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Apolipoproteins (APO proteins) are the lipoprotein family proteins that play key roles in transporting lipoproteins all over the body. There are nearly more than twenty members reported in the APO protein family, among which the A, B, C, E, and L play major roles in contributing genetic risks to several disorders. Among these genetic risks, the single nucleotide polymorphisms (SNPs), involving the variation of single nucleotide base pairs, and their contributing polymorphisms play crucial roles in the apolipoprotein family and its concordant disease heterogeneity that have predominantly recurred through the years. In this review, we have contributed a handful of information on such genetic polymorphisms that include APOE, ApoA1/B ratio, and A1/C3/A4/A5 gene cluster-based population genetic studies carried throughout the world, to elaborately discuss the effects of various genetic polymorphisms in imparting various medical conditions, such as obesity, cardiovascular, stroke, Alzheimer's disease, diabetes, vascular complications, and other associated risks.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

In this paper, for a bounded linear operator defined on a complex Banach space of infinite dimension, we consider the set of isolated points in its approximate point spectrum, which are eigenvalues of finite multiplicity; this set can be equal to the spectrum of the operator but without its upper semi-Fredholm spectrum, and this relation or equality defines in the literature a new spectral property called the property $ (\omega{ \pi }) $ and is a generalization of the classical a-Weyl theorem. We establish some characterizations and consequences about the property $ (\omega{ \pi }) $, some with topological aspects. Furthermore, we study this property through the Riesz functional calculus. Part of the spectral structure of a linear operator verifying property $ (\omega{ \pi }) $ is described, obtaining some associated properties.

Abstract Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

In many areas of diagnosis and treatment, psychiatry and ophthalmology overlap significantly. A patient who has had a great deal of psychological stress may exhibit vision loss. The results of neuro-ophthalmological testing might influence the psychiatric diagnosis and course of therapy. There is a wide range of psychiatric signs and symptoms noted in various ophthalmological disorders which an ophthalmologist witnesses every day. As a result, there is a great deal of overlap between the two disciplines methods to treatment. It goes without saying that the connection between psychiatry and ophthalmology has not gotten the attention it merits.

Abstract Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.

This study aimed to prepare and characterize the zinc alginate complexes using SEM-EDAX, XRD, FTIR and evaluate their zinc retention percentage in cockerels. Three complexes were prepared using zinc sulfate (Zn-Alg- CM1), zinc carbonate (Zn-Alg-CM2), and zinc nitrate (Zn-Alg-CM3). Zn-Alg-CM3 was amorphous with smooth surfaces and showed a shifted absorption spectrum, indicating strong zinc binding compared to Zn-Alg-CM1 and Zn- Alg-CM2. Although Zn-Alg-CM2 had higher zinc composition, Zn-Alg-CM3 at 45 ppm significantly improved the digestibility of crude protein, crude fibre and zinc retention compared to Zn-Alg-CM1, Zn-Alg-CM2, and the control with zinc oxide in cockerels. Zn-Alg-CM3 exhibited antibacterial activity against E. coli, Salmonella and S. aureus. Therefore, Zn-Alg-CM3 showed promising potential as a novel feed supplement in cockerels and further research is essential to fully understand its impact on growth performance, antioxidant activity, and intestinal health in poultry.

Selenium, an essential micronutrient with potent anticancer and antioxidant properties, the inorganic form of selenium is highly toxic, while organic and elemental nanoforms are more bioavailable and less toxic and have gained attention owing to their dietary and clinical relevance. This study aims to optimize conditions for the biosynthesis and production of elemental selenium nanoparticles for selenium supplements using marine microalgae, Nannochloropsis oceanica CASA CC201. The 10 mM precursor solution treated with 1 % of the algal extract (10:1 ratio of precursor and algal extract, respectively) was shown to be the optimal concentration for synthesizing highly stable selenium nanoparticles with a size of 183 nm and a zeta potential of −38.5 mV. AFM and TEM analysis suggest that the spherical-shaped nanoparticles with smooth surfaces were polydispersely distributed. The nanoparticles are well characterized using various analytical and advanced techniques, including Raman spectroscopy and X-ray photoelectron spectroscopy. FT-IR analyses reveal the presence of microalgae proteins and peptides as stabilizing and fabricating agents of Se-NPs to further understand the mode of bioreduction. The synthesized elemental nanoform (Se0) has been validated for its biological functions, showing enhanced radical scavenging activity (74 % in a concentration-dependent manner). Subsequently, algal-mediated selenite reduction and nanoparticle synthesis is an eco-friendly, non-toxic, and sustainable method for the large-scale production of highly stable Se-NPs for niche applications as dietary and feed supplements.

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Abstract Background Uttar Pradesh (UP) is the most populous state in India, with a historically lower level of family planning coverage than the national average. In recent decades, family planning coverage in UP has significantly increased, yet there are considerable geographic and socio-economic inequalities. Methods The data used for the study is derived from a cross-sectional quantitative survey of 12,200 currently married women conducted during December 2020–February 2021 in UP by the Technical Support Unit. Univariate and bivariate analyses were performed and equiplots were used to make visualizing inequalities easy. Results The findings of the study reveal significant variation in family planning coverage indicators amongst currently married women in reproductive ages by administrative divisions in UP. For instance, in the Jhansi division, it was 72.4%, while in Faizabad, it was 39.3%. Jhansi division experienced the highest modern contraceptive coverage with the lowest inequity compared to other divisions. However, the range of coverage within the division by Accredited Social Health Activist (ASHA) areas is 25% to 75%. In fact, for some ASHA areas in the Jhansi division, the family planning demand satisfied for modern contraception ranged from more than 85% to less than 22%. On the other hand, the Gonda division with the lowest coverage and lowest inequity for demand satisfied for modern contraception has some ASHA areas with less than 5% and some with more than 36%. The study also revealed intersectionality of education, wealth, place of residence and geographic divisions in identifying inequity patterns. For instance, in case of Mirzapur and Varanasi, the demand satisfied among the illiterates was 69% and the corresponding percentage for literates was 49%. With respect to place of residence, Basti division, where the coverage for modern contraception is extremely low, demand satisfied for modern contraceptive methods is 16.3% among rural residents compared to 57.9% in the case of urban residents. Conclusions The findings showed inequality in the modern family planning methods coverage in UP in both best and worst performing divisions. The inequalities exist even in extremely small geographies such as ASHA areas. Within the geographies as well, the socio-economic inequalities persisted. These inequalities at multiple levels are important to consider for effective resource allocation and utilization.

Abstract Background Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF. Methods We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes. Results We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p

Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.

ABSTRACT: The objective of this study was to evaluate the effects of 25% and 35% arginine supplementation in partially alleviating the effects of necrotic enteritis (NE) challenge on the production performance, intestinal integrity, and relative gene expression of tight junction proteins and inflammatory cytokines in broilers. Four hundred and eighty 1-day-old chicks were randomly allocated to the 4 treatments- Uninfected + Basal, NE + Basal, NE + Arg 125%, and NE + Arg 135%. NE was induced by inoculating 1 × 104 Eimeria maxima sporulated oocysts on d 14 and 1 × 108 CFU/bird C. perfringens on d 19, 20, and 21 of age by oral gavage. The NE challenge significantly decreased body weight gain (BWG) (p < 0.05) and increased the feed conversion ratio (FCR) (p < 0.05). On d 21, the NE challenge also increased the jejunal lesion score (p < 0.05) and relative gene expression of IL-10 and decreased the expression of the tight junction proteins occludin (p < 0.05) and claudin-4 (p < 0.05). The 125% arginine diet significantly increased intestinal permeability (p < 0.05) and the relative gene expression of iNOS (p < 0.05) and IFN-γ (p < 0.05) on d 21 and the bile anti-C. perfringens IgA concentration by 39.74% (p < 0.05) on d 28. The 135% arginine diet significantly increased the feed intake during d 0 – 28 (p < 0.05) and 0 to 35 (p < 0.05) and increased the FCR on d 0 to 35 (p < 0.05). The 135% and 125% arginine diet increased the spleen CD8+: CD4+ T-cell ratio on d 28 (p < 0.05) and 35 (p < 0.05), respectively. The 135% arginine diet increased the CT CD8+:CD4+ T-cell ratio on d 35 (p < 0.05). In conclusion, the 125% and 135% arginine diets did not reverse the effect of the NE challenge on the growth performance. However, the 125% arginine diet significantly increased the cellular and humoral immune response to the challenge. Hence, the 125% arginine diet could be used with other feed additives to improve the immune response of the broilers during the NE challenge.