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  <head>
    <title>003-02 Genome maintenance, organelle stress, and tissue consequences</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Genome maintenance, organelle stress, tissue consequences">
      <outline text="From variant to phenotype">
        <outline text="Disease only through a chain of consequences"/>
        <outline text="Does it change amount, location, timing, function?"/>
        <outline text="Phenotype depends on tissue, stage, exposure, reserve"/>
        <outline text="Loss of function reduces useful activity">
          <outline text="One normal allele enough: recessive"/>
          <outline text="Amount insufficient: haploinsufficiency, dominant"/>
        </outline>
        <outline text="Dominant negative interferes with normal product">
          <outline text="Both assemble into a larger structure"/>
        </outline>
        <outline text="Gain of function: excessive, constitutive, novel"/>
        <outline text="Mechanism suggests therapy better than the label"/>
      </outline>
      <outline text="Mosaicism and variant interpretation">
        <outline text="Mosaicism: variant arises after fertilisation">
          <outline text="Earlier events affect more tissues"/>
        </outline>
        <outline text="Somatic mosaicism: segmental disease or cancer"/>
        <outline text="Germline mosaicism: sibling recurrence">
          <outline text="Even with a negative parental blood test"/>
        </outline>
        <outline text="Mitochondrial threshold effects">
          <outline text="Symptoms when dysfunction exceeds tissue tolerance"/>
        </outline>
        <outline text="Interpretation combines frequency, segregation, function"/>
        <outline text="Uncertain significance is not a diagnosis">
          <outline text="Reclassification as evidence accumulates"/>
        </outline>
        <outline text="Consent and genetic counselling are essential"/>
      </outline>
      <outline text="Protein quality control">
        <outline text="Chaperones assist folding"/>
        <outline text="Ubiquitin tags misfolded proteins for proteasomes"/>
        <outline text="Autophagosomes deliver aggregates to lysosomes"/>
        <outline text="ER monitors secretory and membrane proteins">
          <outline text="Unfolded protein reduces translation"/>
          <outline text="Raises chaperone capacity and degradation"/>
          <outline text="Persistent stress triggers inflammation, apoptosis"/>
        </outline>
        <outline text="Proteostasis declines with ageing">
          <outline text="Damaged proteins seed further aggregation"/>
        </outline>
        <outline text="Aggregates may not be the only toxic species"/>
      </outline>
      <outline text="Mitochondria and oxidants">
        <outline text="Integrate energy, calcium, biosynthesis, death signals"/>
        <outline text="Divide, fuse, move, undergo quality control"/>
        <outline text="Fission and mitophagy remove damaged regions">
          <outline text="Failure: less ATP, more reactive oxygen species"/>
        </outline>
        <outline text="Reactive oxygen species also signal and defend"/>
        <outline text="Injury when production exceeds antioxidant capacity">
          <outline text="Respiratory chain, inflammatory cells, radiation"/>
        </outline>
        <outline text="Superoxide dismutase, catalase, glutathione limit damage"/>
        <outline text="Excess oxidants modify lipids, proteins, nucleic acids">
          <outline text="Open permeability pathways that commit to death"/>
        </outline>
      </outline>
      <outline text="Hypoxia and cancer metabolism">
        <outline text="Hypoxia-responsive transcription">
          <outline text="More glycolysis, angiogenic signalling"/>
          <outline text="Kidney-derived erythropoietin"/>
        </outline>
        <outline text="Cannot fully replace aerobic energy production"/>
        <outline text="Chronic activation aids remodelling, tumours"/>
        <outline text="Cancer cells reorganise metabolism for growth">
          <outline text="Aerobic glycolysis supplies biosynthetic intermediates"/>
        </outline>
        <outline text="Oxygen still matters in tumours"/>
      </outline>
      <outline text="Membrane injury and intracellular calcium">
        <outline text="Lipid peroxidation makes membranes leaky"/>
        <outline text="Impaired phospholipid repair and cytoskeleton damage"/>
        <outline text="Lysosomal disruption releases hydrolases"/>
        <outline text="Cytosolic calcium normally kept very low">
          <outline text="Injury allows entry and store release"/>
        </outline>
        <outline text="Calcium activates destructive enzymes">
          <outline text="Phospholipases, proteases, endonucleases"/>
        </outline>
        <outline text="Mitochondrial calcium worsens permeability, oxidants"/>
        <outline text="No single point of no return">
          <outline text="Cells cross the threshold at different times"/>
        </outline>
      </outline>
      <outline text="Patterns of regulated death">
        <outline text="Apoptosis: caspase cascade, membranes intact"/>
        <outline text="Intrinsic pathway: B-cell lymphoma two family balance"/>
        <outline text="DNA damage activates checkpoint proteins">
          <outline text="Pause, repair, or apoptosis if repair fails"/>
        </outline>
        <outline text="Extrinsic: death receptors recruit complexes"/>
        <outline text="Necroptosis: kinase-controlled membrane rupture"/>
        <outline text="Pyroptosis: inflammasome and pore formation"/>
        <outline text="Ferroptosis: iron-associated lipid peroxidation"/>
        <outline text="Tissue injury often mixes several pathways"/>
        <outline text="Necrotic release recruits inflammation"/>
        <outline text="Apoptotic cells signal quiet clearance">
          <outline text="Failed clearance: secondary membrane breakdown"/>
        </outline>
      </outline>
      <outline text="Tissue architecture, biomarkers, recovery">
        <outline text="Outcome depends on scaffold, microcirculation, location">
          <outline text="Small brainstem lesion can be devastating"/>
          <outline text="Patchy injury leaves viable bridges"/>
        </outline>
        <outline text="Biomarkers sample injury indirectly">
          <outline text="Level reflects release, distribution, clearance"/>
          <outline text="Serial change separates evolving from chronic"/>
        </outline>
        <outline text="Tissue markers locate injury, not mechanism"/>
        <outline text="Recovery: repair, proliferation, remodelling, scar"/>
        <outline text="Normal biomarker despite lost reserve"/>
        <outline text="Identify stress, judge reversibility, remove cause"/>
      </outline>
    </outline>
  </body>
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