ release → troponin → sliding filament → contraction", C.blue],
    ["DISEASE", "MG (anti-AChR/MuSK), LEMS (anti-Cav2.1), CMS (genetic); each targets different NMJ component", C.red],
    ["PHARMACOLOGY", "NMBDs (depolarizing/non-depolarizing), AChE inhibitors, sugammadex, amifampridine — all exploit NMJ biology", C.navy],
  ];

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// ─── Save ─────────────────────────────────────────────────────
pres.writeFile({ fileName: "/home/daytona/workspace/nmj-ppt/NMJ_Anatomy_Physiology_Metabolism.pptx" })
  .then(() => console.log("DONE: NMJ_Anatomy_Physiology_Metabolism.pptx created"))
  .catch(e => { console.error("ERROR:", e); process.exit(1); });