Flagellar motility and the mucus environment influence aggregation mediated antibiotic tolerance of in chronic lung infection.

frequently causes chronic lung infection in individuals with muco-obstructive airway diseases (MADs). Chronic infections are difficult to treat, primarily owing to antibiotic treatment failure, which is often observed in the absence of antimicrobial resistance. In MADs, forms biofilm-like aggregates within the luminal mucus.

A qualitative evaluation of trainee and educator experiences of Integrated Training Posts in one Vocational Training Scheme.

Integrated Training Posts (ITPs) were conceived in the 1990s and have recently increased in the Southwest of England. Most ITP evaluations have been small and undertaken over 13 years ago, so do not reflect the current training landscape. This qualitative study aimed to explore the views and experiences of ITPs amongst general practice trainees and educators.

Clinical practices for defining, detecting, and diagnosing postoperative atrial fibrillation after coronary revascularization surgery - A scoping review.

Objectives: This scoping review was undertaken to understand the degree of variation in clinical practices associated with postoperative atrial fibrillation (POAF), following coronary revascularization surgery by collating and synthesising key concepts from current published literature.

Review Methods And Data Sources: This scoping review was conducted following the framework outlined by Askey and O'Malley. Reporting of this scoping review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist.

Impact of Unitary Synaptic Inhibition on Spike Timing in Ventral Tegmental Area Dopamine Neurons.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus and ventral pallidum afferents.

Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied RNA sequencing and genome-scale loss-of-function clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations.

Lifting the veil off treatment effect heterogeneity.

Clinicians often suspect that a treatment effect can vary across individuals. However, they usually lack "evidence-based" guidance regarding potential heterogeneity of treatment effects (HTE). Potentially actionable HTE is rarely discovered in clinical trials and is widely believed (or rationalized) by researchers to be rare.

Mucus polymer concentration and adaptation converge to define the antibiotic response of during chronic lung infection.

Unlabelled: The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including , which is responsible for the majority of morbidity and mortality in MADs.

Deficiency of the paternally-expressed imprinted gene in mice has sexually dimorphic consequences for offspring communication and social behaviour.

Introduction: Imprinted genes are expressed from one parental allele as a consequence of epigenetic processes initiated in the germline. Consequently, their ability to influence phenotype depends on their parent-of-origin. Recent research suggests that the sex of the individual expressing the imprinted gene is also important.

Mucus polymer concentration and adaptation converge to define the antibiotic response of during chronic lung infection.

Unlabelled: The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including , which is responsible for the majority of morbidity and mortality in MADs.

A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Infection.

People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life and contribute to progressive lung failure. CF is caused by mutations in the CF transmembrane conductance regulator () gene, which encodes an ion channel important for maintaining the proper hydration of pulmonary surfaces. When CFTR function is ablated or impaired, airways develop thickened, adherent mucus that contributes to a vicious cycle of infection and inflammation.

The parenting hub of the hypothalamus is a focus of imprinted gene action.

Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour.

Imprinted genes and the manipulation of parenting in mammals.

Genomic imprinting refers to the parent-of-origin expression of genes, which originates from epigenetic events in the mammalian germ line. The evolution of imprinting may reflect a conflict over resource allocation early in life, with silencing of paternal genes in offspring soliciting increased maternal provision and silencing of maternal genes limiting demands on the mother. Parental caregiving has been identified as an area of potential conflict, with several imprinted genes serendipitously found to directly influence the quality of maternal care.

An Aurora kinase A-BOD1L1-PP2A B56 Axis promotes chromosome segregation fidelity.

Cancer cells are often aneuploid and frequently display elevated rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). CIN is commonly caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduces the efficiency of correction of erroneous K-MT attachments. We recently showed that UMK57, a chemical agonist of MCAK (alias KIF2C) improves chromosome segregation fidelity in CIN cancer cells although cells rapidly develop adaptive resistance.

C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.

While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress.

Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency.

Inherited bone marrow failure associated with heterozygous mutations in GATA2 predisposes toward hematological malignancies, but the mechanisms remain poorly understood. Here, we investigate the mechanistic basis of marrow failure in a zebrafish model of GATA2 deficiency. Single-cell transcriptomics and chromatin accessibility assays reveal that loss of gata2a leads to skewing toward the erythroid lineage at the expense of myeloid cells, associated with loss of cebpa expression and decreased PU.

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons.

Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input-output properties of pacemaking neurons can be characterized by the phase-resetting curve (PRC), which describes the sensitivity of interspike interval (ISI) length to inputs arriving at different phases of the firing cycle.

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited.

Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans.

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a "JmjC-only" protein hydroxylase that is essential for murine embryonic development and viability.

Competency-Based Assessments: Leveraging Artificial Intelligence to Predict Subcompetency Content.

Purpose: Faculty feedback on trainees is critical to guiding trainee progress in a competency-based medical education framework. The authors aimed to develop and evaluate a Natural Language Processing (NLP) algorithm that automatically categorizes narrative feedback into corresponding Accreditation Council for Graduate Medical Education Milestone 2.0 subcompetencies.

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare germline missense variants in ; one identical variant was found in five individuals and another variant in two individuals.

Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution.

Background: Although a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels.

Results: We established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types.