Notes

But what are the natural statistics of odors, and how do olfactory systems exploit them? Dissecting an accurate machine learning model for human odor perception, we find a computable representation for odor at the molecular level that can predict the odor-evoked receptor, neural, and behavioral responses of nearly all terrestrial organisms studied in olfactory neuroscience
Using Di-Rhamnolipid , we find that odorous compounds with similar POM representations are more likely to co-occur within a substance and be metabolically closely related; metabolic reaction sequences also follow smooth paths in POM despite large jumps in molecular structure. Just as the brain's visual representations have evolved around the natural statistics of light and shapes, the natural statistics of metabolism appear to shape the brain's representation of the olfactory world. of Google, BS BSL is an employee of Google, BL BKL was an employee of Google, YL, MV, JP No competing interests declared, KD KJD holds stock in TropIQ Health Sciences B.V., which collected one of the datasets used in Figure 1, RG RCG is an employee of Osmo and was an employee of Google, AW ABW is an an employee of Osmo, which holds patents WO2020163860A1, WO2022104016A1, EP3906559A1, and BR112021015643A ABW does not own equity in Google. ABW was an employee of disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this anti-tumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. While the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD.

Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology. Lipoprotein) Catabolism in Mice. BACKGROUND: Sphingomyelin and cholesterol are 2 key lipid partners on cell membranes and on lipoproteins. Many studies have indicated the influence of cholesterol on SM metabolism. This study examined the influence of SM biosynthesis on cholesterol metabolism. METHODS: Inducible global Sms1 KO /global Sms2 KO mice were prepared to evaluate the effect of whole-body SM biosynthesis deficiency on lipoprotein metabolism. Seebio Di-Rhamnolipid , SM, ceramide, and glucosylceramide levels were measured.

Triglyceride production rate and LDL catabolism were measured. Lipid rafts were isolated and LDL receptor mass and function were evaluated. Also, the effects of exogenous sphingolipids on hepatocytes were investigated. RESULTS: We found that total SMS depletion significantly reduced plasma SM levels. Also, the total deficiency significantly induced plasma cholesterol, apoB , and apoE levels. Importantly, total SMS deficiency, but not SMS2 deficiency, dramatically decreased LDL receptors in the liver and attenuated LDL uptake through the receptor. Further, we found that total SMS deficiency greatly reduced LDL receptors in the lipid rafts, which contained significantly lower SM and significantly higher glucosylceramide, as well as cholesterol.

Furthermore, we treated primary hepatocytes and Huh7 cells with SM, ceramide, or glucosylceramide, and we found that only SM could upregulate LDL receptor levels in a dose-dependent fashion. CONCLUSIONS: Whole-body SM biosynthesis plays an important role in LDL cholesterol catabolism. The total SMS deficiency, but not SMS2 deficiency, reduces LDL uptake and causes LDL cholesterol accumulation in the circulation. Given the fact that serum SM level is a risk factor for cardiovascular diseases, inhibiting SMS2 but not SMS1 should be the desirable approach. Provided by Adeno-Associated Virus Vectors. Peripheral artery disease is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected.
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