عذرا

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 عذرا يا من كان عزيزا اسمُك

لقد لطخوه في الوحل

و داسوه بأقدامهم

فضحكوا و ضحك الناس جميعا

عذرا يا حبوب الهلوسة

من يحتاج اليك الآن

و كذلك محبوبتي

لا يعبأ بها أحد

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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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What is biological information?

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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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Why LOF was lost? When a protein aggregates, two things happen, one is certain and the other is uncertain. -  The certain consequence is that the protein loses its function, because any protein needs its native conformation and solubility to function  →  loss-of-function (LOF) - The uncertain consequence is that the resulting aggregates become particularly more toxic  →  gain-of-function (GOF) While the two mirror-image possibilities are scientifically valid, the majority of the field studying amyloids, especially within neurodegenerative diseases, chose to focus on the uncertain consequence (GOF) and almost completely ignore the certain one (LOF). A friend of mine asked me why? Why something as obvious as LOF became almost unthinkable and is only mentioned shyly as a heretic belief on the outskirts of the literature? Here, I will try to discuss the historical factors that I think contributed to this huge asymmetry in amyloid science, and how this uni...
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Genetics (only) won’t save us

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In November 2020, a news feature in Nature discussed “ A fringe theory [that] links microbes in the brain with the onset of dementia ” (Figure 1). While it was nice to see that this “fringe” theory is finally being considered worthy of discussion by top journals, the article also highlighted the mainstream view, the one which kept this theory on the fringes for a long time. “ But I don’t think it is going to be provable ” the article quotes Dr. John Hardy, the father of the amyloid cascade hypothesis, “ and I don’t think there is much left that needs to be explained about Alzheimer’s beyond the genetics ”, he added. This statement is not only inaccurate, but it also reflects the core framework that has dominated the field of neurodegeneration for the past four decades. This framework emphasizes that nothing more than genetics is needed to understand these diseases, and if we just keep sequencing more people and conducting more genetic studies, the problem will eventually be solved. ...
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Life & death between the double helix & the cross-β sheet

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The DNA double helix is probably the most famous structure in the world. Since its discovery in 1953; it became an icon for the molecular basis of life, featured in arts and architecture as a symbol of science's triumph and beauty. However, it is less known that another double-stranded structure is involved in devastating diseases such as Alzheimer's, Parkinson's, and mad cow diseases; the cross-β structure . This structure forms the basis of all amyloids and prions.  Both the double helix and the  cross-β  structures are said to have the capacity to replicate and transmit biological information.  But how similar/different are these two double-stranded structures? Why one of them encodes life while the other causes death? The  double-helix/ cross-β  is the relevant comparison when we want to study the question of whether amyloids/prions can self-replicate and what are their functions in biology and disease. We should not be discussing the amyloid supers...
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Cores & Protective Belts in Amyloid Thinking

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

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