The timing and indications for surgical intervention in asymptomatic patients with severe aortic stenosis remain controversial.
In a multicenter trial, we randomly assigned 145 asymptomatic patients ...with very severe aortic stenosis (defined as an aortic-valve area of ≤0.75 cm
with either an aortic jet velocity of ≥4.5 m per second or a mean transaortic gradient of ≥50 mm Hg) to early surgery or to conservative care according to the recommendations of current guidelines. The primary end point was a composite of death during or within 30 days after surgery (often called operative mortality) or death from cardiovascular causes during the entire follow-up period. The major secondary end point was death from any cause during follow-up.
In the early-surgery group, 69 of 73 patients (95%) underwent surgery within 2 months after randomization, and there was no operative mortality. In an intention-to-treat analysis, a primary end-point event occurred in 1 patient in the early-surgery group (1%) and in 11 of 72 patients in the conservative-care group (15%) (hazard ratio, 0.09; 95% confidence interval CI, 0.01 to 0.67; P = 0.003). Death from any cause occurred in 5 patients in the early-surgery group (7%) and in 15 patients in the conservative-care group (21%) (hazard ratio, 0.33; 95% CI, 0.12 to 0.90). In the conservative-care group, the cumulative incidence of sudden death was 4% at 4 years and 14% at 8 years.
Among asymptomatic patients with very severe aortic stenosis, the incidence of the composite of operative mortality or death from cardiovascular causes during the follow-up period was significantly lower among those who underwent early aortic-valve replacement surgery than among those who received conservative care. (Funded by the Korean Institute of Medicine; RECOVERY ClinicalTrials.gov number, NCT01161732.).
Gut microbiota is found in virtually any metazoan, from invertebrates to vertebrates. It has long been believed that gut microbiota, more specifically, the activity of the microbiome and its ...metabolic products, directly influence a variety of aspects in metazoan physiology. However, the exact molecular relationship among microbe-derived gut metabolites, host signaling pathways, and host physiology remains to be elucidated. Here we review recent discoveries regarding the molecular links between gut metabolites and host physiology in different invertebrate and vertebrate animal models. We describe the different roles of gut microbiome activity and their metabolites in regulating distinct host physiology and the molecular mechanisms by which gut metabolites cause physiological homeostasis via regulating specific host signaling pathways. Future studies in this direction using different animal models will provide the key concepts to understanding the evolutionarily conserved chemical dialogues between gut microbiota and metazoan cells and also human diseases associated with gut microbiota and metabolites.
The uniform growth of single-crystal graphene over wafer-scale areas remains a challenge in the commercial-level manufacturability of various electronic, photonic, mechanical, and other devices based ...on graphene. Here, we describe wafer-scale growth of wrinkle-free single-crystal monolayer graphene on silicon wafer using a hydrogen-terminated germanium buffer layer. The anisotropic twofold symmetry of the germanium (110) surface allowed unidirectional alignment of multiple seeds, which were merged to uniform single-crystal graphene with predefined orientation. Furthermore, the weak interaction between graphene and underlying hydrogen-terminated germanium surface enabled the facile etch-free dry transfer of graphene and the recycling of the germanium substrate for continual graphene growth.
The timing and indications for surgical intervention to prevent systemic embolism in infective endocarditis remain controversial. We conducted a trial to compare clinical outcomes of early surgery ...and conventional treatment in patients with infective endocarditis.
We randomly assigned patients with left-sided infective endocarditis, severe valve disease, and large vegetations to early surgery (37 patients) or conventional treatment (39). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks after randomization.
All the patients assigned to the early-surgery group underwent valve surgery within 48 hours after randomization, whereas 30 patients (77%) in the conventional-treatment group underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The primary end point occurred in 1 patient (3%) in the early-surgery group as compared with 9 (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval CI, 0.01 to 0.82; P=0.03). There was no significant difference in all-cause mortality at 6 months in the early-surgery and conventional-treatment groups (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59). The rate of the composite end point of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months was 3% in the early-surgery group and 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02).
As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism. (EASE ClinicalTrials.gov number, NCT00750373.).
Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute ...to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.
Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, ...strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.
Oxidative stress induced by reactive oxygen species (ROS) plays crucial roles in a wide range of physiological processes and is also implicated in various diseases, including cancer, chronic ...inflammatory diseases, and neurodegenerative disorders. Among the various ROS, hypochlorous acid (HOCl) plays as a powerful microbicidal agent in the innate immune system. The regulated production of microbicidal HOCl is required for the host to control the invading microbes. However, as a result of the highly reactive and diffusible nature of HOCl, its uncontrolled production may lead to an adverse effect on host physiology. Because of its biological importance, many efforts have been focused on developing selective fluorescent probes to image ROS. However, it is still challenging to design a fluorescent probe with exclusive selectivity toward a particular member of ROS. In the current work, we designed FBS as a new fluorescent HOCl probe which has high selectivity, sensitivity, and short response time in a broad range of pH. Compared with other sensors, the “dual-lock” structure of FBS has an advantage of eliminating interferences from other ROS/RNS. Importantly, we further showed that our HOCl probe could be applied for the in vivo imaging of physiological HOCl production in the mucosa of live animals. This probe provides a promising tool for the study of HOCl production.
Abstract
Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF-target interactions is a key step toward understanding the regulatory ...circuitry underlying complex traits such as human diseases. We previously published a reference TF-target interaction database for humans-TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)-which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF-target interactions in mice, including 6552 TF-target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF-target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.
Although the different age groups had differences in sensitivity of asthma exacerbations (AEs) to environmental factors, no comprehensive study has examined the age-stratified effects of ...environmental factors on AEs.
We sought to examine the short-term effects in age-stratified groups (infants, preschool children, school-aged children, adults, and the elderly) of outdoor environmental factors (air pollutants, weather conditions, aeroallergens, and respiratory viral epidemics) on AEs.
We performed an age-stratified analysis of the short-term effects of 4 groups of outdoor environmental factors on AEs in Seoul Metropolitan City (Korea) from 2008 and 2012. The statistical analysis used a Poisson generalized linear regression model, with a distributed lag nonlinear model for identification of lagged and nonlinear effects and convergent cross-mapping for identification of causal associations.
Analysis of the total population (n = 10,233,519) indicated there were 28,824 AE events requiring admission to an emergency department during the study period. Diurnal temperature range had significant effects in pediatric (infants, preschool children, and school-aged children) and elderly (relative risk RR, 1.056-1.078 and 1.016, respectively) subjects. Tree and weed pollen, human rhinovirus, and influenza virus had significant effects in school-aged children (RR, 1.014, 1.040, 1.042, and 1.038, respectively). Tree pollen and influenza virus had significant effects in adults (RR, 1.026 and 1.044, respectively). Outdoor air pollutants (particulate matter of ≤10 μm in diameter, nitrogen dioxide, ozone, carbon monoxide, and sulfur dioxide) had significant short-term effects in all age groups (except for carbon monoxide and sulfur dioxide in infants).
These findings provide a need for the development of tailored strategies to prevent AE events in different age groups.
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•A composite electrode of Li and Ag-coated Cu powder (Li/Cu@Ag) is prepared.•Ag is coated via galvanic replacement and Li/Cu@Ag has a free-standing form.•Li plating occurs ...preferentially on Ag-coated Cu powder due to the lithiophilic Ag.•Li-dendrite growth and dead Li formation are greatly inhibited on Li/Cu@Ag.•As a result, Li/Cu@Ag shows low nucleation overpotential and stable cycling.
In this study, we fabricate a composite electrode of lithium metal powder (LMP) and Ag-coated Cu powder (Li/Cu@Ag) for lithium metal battery simply by Ag-coating on Cu powder through galvanic replacement and pelletizing their mixture. Due to the structure of the composite electrode and high surface area of LMP, local current density can be reduced. The lithiophilic Ag particles on the Cu powder lower lithium nucleation overpotential and enable uniform lithium plating. The Li/Cu@Ag electrode shows superior electrochemical performance with this synergetic effect and the reason for the improvement has been investigated. Specifically, a long lifespan of 400 h at a current density of 1 mA/cm2 is achieved with a Li||Li symmetric cell when using the Li/Cu@Ag electrode in a corrosive carbonate electrolyte. In addition, LiFePO4||Li/Cu@Ag cell shows excellent cycling stability and high-capacity retention (over 74 % after 400 cycles at 3C).
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