Fetal programming by the parental microbiome of offspring behavior, and DNA methylation and gene expression within the hippocampus.

Background: The microorganisms colonizing the gastrointestinal tract of animals, collectively referred to as the gut microbiome, affect numerous host behaviors dependent on the central nervous system (CNS). Studies comparing germ-free mice to normally colonized mice have demonstrated influences of the microbiome on anxiety-related behaviors, voluntary activity, and gene expression in the CNS. Additionally, there is epidemiologic evidence supporting an intergenerational influence of the maternal microbiome on neurodevelopment of offspring and behavior later in life.

Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non-Small Cell Lung Cancer Patient-Derived Tumor Organoids.

Purpose: Systemic treatments given to patients with non-small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.

Experimental Design: PDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors.

Vaccination with a Protective Ipa Protein-Containing Nanoemulsion Differentially Alters the Transcriptomic Profiles of Young and Elderly Mice following Infection.

spp. are responsible for bacillary dysentery or shigellosis transmitted via the fecal-oral route, causing significant morbidity and mortality, especially among vulnerable populations. There are currently no licensed vaccines.

The Effect of Broccoli Glucoraphanin Supplementation on Ameliorating High-Fat-Diet-Induced Obesity through the Gut Microbiome and Metabolome Interface.

Scope: Obesity and its metabolic comorbidities pose a major global challenge for public health. Glucoraphanin (GRN) is a natural bioactive compound enriched in broccoli that is known to have potential health benefits against various human chronic diseases.

Methods And Results: This study investigats the effects of broccoli GRN supplementation on body weight, metabolic parameters, gut microbiome and metabolome associated with obesity.

Somatic mutation variant analysis in rural, resectable non-small cell lung carcinoma patients.

Rural non-small cell lung cancer (NSCLC) patients do worse, largely related to lack of access to care. In this study, the mutational characteristics and potential for targeted therapy in rural, resectable NSCLC patients using whole exome sequencing (WES) were analyzed. WES was performed on tumor-adjacent normal pairs from rural patients undergoing resection for NSCLC.

Risk factors and outcomes associated with Left Ventricular Thrombus in patients with Peripartum Cardiomyopathy: An insight from National Inpatient Sample Database.

Background: We sought to assess the prevalence and impact of left ventricular thrombus (LVT) in patients with peripartum cardiomyopathy (PPCM).

Methods: We performed a retrospective cohort study of all admissions with PPCM as the primary diagnosis from the Nationwide Inpatient Sample database over a 11-year period. Univariate analysis of all risk factors and outcomes and multivariable logistic regression analysis of certain variables were performed and represented as odds ratio (OR) with 95% confidence interval (CI).

Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis.

Monocarboxylate transporter 2 (MCT2) is a major high-affinity pyruvate transporter encoded by the SLC16A7 gene, and is associated with glucose metabolism and cancer. Changes in the gut microbiota and host immune system are associated with many diseases, including cancer. Using conditionally expressed MCT2 in mice and the TC1 lung carcinoma model, we examined the effects of MCT2 on lung cancer tumor growth and local invasion, while also evaluating potential effects on fecal microbiome, plasma metabolome, and bulk RNA-sequencing of tumor macrophages.

Acute Ischemic Stroke and COVID-19: An Analysis of 27 676 Patients.

Background And Purpose: Acute ischemic stroke may occur in patients with coronavirus disease 2019 (COVID-19), but risk factors, in-hospital events, and outcomes are not well studied in large cohorts. We identified risk factors, comorbidities, and outcomes in patients with COVID-19 with or without acute ischemic stroke and compared with patients without COVID-19 and acute ischemic stroke.

Methods: We analyzed the data from 54 health care facilities using the Cerner deidentified COVID-19 dataset.

Cell-penetrating Chaperone Peptide Prevents Protein Aggregation And Protects Against Cell Apoptosis.

Many of the newly discovered therapeutic peptides and molecules are limited by their inability to cross the cell membrane. In the present study we employed a cell penetrating peptide (CPP), VPTLK, derived from Ku70 protein, to facilitate the entry of a mini-chaperone across the cell membrane. Our previous studies suggest that the mini-chaperone peptide representing the chaperone site in αA-crystallin, which can inhibit protein aggregation associated with proteopathies, has therapeutic potential.

Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1α Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells.

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting over five million individuals worldwide. The exact molecular events underlying PD pathogenesis are still not clearly known. Glia maturation factor (GMF), a neuroinflammatory protein in the brain plays an important role in the pathogenesis of PD.

Lens Endogenous Peptide αA66-80 Generates Hydrogen Peroxide and Induces Cell Apoptosis.

In previous studies, we reported the presence of a large number of low-molecular-weight (LMW) peptides in aged and cataract human lens tissues. Among the LMW peptides, a peptide derived from αA-crystallin, αA66-80, was found in higher concentration in aged and cataract lenses. Additional characterization of the αA66-80 peptide showed beta sheet signature, and it formed well-defined unbranched fibrils.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Background: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition.

Background: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

Alpha-crystallin-derived peptides as therapeutic chaperones.

Background: The demonstration of chaperone-like activity in peptides (mini-chaperones) derived from α-crystallin's chaperone region has generated significant interest in exploring the therapeutic potential of peptide chaperones in diseases of protein aggregation. Recent studies in experimental animals show that mini-chaperones could reach intended targets and alter the disease phenotype. Although mini-chaperones show potential benefits against protein aggregation diseases, they do tend to form aggregates on storage.

Role of αA-crystallin-derived αA66-80 peptide in guinea pig lens crystallin aggregation and insolubilization.

Earlier we reported that low molecular weight (LMW) peptides accumulate in aging human lens tissue and that among the LMW peptides, the chaperone inhibitor peptide αA66-80, derived from α-crystallin protein, is one of the predominant peptides. We showed that in vitro αA66-80 induces protein aggregation. The current study was undertaken to determine whether LMW peptides are also present in guinea pig lens tissue subjected to hyperbaric oxygen (HBO) in vivo.

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART).

Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Background: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

Methods: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013.

Addition of αA-crystallin sequence 164-173 to a mini-chaperone DFVIFLDVKHFSPEDLT alters the conformation but not the chaperone-like activity.

It has been shown that αA-mini-chaperone, a peptide representing the chaperone binding site in αA-crystallin, prevents destabilized protein aggregation. αA-Mini-chaperone has been shown to form amyloid fibrils. This study was undertaken to improve the stability of αA-mini-chaperone while preserving its anti-aggregation activity by fusing the flexible and solvent-exposed C-terminal 164-173 region of αA-crystallin to the mini-chaperone sequence DFVIFLDVKHFSPEDLT.

Lens crystallin modifications and cataract in transgenic mice overexpressing acylpeptide hydrolase.

The accumulation of crystallin fragments in vivo and their subsequent interaction with crystallins are responsible, in part, for protein aggregation in cataracts. Transgenic mice overexpressing acylpeptide hydrolase (APH) specifically in the lens were prepared to test the role of protease in the generation and accumulation of peptides. Cataract development was seen at various postnatal days in the majority of mice expressing active APH (wt-APH).

The critical role of the central hydrophobic core (residues 71-77) of amyloid-forming αA66-80 peptide in α-crystallin aggregation: a systematic proline replacement study.

Age-related cataract formation is marked by the progressive aggregation of lens proteins. The formation of protein aggregates in the aging lens has been shown to correlate with the progressive accumulation of a range of post-translational crystallin modifications, including oxidation, deamidation, racemization, methylation, acetylation, N- and C-terminal truncations and low molecular weight (LMW) crystallin fragments. We found that an αA-crystallin-derived peptide, αA66-80 (1.

The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.

Importance: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy.

Objectives: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries.

Design: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.

Background: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex.

Methods: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries.

αA-Crystallin-derived mini-chaperone modulates stability and function of cataract causing αAG98R-crystallin.

Background: A substitution mutation in human αA-crystallin (αAG98R) is associated with autosomal dominant cataract. The recombinant mutant αAG98R protein exhibits altered structure, substrate-dependent chaperone activity, impaired oligomer stability and aggregation on prolonged incubation at 37 °C. Our previous studies have shown that αA-crystallin-derived mini-chaperone (DFVIFLDVKHFSPEDLTVK) functions like a molecular chaperone by suppressing the aggregation of denaturing proteins.

αA-crystallin peptide SDRDKFVIFLDVKHF accumulating in aging lens impairs the function of α-crystallin and induces lens protein aggregation.

Background: The eye lens is composed of fiber cells that are filled with α-, β- and γ-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of α-crystallin. With aging, the chaperone function of α-crystallin decreases, with the concomitant accumulation of water-insoluble, light-scattering oligomers and crystallin-derived peptides.