Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells.

Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor.

Impact of population screening for Lynch syndrome insights from the All of Us data.

Lynch Syndrome (LS) is a common genetic cancer condition that allows for personalized cancer prevention and early cancer detection in identified gene carriers. We used data from the All of Us (AOU) Research Initiative to assess the prevalence of LS in the general U.S.

Genetically Labeled Premyelinating Oligodendrocytes: Bridging Oligodendrogenesis and Neuronal Activity.

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied.

Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14.

Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most -methyladenosine (mA) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for mA can promote oncogenesis.

DPAM-AI: a domain parser for AlphaFold models powered by artificial intelligence.

Motivation: Due to the breakthrough in protein structure prediction by AlphaFold, the scientific community has access to 200 million predicted protein structures with near-atomic accuracy from the AlphaFold protein structure DataBase (AFDB), covering nearly the entire protein universe. Segmenting these models into domains and classifying them into an evolutionary hierarchy hold tremendous potential for unraveling essential insights into protein function.

Results: We introduce DPAM-AI, a Domain Parser for AlphaFold Models based on Artificial Intelligence.

Prevalence of Transcription Factor 4 Gene Triplet Repeat Expansion Associated with Fuchs' Endothelial Corneal Dystrophy in the United States and Global Populations.

Objective: An intronic cytosine-thymine-guanine (CTG) triplet repeat expansion in the transcription factor 4 gene () gene (CTG18.1) confers significant risk for the development of Fuchs' endothelial corneal dystrophy (FECD). The objective of this study was to conduct an unbiased survey of the CTG18.

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903).

Gain of function NOTCH3 variants cause familial partial lipodystrophy due to activation of senescence pathways.

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr in NOTCH3 meeting the filtering criteria.

The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.

During persistent antigen stimulation, exhausted CD8 T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8 T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway.

Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration.

Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM.

AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice.

The SLC6A1 gene encodes the gamma-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed two AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1 KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1-/- or Slc6a1+/- mice, as well as improvement in several behavioral phenotypes of Slc6a1-/- mice.

ECOD: integrating classifications of protein domains from experimental and predicted structures.

The evolutionary classification of protein domains (ECOD) classifies protein domains using a combination of sequence and structural data (http://prodata.swmed.edu/ecod).

KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation.

Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation.

PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis.

Background & Aims: PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is the most impactful genetic risk factor for steatotic liver disease (SLD). A key unresolved issue is whether PNPLA3(148M) confers a loss- or gain-of-function. Here we test the hypothesis that PNPLA3 causes steatosis by sequestering ABHD5 (α/β hydrolase domain-containing protein 5), the cofactor of ATGL (adipose TG lipase), thus limiting mobilization of hepatic triglyceride (TG).

Orthogonalized human protease control of secreted signals.

Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. While protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. Here, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins.

Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression.

Global Epidemiological Impact of PNPLA3 I148M on Liver Disease.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver-related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors.

Fatal consequences of limited health literacy in a patient with a rare metabolic disease.

A Black young adult female diagnosed with argininosuccinate lyase deficiency at 6 months of age encountered significant barriers to care for the first 16 years of her life due to socioeconomic factors and parental neglect. Once in the care of her paternal grandmother, she received appropriate treatment with a nitrogen scavenger, amino acid supplementation, and a low-protein diet. However, due to repeated hyperammonemic crises early in her life, she was minimally communicative and unable to perform activities of daily living.

Protein interactions in human pathogens revealed through deep learning.

Identification of bacterial protein-protein interactions and predicting the structures of these complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here we developed RoseTTAFold2-Lite, a rapid deep learning model that leverages residue-residue coevolution and protein structure prediction to systematically identify and structurally characterize protein-protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1,923 confidently predicted complexes involving essential genes and 256 involving virulence factors.

Range-wide population genomic structure of the Karner blue butterfly, () .

The Karner blue butterfly, () , is an endangered North American climate change-vulnerable species that has undergone substantial historical habitat loss and population decline. To better understand the species' genetic status and support Karner blue conservation, we sampled 116 individuals from 22 localities across the species' geographical range in Wisconsin (WI), Michigan (MI), Indiana (IN), and New York (NY). Using genomic analysis, we found that these samples were divided into three major geographic groups, NY, WI, and MI-IN, with populations in WI and MI-IN each further divided into three subgroups.