Role of the nitric oxide-soluble guanylyl cyclase pathway in obstructive airway diseases

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Airway surface dehydration aggravates cigarette smoke-induced hallmarks of COPD in mice

Introduction: Airway surface dehydration, caused by an imbalance between secretion and absorption of ions and fluid across the epithelium and/or increased epithelial mucin secretion, impairs mucociliary clearance. Recent evidence suggests that this mechanism may be implicated in chronic obstructive pulmonary disease (COPD). However, the role of airway surface dehydration in the pathogenesis of cigarette smoke (CS)-induced COPD remains unknown. Objective: We aimed to investigate in vivo the effect of airway surface dehydration on several CS-induced hallmarks of COPD in mice with airway-specific overexpression of the β-subunit of the epithelial Na+ channel (βENaC). Methods: βENaC-Tg mice and wild-type (WT) littermates were exposed to air or CS for 4 or 8 weeks. Pathological hallmarks of COPD, including goblet cell metaplasia, mucin expression, pulmonary inflammation, lymphoid follicles, emphysema and airway wall remodelling were determined and lung function was measured. Results: Airway surface dehydration in βENaC-Tg mice aggravated CS-induced airway inflammation, mucin expression and destruction of alveolar walls and accelerated the formation of pulmonary lymphoid follicles. Moreover, lung function measurements demonstrated an increased compliance and total lung capacity and a lower resistance and hysteresis in βENaC-Tg mice, compared to WT mice. CS exposure further altered lung function measurements. Conclusions: We conclude that airway surface dehydration is a risk factor that aggravates CS-induced hallmarks of COPD

The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone

Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria and a promising target for the development of vaccines and antimicrobial compounds against Staphylococcus aureus. Here we demonstrate that mutations in the conditionally essential ltaS (LTA synthase) gene arise spontaneously in an S. aureus mutant lacking the ClpX chaperone. A wide variety of ltaS mutations were selected, and among these, a substantial portion resulted in premature stop codons and other changes predicted to abolish LtaS synthesis. Consistent with this assumption, the clpX ltaS double mutants did not produce LTA, and genetic analyses confirmed that LTA becomes nonessential in the absence of the ClpX chaperone. In fact, inactivation of ltaS alleviated the severe growth defect conferred by the clpX deletion. Microscopic analyses showed that the absence of ClpX partly alleviates the septum placement defects of an LTA-depleted strain, while other phenotypes typical of LTA-negative S. aureus mutants, including increased cell size and decreased autolytic activity, are retained. In conclusion, our results indicate that LTA has an essential role in septum placement that can be bypassed by inactivating the ClpX chaperone. IMPORTANCE Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.Peer reviewe

A 1D microphysical cloud model for Earth, and Earth-like exoplanets. Liquid water and water ice clouds in the convective troposphere

One significant difference between the atmospheres of stars and exoplanets is the presence of condensed particles (clouds or hazes) in the atmosphere of the latter. The main goal of this paper is to develop a self-consistent microphysical cloud model for 1D atmospheric codes, which can reproduce some observed properties of Earth, such as the average albedo, surface temperature, and global energy budget. The cloud model is designed to be computationally efficient, simple to implement, and applicable for a wide range of atmospheric parameters for planets in the habitable zone. We use a 1D, cloud-free, radiative-convective, and photochemical equilibrium code originally developed by Kasting, Pavlov, Segura, and collaborators as basis for our cloudy atmosphere model. The cloud model is based on models used by the meteorology community for Earth's clouds. The free parameters of the model are the relative humidity and number density of condensation nuclei, and the precipitation efficiency. In a 1D model, the cloud coverage cannot be self-consistently determined, thus we treat it as a free parameter. We apply this model to Earth (aerosol number density 100 cm^-3, relative humidity 77 %, liquid cloud fraction 40 %, and ice cloud fraction 25 %) and find that a precipitation efficiency of 0.8 is needed to reproduce the albedo, average surface temperature and global energy budget of Earth. We perform simulations to determine how the albedo and the climate of a planet is influenced by the free parameters of the cloud model. We find that the planetary climate is most sensitive to changes in the liquid water cloud fraction and precipitation efficiency. The advantage of our cloud model is that the cloud height and the droplet sizes are self-consistently calculated, both of which influence the climate and albedo of exoplanets.Comment: To appear in Icaru

Norovirus acute gastroenteritis among US and European travellers to areas of moderate to high risk of travellers' diarrhoea: a prospective cohort study

BACKGROUND Acute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact among travellers is limited. METHODS Prospective, multi-site, observational cohort study conducted 2015-2017, among adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms while travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive, and tested for other common enteric pathogens by Luminex xTAG GPP. RESULTS Of the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks (95% CI: 22.4; 27.1). Twenty NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). Eighty percent of NoV-positive participants (vs. 38.9% in NoV-negative) reported at least moderate impact on travel plans. CONCLUSIONS AGE is a prevalent disease among travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology

Reconstruction of a Bacterial Genome from DNA Cassettes

This basic research program comprised two major areas: (1) acquisition and analysis of marine microbial metagenomic data and development of genomic analysis tools for broad, external community use; (2) development of a minimal bacterial genome. Our Marine Metagenomic Diversity effort generated and analyzed shotgun sequencing data from microbial communities sampled from over 250 sites around the world. About 40% of the 26 Gbp of sequence data has been made publicly available to date with a complete release anticipated in six months. Our results and those mining the deposited data have revealed a vast diversity of genes coding for critical metabolic processes whose phylogenetic and geographic distributions will enable a deeper understanding of carbon and nutrient cycling, microbial ecology, and rapid rate evolutionary processes such as horizontal gene transfer by viruses and plasmids. A global assembly of the generated dataset resulted in a massive set (5Gbp) of genome fragments that provide context to the majority of the generated data that originated from uncultivated organisms. Our Synthetic Biology team has made significant progress towards the goal of synthesizing a minimal mycoplasma genome that will have all of the machinery for independent life. This project, once completed, will provide fundamentally new knowledge about requirements for microbial life and help to lay a basic research foundation for developing microbiological approaches to bioenergy

Cardiac manifestations of MIS-C: cardiac magnetic resonance and speckle-tracking data

BackgroundCardiac involvement is central in MIS-C and represents the main cause of morbidity. In this study, we aimed to assess myocardial damage in patients with MIS-C using cardiac magnetic resonance (CMR) during the acute phase, as well as left ventricular and atrial longitudinal strain on admission, at discharge, and after 3 months.MethodsWe performed a single-center prospective cohort study and case–control study. Between September 2020 and February 2022, we enrolled 39 patients hospitalized for MIS-C at our center. We performed left ventricular and atrial longitudinal 2D strain analysis on admission and during follow-up; echocardiographic data were compared to a matched control population. Patients above 4 years old with increased troponin underwent CMR.ResultsOf 24 patients (mean age: 8.2 ± 4.9 years) who underwent CMR, 14 (58%) presented myocardial edema and 6 (25%) late gadolinium enhancement (LGE). LGE was associated with older age (p < 0.01), increased BMI (p = 0.03), increased ferritin levels (p < 0.001), lower left ventricular (LV) ejection fraction (p < 0.001), LV longitudinal strain (p = 0.004), left atrial (LA) strain (p = 0.05), and prolonged hospital stay (p = 0.02). On admission, LV ejection fraction, LV longitudinal strain, and LA strain were impaired, but each improved gradually over time; LVEF was the fastest to recover, while global LV longitudinal strain was still impaired as compared to controls after 3 months (p = 0.01).ConclusionOur study demonstrates that myocardial injury is present in a quarter of MIS-C patients, and impaired LA and LV myocardial deformation persist for at least several weeks after the acute phase. CMR and LV/LA strain could help us to individualize follow-up of MIS-C patients

Glucose testing and insufficient follow-up of abnormal results: a cohort study

BACKGROUND: More than 6 million Americans have undiagnosed diabetes. Several national organizations endorse screening for diabetes by physicians, but actual practice is poorly understood. Our objectives were to measure the rate, the predictors and the results of glucose testing in primary care, including rates of follow-up for abnormal values. METHODS: We conducted a retrospective cohort study of 301 randomly selected patients with no known diabetes who received care at a large academic general internal medicine practice in New York City. Using medical records, we collected patients' baseline characteristics in 1999 and followed patients through the end of 2002 for all glucose tests ordered. We used multivariate logistic regression to measure associations between diabetes risk factors and the odds of glucose testing. RESULTS: Three-fourths of patients (78%) had at least 1 glucose test ordered. Patient age (≥45 vs. <45 years), non-white ethnicity, family history of diabetes and having more primary care visits were each independently associated with having at least 1 glucose test ordered (p < 0.05), whereas hypertension and hyperlipidemia were not. Fewer than half of abnormal glucose values were followed up by the patients' physicians. CONCLUSION: Although screening for diabetes appears to be common and informed by diabetes risk factors, abnormal values are frequently not followed up. Interventions are needed to trigger identification and further evaluation of abnormal glucose tests