Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design

β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer’s disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors

RETRACTED ARTICLE: Age-dependent Increase in Desmosterol Restores DRM Formation and Membrane-related Functions in Cholesterol-free DHCR24−/− Mice

Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24−/− mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased β-secretase activity and diminished Aβ generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24−/− mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24−/− mouse

Science Opportunities offered by Mercury's Ice-Bearing Polar Deposits

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Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

BACKGROUND: Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. METHODS: We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. RESULTS: We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78(MX1 )protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. CONCLUSION: Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects

XVI Agricultural Science Congress 2023: Transformation of Agri-Food Systems for Achieving Sustainable Development Goals

The XVI Agricultural Science Congress being jointly organized by the National Academy of Agricultural Sciences (NAAS) and the Indian Council of Agricultural Research (ICAR) during 10-13 October 2023, at hotel Le Meridien, Kochi, is a mega event echoing the theme “Transformation of Agri-Food Systems for achieving Sustainable Development Goals”. ICAR-Central Marine Fisheries Research Institute takes great pride in hosting the XVI ASC, which will be the perfect point of convergence of academicians, researchers, students, farmers, fishers, traders, entrepreneurs, and other stakeholders involved in agri-production systems that ensure food and nutritional security for a burgeoning population. With impeding challenges like growing urbanization, increasing unemployment, growing population, increasing food demands, degradation of natural resources through human interference, climate change impacts and natural calamities, the challenges ahead for India to achieve the Sustainable Development Goals (SDGs) set out by the United Nations are many. The XVI ASC will provide an interface for dissemination of useful information across all sectors of stakeholders invested in developing India’s agri-food systems, not only to meet the SDGs, but also to ensure a stable structure on par with agri-food systems around the world. It is an honour to present this Book of Abstracts which is a compilation of a total of 668 abstracts that convey the results of R&D programs being done in India. The abstracts have been categorized under 10 major Themes – 1. Ensuring Food & Nutritional Security: Production, Consumption and Value addition; 2. Climate Action for Sustainable Agri-Food Systems; 3. Frontier Science and emerging Genetic Technologies: Genome, Breeding, Gene Editing; 4. Livestock-based Transformation of Food Systems; 5. Horticulture-based Transformation of Food Systems; 6. Aquaculture & Fisheries-based Transformation of Food Systems; 7. Nature-based Solutions for Sustainable AgriFood Systems; 8. Next Generation Technologies: Digital Agriculture, Precision Farming and AI-based Systems; 9. Policies and Institutions for Transforming Agri-Food Systems; 10. International Partnership for Research, Education and Development. This Book of Abstracts sets the stage for the mega event itself, which will see a flow of knowledge emanating from a zeal to transform and push India’s Agri-Food Systems to perform par excellence and achieve not only the SDGs of the UN but also to rise as a world leader in the sector. I thank and congratulate all the participants who have submitted abstracts for this mega event, and I also applaud the team that has strived hard to publish this Book of Abstracts ahead of the event. I wish all the delegates and participants a very vibrant and memorable time at the XVI ASC

Potent amyloidogenicity and pathogenicity of Aβ43.

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer\u27s disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Wave attenuation in presence of mangroves: A sensitivity study for varying bottom slopes

Mangroves thrive in the intertidal areas (interface between land and sea) of tropical and sub-tropical belt and play an important role in overall attenuation of nearshore waves. Multiple interactions of waves with mangrove trunks and roots and bottom friction are the two primary mechanisms responsible for wave attenuation in mangrove forests. Earlier studies, comprising both analytical and experimental, reported an exponential decay in wave height for waves propagating over vegetation with idealized bottom topography and a few on sloping bottom. But hardly studies have attempted to characterize the wave attenuation by vegetation over varying seabed slopes since mangroves generally grow luxuriantly on gradual topography having large tidal amplitudes. Nowadays, several studies are being carried out on development of artificial mangroves to reduce the coastal hazard risks; thenceforth, there is an imperative requirement to study the wave damping characteristics of mangroves on varying seabed slopes. Consequently, this study performs sensitivity experiments to analyze the wave attenuation over mangroves with different sea-bottom slopes using a third-generation wave model. The study exposes sensitivity of wave attenuation characteristics to different beach slopes in the presence of mangroves and aims at understanding how the wave attenuation characteristics by mangroves differ with varying bottom slopes. The total percentage energy reduction for waves reaching the shoreline after propagating through mangroves on mild slope (1:80, 1:40) is observed to be 93%–98%, nearly 84% for 1:20 slope, and 67% for steep slope (1:10). The study reveals that the wave height decays exponentially for the mild slope and found to be consistent with the earlier studies, but as the degree of bottom steepness increases, the wave height reduction becomes gradual, and this can be attributed to the water depth variation, shoaling, breaking, and reflection characteristics associated with different slopes, in the presence of mangroves