Associations of Combined Genetic and Lifestyle Risks with Incident Type 2 Diabetes in the UK Biobank.

Background: Type 2 diabetes (T2D) results from a complex interplay between genetic predisposition and lifestyle factors. Both genetic susceptibility and unhealthy lifestyle are known to be associated with elevated T2D risk. However, their combined effects on T2D risk are not well studied.

Integrated clinical risk prediction of type 2 diabetes with a multifactorial polygenic risk score.

Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors.

Multi-omics characterization of type 2 diabetes associated genetic variation.

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits.

Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h.

Aims/hypothesis: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes.

Gun violence revictimization in New York State: What increases the risk of being shot again?

Background: While gun injuries are more likely to occur in urban settings and affect people of color, factors associated with gun violence revictimization-suffering multiple incidents of gun violence-are unknown. We examined victim demographics and environmental factors associated with gun violence revictimization in New York State (NYS).

Methods: The 2005 to 2020 NYS hospital discharge database was queried for patients aged 12 years to 65 years with firearm-related hospital encounters.

An integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D associated genes and regulatory signals.

Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions.

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival.

Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 hours.

Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycemia, beta cell glucotoxicity, and ultimately type 2 diabetes (T2D). In this study, we sought to explore the effects of hyperglycemia on human pancreatic islet (HPI) gene expression by exposing HPIs from two donors to low (2.8mM) and high (15.

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases.

Biallelic TLR4 deficiency in humans.

Background: Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins.

Objective: We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency.

A community-university run conference as a catalyst for addressing health disparities in an urban community.

The African American population of Buffalo, New York experiences striking race-based health disparities due to adverse social determinants of health. A team of community leaders and university faculty determined that a community dialogue was needed to focus research and advocacy on the root causes of these disparities. In response, we organized the annual conference series that has become the premier conference on health disparities in the region.

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST).

Purpose: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital.

Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease.

Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases.

Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.

In Alzheimer's disease, soluble oligomers of the amyloid-β peptide (Aβ) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβ-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD).

Biallelic PI4KA variants cause neurological, intestinal and immunological disease.

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions.

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate.

You're Going to Do What? Patients' Myths Regarding Hypnotherapy as Described by South African Psychologists.

The aim of this qualitative study was to explore and describe South African registered psychologists' account of their patients' myths regarding hypnotherapy. A social constructivist approach was employed to explore the descriptions of eight psychologists. This article converges on myths of participants' patients and where they originate from, as described by the participants.

A Novel Optical Quantal Analysis of Miniature Events Reveals Enhanced Frequency Following Amyloid β Exposure.

Non-evoked miniature release of neurotransmitters is increasingly recognized as playing an important role in neural function and is implicated in synaptic plasticity, metaplasticity, and homeostasis. Spontaneous miniature release events (minis) are usually measured electrophysiologically by recording the miniature postsynaptic currents (mEPSCs) that they evoke. However, this indirect technique can be confounded by changes within the postsynaptic neuron.