Kaydedildi:
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| Materyal Türü: | Recurso digital |
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Zenodo
2026
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| Konular: | |
| Online Erişim: | https://doi.org/10.5281/zenodo.19452739 |
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Etiketle
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İçindekiler:
- <p dir="ltr"><span>Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease whose geographic and genetic epidemiology has remained without a unified mechanistic account. The Ancestral Mismatch Series proposes that MS is a predictable consequence of evolutionary dietary mismatch in populations carrying loss-of-function variants at FADS1, FADS2, and ELOVL2 -- the enzymatic loci governing long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis -- who no longer consume the cold-water marine diet under which those variants were phenotypically silent. Papers 1 and 2 established the genetic architecture and the biosynthetic kinetic bottleneck at FADS2. The present paper introduces homeoviscous adaptation (HVA) and the Lands cycle as the holistic kinetic framework that unifies and extends this prior work. HVA is the membrane-autonomous programme maintaining optimal phospholipid composition via continuous acyl chain remodelling at sn-2 of glycerophospholipids. The Lands cycle -- phospholipase A2-mediated deacylation followed by lysophospholipid acyltransferase (LPAT)-mediated reacylation -- is the effector mechanism of this programme and constitutes an inverse rate-limiting step: it determines not how much DHA can be synthesised, but whether synthesised or dietary DHA arrives at sn-2 fast enough to satisfy ongoing deacylation demand -- a demand that actively escalates under DHA deficiency, as the accumulating AA-dominant membrane composition upregulates cPLA2alpha via NF-kB, generating an intensifying deacylation signal that represents the membrane asking more and more urgently for the DHA it cannot receive. Critically, the FADS2 biosynthetic bottleneck and the Lands cycle remodelling bottleneck are not independent -- they are inseparable failure modes exposed simultaneously when dietary preformed DHA is removed, operating in series to generate a three-tier kinetic cascade. A direct structural consequence of this combined failure is the depletion of ethanolamine plasmalogen species (plasmenyl-PE) -- the vinyl ether-DHA structural units that constitute the dominant phospholipid of myelin and serve as its primary sacrificial antioxidant buffer. Reduced plasmalogen levels in MS white matter lesion tissue are documented; this paper proposes that this deficit is a mechanistically inevitable outcome of combined FADS kinetic failure and Lands cycle substrate limitation operating under an elevated reactive oxygen species (ROS) load generated by the AA/COX-2/5-LOX/15-LOX eicosanoid imbalance -- functioning as a basal causative potentiation factor driving the condition of MS that is further compounded by exogenous pro-oxidative insults such as cigarette smoking, environmental toxin load, and chronic gut dysbiosis. The latitude gradient in MS prevalence maps closely onto predicted combined FADS and HVA failure, with systematic exceptions in populations maintaining high marine food intake. A self-reinforcing estrogenic compensatory feedback loop is presented as a downstream consequence. The framework throughout emphasises that HVA failure is not an alternative to the FADS loss-of-function hypothesis -- it is its membrane-level mechanistic elaboration.</span></p>