ساعات

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 ساعات بنندم عل القرار

و ساعات بنندم عل الندم

و ساعات بنضحك عل المرار

و كتير بنبكي من الألم

و نعيش نجاهد في العمار

و كله بيروح للعدم

و من بعيد نور الفنار

فخ و غميق و المية دم 

زي الفراش شده الشرار

قرب و جرب و اتصدم

طريق و معروف المسار

و كله كافح و انهزم

و لسة بندور في المدار

و درس عمره ما اتفهم

بنخاف من الديب ليل نهار

و الراعي دباح الغنم 

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Heresy, Orthodoxy & Time

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Following up on yesterday's discussions about lecanemab , some points to address. Maybe I am old-fashioned, but I believe that science should be about well-defined entities and mechanisms. I also believe that scientific theories should not be self-contradictory and must make sense within the known laws of physics, chemistry, and biology. From this perspective, I do not think that the two major hypotheses used to describe the amyloid phenomenon (The Amyloid Cascade Hypothesis (ACH) & The Prion Hypothesis (PrH)) fulfill these criteria. I also think that this is the reason behind much of the confusion and the scarcity of clinical success in the field. The ACH & the PrH were unorthodox hypotheses when they were developed in the 80s & 90s. The ACH boldly stated, in contrast to conventional biological and physicochemical wisdom at the time, that the endogenous proteins that form aggregates, even if evolutionary conserved & highly expressed in their native state, are j...
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Amyloid Toxicity: Myths, Contradictions & Failures

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For over a hundred years, since Alois Alzheimer published his famous plaque and tangle pictures, it has been taken for granted that these plaques and tangles are actively killing the neurons by being toxic. There was no proof needed of why or how they are toxic, the details and mechanisms were to come eventually over time to prove what we already knew all along, these structures are toxic. Observations and experiments were not performed to test the toxic gain -of-function ( GOF) theory of amyloid pathology, but just to verify what we already know, they are toxic. Here, and exactly here, is where the pathology (as a scientific discipline) got its own disease; confirmation bias. No amount of counterevidence was ever enough to challenge GOF. Any counterevidence was either accommodated somehow or simply dismissed, leading to a group of myths and contradictory arguments that are recited almost religiously in papers, reviews, conferences, and media interactions to defend GOF. A smokescreen o...
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Different Colored Eggs in One Basket is Still Risky

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A n interesting paper was recently published by Dr. John Hardy, the father of the amyloid cascade hypothesis, introducing a hypothesis for explaining late-onset neurodegenerative diseases (NDDs) based on the failure of degradation of amyloidogenic proteins. This adds to the list of other interesting hypotheses aiming to explain the etiology and pathophysiology of NDDs, especially the prevalent sporadic forms. The list includes the inflammation hypothesis, the antimicrobial hypothesis, the innate immune hypothesis, and the autoimmune hypothesis. All are interesting and each has its own merits; however, they all have one common problem. They are all gain-of-toxic-function (GOF) hypotheses . They all assume that either amyloids are toxic or that they trigger other toxic cascades that ultimately kill neurons. At the same ti me, they all ignore the very plausible possibility that these peptides and proteins have original functions that are lost due to their ...
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The "Protein-Only" Hypothesis: The Emperor Without Clothes

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Why LOF was lost?

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Genetics (only) won’t save us

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Debate Follow-Up: Can Toxic Gain-of-Function (GOF) in Amyloid Pathologies Be Defended?

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