Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen.

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging.

The T cell receptor sequence influences the likelihood of T cell memory formation.

The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells.

Family Genetic Risk Communication and Reverse Cascade Testing in the BabySeq Project.

Purpose: Genomic sequencing of newborns (NBSeq) can initiate disease surveillance and therapy for children, and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and had a risk for autosomal dominant disease identified.

Methods: We conducted semi-structured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely-pathogenic (P/LP) variant associated with an autosomal dominant (AD) childhood- and/or adult-onset disease returned.

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Purpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.

Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.

Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research.

Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1-4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions.

Modulating cell-free DNA biology as the next frontier in liquid biopsies.

Technical advances over the past two decades have enabled robust detection of cell-free DNA (cfDNA) in biological samples. Yet, higher clinical sensitivity is required to realize the full potential of liquid biopsies. This opinion article argues that to overcome current limitations, the abundance of informative cfDNA molecules - such as circulating tumor DNA (ctDNA) - collected in a sample needs to increase.

Heparan sulfate regulates the fate decisions of human pluripotent stem cells.

Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1 hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells.

Ischemic Stroke in Women: Understanding Sex-Specific Risk Factors, Treatment Considerations, and Outcomes.

Ischemic stroke is a major cause of mortality and disability and has become a significant public health concern among women. Overall, women have more ischemic stroke events than men, in part due to their longer life span, and also suffer from more severe stroke-related disabilities compared to men. Women are also more likely than men to present with atypical non-focal neurological symptoms, potentially leading to delayed diagnosis and treatment.

Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia.

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.

Clinical and genomic characterization of Klebsiella pneumoniae infections in Dhaka, Bangladesh.

Background: Klebsiella pneumoniae (Kpn), a WHO priority pathogen with high rates of antimicrobial resistance (AMR), has emerged as a leading cause of hospital acquired pneumonia and neonatal sepsis.

Objective: We aimed to define the clinical characteristics of a cohort of patients with Kpn infection in Dhaka, Bangladesh and to perform phenotypic and genetic characterization of the associated isolates.

Methods: We retrospectively extracted clinical data about patients at Dhaka Medical College Hospital from whom Klebsiella spp was isolated from a clinical specimen collected between February and September 2022.

Resolving the bone - optimizing decalcification in spatial transcriptomics and molecular pathology.

Bone tissue poses critical roadblocks for spatial transcriptomics and molecular pathology due to a combination of its dense, calcified matrix and inadequate preservation of biomolecules in conventional decalcification. Decalcification is a complex and nuanced histological process to concomitantly preserve nucleic acids, proteins, and tissue architecture, ensuring molecular integrity for downstream assays. However, commonly used agents like formic and hydrochloric acids, while efficient, can degrade biomolecules to varying extents, complicating assays such as PCR, sequencing, immunohistochemistry, and hybridization.

The Genetic and Molecular Drivers of Multiple Myeloma: Current Insights, Clinical Implications, and the Path Forward.

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease's complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression.

Methods: This review was conducted through a state-of-The-art literature search, primarily utilizing PubMed to gather peer-reviewed articles.

Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability.

E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder.

LDB1 establishes multi-enhancer networks to regulate gene expression.

How specific enhancer-promoter pairing is established remains mostly unclear. Besides the CTCF/cohesin machinery, few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Using a murine erythroid cell model, we show via acute degradation experiments that LDB1 directly and broadly promotes connectivity among regulatory elements.

Genomic structural equation modeling of reward-related traits: exploring the genetic factor structure and its relationship with psychopathology.

Reward sensitivity has a partial genetic background, and extreme levels may increase vulnerability to psychopathology. This study explores the genetic factor structure underlying reward-related traits and examines how genetic variance links to psychopathology. We modeled GWAS data from ten reward-related traits: risk tolerance (N = 975,353), extraversion (N = 122,886), sensation seeking (N = 132,395), (lack of) premeditation (N = 132,667), (lack of) perseverance (N = 133,517), positive urgency (N = 132,132), negative urgency (N = 132,559), attentional impulsivity (N = 124,739), motor impulsivity (N = 124,104), and nonplanning impulsivity (N = 123,509) to derive their genetic factor structure.

Genetic vulnerability and adverse mental health outcomes following mild traumatic brain injury: a meta-analysis of CENTER-TBI and TRACK-TBI cohorts.

Background: Post-traumatic stress disorder (PTSD) and depression are common after mild traumatic brain injury (mTBI), but their biological drivers are uncertain. We therefore explored whether polygenic risk scores (PRS) derived for PTSD and major depressive disorder (MDD) are associated with the development of cognate TBI-related phenotypes.

Methods: Meta-analyses were conducted using data from two multicenter, prospective observational cohort studies of patients with mTBI: the CENTER-TBI study (ClinicalTrials.

The Scalable Variant Call Representation: Enabling Genetic Analysis Beyond One Million Genomes.

Motivation: The Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150,000 genome VCF would occupy 900 TiB, making it costly and complicated to produce, analyze, and store. The issue stems from VCF's requirement to densely represent both reference-genotypes and allele-indexed arrays.

Attenuated sex-related DNA methylation differences in cancer highlight the magnitude bias mediating existing disparities.

Background: DNA methylation (DNAm) influences both sex differences and cancer development, yet the mechanisms connecting these factors remain unclear.

Methods: Utilizing data from The Cancer Genome Atlas, we conducted a comprehensive analysis of sex-related DNAm effects in nine non-reproductive cancers, compared to paired normal adjacent tissues (NATs), and validated the results using independent datasets. First, we assessed the extent of sex differential DNAm between cancers and NATs to explore how sex-related DNAm differences change in cancerous tissues.

Response of the gut microbiome and metabolome to dietary fiber in healthy dogs.

Unlabelled: Dietary fiber confers multiple health benefits originating from the expansion of beneficial gut microbial activity. However, very few studies have established the metabolic consequences of interactions among specific fibers, microbiome composition, and function in either human or representative animal models. In a study design reflective of realistic population dietary variation, fecal metagenomic and metabolomic profiles were analyzed from healthy dogs fed 12 test foods containing different fiber sources and quantities (5-13% as-fed basis).

MaAsLin 3: Refining and extending generalized multivariable linear models for meta-omic association discovery.

A key question in microbial community analysis is determining which microbial features are associated with community properties such as environmental or health phenotypes. This statistical task is impeded by characteristics of typical microbial community profiling technologies, including sparsity (which can be either technical or biological) and the compositionality imposed by most nucleotide sequencing approaches. Many models have been proposed that focus on how the relative abundance of a feature (e.

Search for a genetic cause of variably protease-sensitive prionopathy.

Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease in which many patients exhibit a family history of dementia. Rare protein-coding variants in , which are causal for all known forms of genetic prion disease, have been ruled out in all VPSPr cases to date, leading to suspicion that VPSPr could be caused by variants in other genes or by non-coding variation in or near . We performed exome sequencing and targeted sequencing of non-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N=67) in order to search for a possible genetic cause.

Effects of commonly used antibiotics on children's developing gut microbiomes and resistomes in peri-urban Lima, Peru.

Background: The effects of antibiotic use on children's gut microbiomes and resistomes are not well characterized in middle-income countries, where pediatric antibiotic consumption is exceptionally common. We characterized the effects of antibiotics commonly used by Peruvian children (i.e.

Transcriptional profile of the rat cardiovascular system at single-cell resolution.

We sought to characterize cellular composition across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We performed single-nucleus RNA sequencing (snRNA-seq) in 78 samples in 10 distinct regions, including the four chambers of the heart, ventricular septum, sinoatrial node, atrioventricular node, aorta, pulmonary artery, and pulmonary veins, which produced 505,835 nuclei. We identified 26 distinct cell types and additional subtypes, with different cellular composition across cardiac regions and tissue-specific transcription for each cell type.