Multidrug‐resistant (MDR) Gram‐negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol‐dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram‐negative bacterial infections.

Caregiving and other interpersonal interactions often require accurate perception of others' pain from nonverbal cues, but perceivers may be subject to systematic biases based on gender, race, and other contextual factors. Such biases could contribute to systematic under-recognition and undertreatment of pain. In 2 experiments, we studied the impact of perceived patient sex on lay perceivers' pain estimates and treatment recommendations. In Experiment 1 (N = 50), perceivers viewed facial video clips of female and male patients in chronic shoulder pain and estimated patients' pain intensity. Multi-level linear modeling revealed that perceivers under-estimated female patients' pain compared with male patients, after controlling for patients' self-reported pain and pain facial expressiveness. Experiment 2 (N = 200) replicated these findings, and additionally found that 1) perceivers' pain-related gender stereotypes, specifically beliefs about typical women's vs. men's willingness to express pain, predicted pain estimation biases; and 2) perceivers judged female patients as relatively more likely to benefit from psychotherapy, whereas male patients were judged to benefit more from pain medicine. In both experiments, the gender bias effect size was on average 2.45 points on a 0−100 pain scale. Gender biases in pain estimation may be an obstacle to effective pain care, and experimental approaches to characterizing biases, such as the one we tested here, could inform the development of interventions to reduce such biases. Perspective: This study identifies a bias towards underestimation of pain in female patients, which is related to gender stereotypes. The findings suggest caregivers' or even clinicians' pain stereotypes are a potential target for intervention.

Background: The development of heart failure (HF) remains a common complication following an acute myocardial infarction (AMI), and is associated with substantial adverse outcomes. However, the specific predictive biomarkers and candidate therapeutic targets for post-infarction HF have not been fully established. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify key modules, hub genes, and possible regulatory targets involved in the development of HF following AMI. Methods: Genes exhibiting the most (top 50%) variation in expression levels across samples in a GSE59867 dataset were imported to the WGCNA. Gene Ontology and pathway enrichment analyses were performed on genes identified in the key module by Metascape. Gene regulatory networks were constructed using the microarray probe reannotation and bioinformatics database. Hub genes were screened out from the key module and validated using other datasets. Results: A total of 10,265 most varied genes and six modules were identified between AMI patients who developed HF within 6 months of follow-up and those who did not. Specifically, the blue module was found to be the most significantly related to the development of post-infarction HF. Functional enrichment analysis revealed that the blue module was primarily associated with the inflammatory response, immune system, and apoptosis. Seven transcriptional factors, including SPI1, ZBTB7A, IRF8, PPARG, P65, KLF4, and Fos, were identified as potential regulators of the expression of genes identified in the blue module. Further, non-coding RNAs, including miR-142-3p and LINC00537, were identified as having close interactions with genes from the blue module. A total of six hub genes (BCL3, HCK, PPIF, S100A9, SERPINA1, and TBC1D9B) were identified and validated for their predictive value in identifying future HFs. Conclusions: By using the WGCNA, we provide new insights into the underlying molecular mechanism and molecular markers correlated with HF development following an AMI, which may serve to improve risk stratification, therapeutic decisions, and prognosis prediction in AMI patients.

Generalized anxiety disorder (GAD) and panic disorder (PD) are most common anxiety disorders with high lifetime prevalence while the pathophysiology and disease-specific alterations still remain largely unclear. Few studies have taken a whole-brain perspective in the functional connectivity (FC) analysis of these two disorders in resting state. It limits the ability to identify regionally and psychopathologically specific network abnormalities with their subsequent use as diagnostic marker and novel treatment strategy. The whole brain FC using a novel FC metric was compared, that is, scaled correlation, which they demonstrated to be a reliable FC statistics, but have higher statistical power in two-sample t-test of whole brain FC analysis. About 21 GAD and 18 PD patients were compared with 22 matched control subjects during resting-state, respectively. It was found that GAD patients demonstrated increased FC between hippocampus/parahippocampus and fusiform gyrus among the most significantly changed FC, while PD was mainly associated with greater FC between somatosensory cortex and thalamus. Besides such regional specificity, it was observed that psychopathological specificity in that the disrupted FC pattern in PD and GAD correlated with their respective symptom severity. The findings suggested that the increased FC between hippocampus/parahippocampus and fusiform gyrus in GAD were mainly associated with a fear generalization related neural circuit, while the greater FC between somatosensory cortex and thalamus in PD were more likely linked to interoceptive processing. Due to the observed regional and psychopathological specificity, their findings bear important clinical implications for the potential treatment strategy.