Linezolid and Rifampicin Combination to Combat cfr-Positive Multidrug-Resistant MRSA in Murine Models of Bacteremia and Skin and Skin Structure Infection.

Linezolid resistance mediated by the cfr gene in MRSA represents a global concern. We investigated relevant phenotype differences between cfr-positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group, cfr-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (P < 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in cfr-positive vs. -negative MRSA. In vitro phenotypes of cfr-positive MRSA translated into poor outcomes of linezolid monotherapy in vivo in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC50 of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against cfr-positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by cfr-positive multidrug resistant MRSA

Zero-shot Domain-sensitive Speech Recognition with Prompt-conditioning Fine-tuning

In this work, we propose a method to create domain-sensitive speech recognition models that utilize textual domain information by conditioning its generation on a given text prompt. This is accomplished by fine-tuning a pre-trained, end-to-end model (Whisper) to learn from demonstrations with prompt examples. We show that this ability can be generalized to different domains and even various prompt contexts, with our model gaining a Word Error Rate (WER) reduction of up to 33% on unseen datasets from various domains, such as medical conversation, air traffic control communication, and financial meetings. Considering the limited availability of audio-transcript pair data, we further extend our method to text-only fine-tuning to achieve domain sensitivity as well as domain adaptation. We demonstrate that our text-only fine-tuned model can also attend to various prompt contexts, with the model reaching the most WER reduction of 29% on the medical conversation dataset.Comment: F-T Liao and Y-C Chan contributed equall

A \gamma-ray emitting NLS1 galaxy SDSS J095909.51+460014.3 identified by multiwavelength contemporaneous brightening

We report on an identification of a new gamma-ray emitting narrow-line Seyfert 1 galaxy (gamma-NLS1), SDSS J095909.51+460014.3 (z = 0.399), by establishing an association with a gamma-ray source 4FGL 0959.6+4606, although its low-energy counterpart was suggested to be a radio galaxy 2MASX J09591976+4603515. WISE long-term light curves of these two sources reveal diverse infrared variability patterns. Brightenings of 2.5 mag are detected for the former source, while flux decays of 0.5 mag are found for the other one. More importantly, the time that the infrared flux of the NLS1 rises, is coincident with the time of flux increase of 4FGL 0959.6+4606. At the same time, no infrared activity of the radio galaxy has been observed. A specific analysis of 15-month Fermi-LAT data, aiming at the high gamma-ray flux state, yields a significant source (TS =43). The corresponding gamma-ray localization analysis suggests that only the NLS1 falls into the uncertainty area, further supporting the updated association relationship. A broadband spectral energy distribution of SDSS J095909.51+460014.3 has been drawn and well described by the classic single-zone homogeneous leptonic jet model. Its jet properties are investigated and found to be comparable with the known gamma-NLS1s.Comment: 8 pages, 7 figures,2 tables, A&A in pres

Structural Characterization and Antioxidative Activity of Low-Molecular-Weights Beta-1,3-Glucan from the Residue of Extracted Ganoderma lucidum Fruiting Bodies

The major cell wall constituent of Ganoderma lucidum (G. lucidum) is β-1,3-glucan. This study examined the polysaccharide from the residues of alkaline-extracted fruiting bodies using high-performance anion-exchange chromatography (HPAEC), and it employed nuclear magnetic resonance (NMR) and mass spectrometry (MS) to confirm the structures. We have successfully isolated low-molecular-weight β-1,3-glucan (LMG), in high yields, from the waste residue of extracted fruiting bodies of G. lucidum. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay evaluated the capability of LMG to suppress H2O2-induced cell death in RAW264.7 cells, identifying that LMG protected cells from H2O2-induced damage. LMG treatment decreased H2O2-induced intracellular reactive oxygen species (ROS) production. LMG also influenced sphingomyelinase (SMase) activity, stimulated by cell death to induce ceramide formation, and then increase cell ROS production. Estimation of the activities of neutral and acid SMases in vitro showed that LMG suppressed the activities of both neutral and acid SMases in a concentration-dependent manner. These results suggest that LMG, a water-soluble β-1,3-glucan recycled from extracted residue of G. lucidum, possesses antioxidant capability against H2O2-induced cell death by attenuating intracellular ROS and inhibiting SMase activity

Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration

ObjectivesThis study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms.BackgroundInflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown.MethodsThe involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro.ResultsInterleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes but not CD4+ helper T cells were a major source of IL-17A. Anti–IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression.ConclusionsIL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration

miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database (http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system

CT radiomics model combined with clinical and radiographic features for discriminating peripheral small cell lung cancer from peripheral lung adenocarcinoma

PurposeExploring a non-invasive method to accurately differentiate peripheral small cell lung cancer (PSCLC) and peripheral lung adenocarcinoma (PADC) could improve clinical decision-making and prognosis.MethodsThis retrospective study reviewed the clinicopathological and imaging data of lung cancer patients between October 2017 and March 2022. A total of 240 patients were enrolled in this study, including 80 cases diagnosed with PSCLC and 160 with PADC. All patients were randomized in a seven-to-three ratio into the training and validation datasets (170 vs. 70, respectively). The least absolute shrinkage and selection operator regression was employed to generate radiomics features and univariate analysis, followed by multivariate logistic regression to select significant clinical and radiographic factors to generate four models: clinical, radiomics, clinical-radiographic, and clinical-radiographic-radiomics (comprehensive). The Delong test was to compare areas under the receiver operating characteristic curves (AUCs) in the models.ResultsFive clinical-radiographic features and twenty-three selected radiomics features differed significantly in the identification of PSCLC and PADC. The clinical, radiomics, clinical-radiographic and comprehensive models demonstrated AUCs of 0.8960, 0.8356, 0.9396, and 0.9671 in the validation set, with the comprehensive model having better discernment than the clinical model (P=0.036), the radiomics model (P=0.006) and the clinical–radiographic model (P=0.049).ConclusionsThe proposed model combining clinical data, radiographic characteristics and radiomics features could accurately distinguish PSCLC from PADC, thus providing a potential non-invasive method to help clinicians improve treatment decisions

Is the whole greater than the sum of its parts? De novo assembly strategies for bacterial genomes based on paired-end sequencing

Number of misassemblies for different assembly strategies. Number of misassemblies for the de novo assembly results for E. coli DH1 and S. Parasanguinis FW213 are shown together with their standard errors of the mean. Group A [PE] and Group A [SE] represent all reads assembled as paired-end reads and single end reads, respectively. Group A [PE + SE] represents all the non-overlapped paired-end reads assembled together with merged reads. Group M [PE] and Group M [SE] represent Group M reads assembled as paired-end reads and single end reads, respectively. The numbers of misassemblies fluctuate a lot when depths of read number are low and gradually decreases until they reach a steady number. The paired-end reads (Group A [PE] and Group M [PE]) in S. Parasanguinis FW213 gave the lowest number of misassemblies when depths of read number are high. (TIFF 669 kb

HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma

BACKGROUND: HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs). METHODS: In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors. RESULTS: HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015). CONCLUSIONS: HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy