Infection by Clonally Related Isolates: The Role of Drinking Water.

Rationale: group bacteria (MABS) cause lethal infections in people with chronic lung diseases. Transmission mechanisms remain poorly understood; the detection of dominant circulating clones (DCCs) has suggested potential for person-to-person transmission.

Objectives: This study aimed to determine the role of drinking water in the transmission of MABS.

Mutations in mexT bypass the stringent response dependency of virulence in Pseudomonas aeruginosa.

Pseudomonas aeruginosa produces a wealth of virulence factors whose production is controlled via an intricate regulatory systems network. Here, we uncover a major player in the evolution and regulation of virulence that enhances host colonization and antibiotic resistance. By characterizing a collection of mutants lacking the stringent response (SR), a system key for virulence, we show that the loss of the central regulator MexT bypasses absence of the SR, restoring full activation of virulence pathways.

Microbial metabolism disrupts cytokine activity to impact host immune response.

Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of with .

Global genomic surveillance of monkeypox virus.

Monkeypox virus (MPXV) is endemic in western and Central Africa, and in May 2022, a clade IIb lineage (B.1) caused a global outbreak outside Africa, resulting in its detection in 116 countries and territories. To understand the global phylogenetics of MPXV, we analyzed all available MPXV sequences, including 10,670 sequences from 65 countries collected between 1958 and 2024.

Evolution and host-specific adaptation of .

The major human bacterial pathogen causes multidrug-resistant infections in people with underlying immunodeficiencies or structural lung diseases such as cystic fibrosis (CF). We show that a few environmental isolates, driven by horizontal gene acquisition, have become dominant epidemic clones that have sequentially emerged and spread through global transmission networks over the past 200 years. These clones demonstrate varying intrinsic propensities for infecting CF or non-CF individuals (linked to specific transcriptional changes enabling survival within macrophages); have undergone multiple rounds of convergent, host-specific adaptation; and have eventually lost their ability to transmit between different patient groups.

A Fragment-Based Competitive F LB-NMR Platform For Hotspot-Directed Ligand Profiling.

Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites.

In vitro platform to model the function of ionocytes in the human airway epithelium.

Background: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult.

Lipoarabinomannan modification as a source of phenotypic heterogeneity in host-adapted isolates.

is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of to the human lung is which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived mutations on the physiology and virulence of , mutations were introduced in the isogenic background of ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection.

Unlocking Amides: A General Method for the Self-Immolative Release of Amide-Containing Molecules.

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload-release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials.

Mutational spectra are associated with bacterial niche.

As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to detect both disruption of DNA repair processes and exposure to niche-specific mutagens. Here we reconstruct mutational spectra for 84 clades from 31 diverse bacterial species and find distinct mutational patterns.

Clinically relevant mutations in the PhoR sensor kinase of host-adapted isolates impact response to acidic pH and virulence.

Difficult-to-treat pulmonary infections caused by nontuberculous mycobacteria of the group have been steadily increasing in the USA and globally. Owing to the relatively recent recognition of as a human pathogen, basic and translational research to address critical gaps in diagnosis, treatment, and prevention of diseases caused by this microorganism has been lagging behind that of the better-known mycobacterial pathogen, . To begin unraveling the molecular mechanisms of pathogenicity of , we here focus on the study of a two-component regulator known as PhoPR which we found to be under strong evolutionary pressure during human lung infection.

Impact of a new hospital with close to 100% single-occupancy rooms on environmental contamination and incidence of vancomycin-resistant Enterococcus faecium colonization or infection: a genomic surveillance study.

Background: Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of nosocomial infection, driven by its ability to spread between patients and persist in the hospital environment.

Aim: To investigate the impact of a long-established cardiothoracic hospital moving to new premises with close to 100% single-occupancy rooms on the rates of environmental contamination and infection or colonization by VRE.

Methods: Prospective environmental surveillance for VRE was conducted at five time-points between April and November 2019, once in the original building, and four times in the new building.

Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF.

A lung-specific mutational signature enables inference of viral and bacterial respiratory niche.

Exposure to different mutagens leaves distinct mutational patterns that can allow inference of pathogen replication niches. We therefore investigated whether SARS-CoV-2 mutational spectra might show lineage-specific differences, dependent on the dominant site(s) of replication and onwards transmission, and could therefore rapidly infer virulence of emergent variants of concern (VOCs). Through mutational spectrum analysis, we found a significant reduction in G>T mutations in the Omicron variant, which replicates in the upper respiratory tract (URT), compared to other lineages, which replicate in both the URT and lower respiratory tract (LRT).

Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.

Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis, and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways.

Evaluating Listening Performance for COVID-19 Detection by Clinicians and Machine Learning: Comparative Study.

Background: To date, performance comparisons between men and machines have been carried out in many health domains. Yet machine learning (ML) models and human performance comparisons in audio-based respiratory diagnosis remain largely unexplored.

Objective: The primary objective of this study was to compare human clinicians and an ML model in predicting COVID-19 from respiratory sound recordings.

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis.

Background: Individuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this.

Cystic Fibrosis-Related Gut Dysbiosis: A Systematic Review.

Background And Aims: Cystic Fibrosis (CF) is associated with gut dysbiosis, local and systemic inflammation, and impaired immune function. Gut microbiota dysbiosis results from changes in the complex gut milieu in response to CF transmembrane conductance regulator (CFTR) dysfunction, pancreatic malabsorption, diet, medications, and environmental influences. In several diseases, alteration of the gut microbiota influences local and systemic inflammation and disease outcomes.

Development and validation of a CRISPR interference system for gene regulation in Campylobacter jejuni.

Background: Campylobacter spp. are the leading cause of bacterial food-borne illness in humans worldwide, with Campylobacter jejuni responsible for 80% of these infections. There is an urgent need to understand fundamental C.

Structural Characterization of Phosphopantetheine Adenylyl Transferase Ligand Interactions: Implications for Fragment-Based Drug Design.

Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for mycobacterial infections like tuberculosis and leprosy and those with emerging opportunistic pathogens such as , where multi-drug resistance leads to increased healthcare cost and mortality. is a highly drug-resistant non-tuberculous which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis.

Exploring Longitudinal Cough, Breath, and Voice Data for COVID-19 Progression Prediction via Sequential Deep Learning: Model Development and Validation.

Background: Recent work has shown the potential of using audio data (eg, cough, breathing, and voice) in the screening for COVID-19. However, these approaches only focus on one-off detection and detect the infection, given the current audio sample, but do not monitor disease progression in COVID-19. Limited exploration has been put forward to continuously monitor COVID-19 progression, especially recovery, through longitudinal audio data.

Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.

Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed.

Using Structure-guided Fragment-Based Drug Discovery to Target Infections in Cystic Fibrosis.

Cystic fibrosis (CF) is progressive genetic disease that predisposes lungs and other organs to multiple long-lasting microbial infections. is the most prevalent and deadly pathogen among these microbes. Lung function of CF patients worsens following chronic infections with and is associated with increased mortality and morbidity.

Antibiotic Management in Bronchiectasis.

Antibiotics are an essential component of the management of patients with bronchiectasis. This article reviews the role of antibiotics in the treatment of exacerbations, for maintenance therapy to reduce exacerbation frequency, and for eradicating potentially harmful organisms such as Pseudomonas aeruginosa.