Systemic inflammation is associated with worse outcomes from SARS-CoV-2 infection but not neutralizing antibody

Systemic inflammation is associated with COVID-19 mortality rates, but the impact of inflammation on neutralizing antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and on outcomes is poorly understood. This study aimed to determine the association between neutralizing antibody responses, inflammation, and clinical outcomes in hospitalized patients with COVID-19. Two hundred and eight patients presenting to the ED with symptomatic SARS-CoV-2 were included. Neutralization was assessed using the architect angiotensin-converting enzyme-2 (ACE2) binding inhibition assay, and inflammation was assessed using C reactive protein (CRP) and interleukin 6 (IL-6). Medical records were examined for 30-day mortality and 10-day intubation. Correlation between biomarkers was assessed and Kaplan-Meier curves and Cox proportional hazards models were constructed for outcomes. Thirty-seven (18%) patients died and 59 (28%) required intubation. There was a correlation between IL-6 and CRP

Molecular basis of TRPV3 channel blockade by intracellular polyamines

ThermoTRPV1-4 channels are involved in the regulation of multiple physiological processes, including thermo- and pain perception, thermoregulation, itch, and nociception and therefore tight control of their activity is a critical requirement for correct perception of noxious stimuli and pain. We previously reported a voltage-dependent inhibition of TRPV1-4 channels by intracellular polyamines that could be explained by high affinity spermine binding in, and passage through, the permeation path. Here, using electrophysiology and cryo-electron microscopy, we elucidate molecular details of TRPV3 blockade by endogenous spermine and its analog NASPM. We identify a high-affinity polyamine interaction site at the intracellular side of the pore, formed by residues E679 and E682, with no significant contribution of residues at the channel selectivity filter. A cryo-EM structure of TRPV3 in the presence of NASPM reveals conformational changes coupled to polyamine blockade. Paradoxically, although the TRPV3 \u27gating switch\u27 is in the \u27activated\u27 configuration, the pore is closed at both gates. A modified blocking model, in which spermine interacts with the cytoplasmic entrance to the channel, from which spermine may permeate, or cause closure of the channel, provides a unifying explanation for electrophysiological and structural data and furnishes the essential background for further exploitation of this regulatory process

Integration of spatial protein imaging and transcriptomics in the human kidney tracks the regenerative potential of proximal tubules

The organizational principles of nephronal segments are based on anatomical and physiological attributes that are linked to the homeostatic functions of the kidney. Recent molecular approaches have uncovered layers of deeper signatures and states in tubular cells that arise at various time points on the disease trajectory. Here, we introduce an analytical pipeline of multiplexed spatial protein imaging integrated with RNA expression to characterize proximal tubular subpopulations and neighborhoods in human kidney tissue. We demonstrate that, in reference tissue, a large proportion of S1 proximal tubular epithelial cells expresses thymus antigen 1 (THY1), a mesenchymal stromal and stem cell marker that regulates differentiation. Kidney disease is associated with loss of THY1 and transition toward expression of prominin 1 (PROM1), another stem cell marker recently linked to failed repair. Our data support a model in which the interplay between THY1 and PROM1 expression in proximal tubules associates with their regenerative potential and marks the timeline of disease progression

Mendelian randomization study of sleep traits and risk of colorectal cancer

A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (O

Injured tubular epithelia-derived CCN1 promotes the mobilization of fibroblasts toward injury sites after kidney injury

Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles of injured tubule-derived cellular communication network factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interaction

The essential calcium channel of sperm CatSper is temperature-gated

The flagellar calcium channel CatSper is essential for male fertility, as it regulates calcium influx to trigger the hyperactive motility required for sperm to fertilize the egg. Precise activation of CatSper is critical, as premature activation can impair sperm function. While optimal temperature is known to influence fertilization, its effect on CatSper remains unknown. By directly recording from mouse spermatozoa, we reveal that CatSper functions as a temperature-gated ion channel, with a thermal threshold of 33.5 °C and a temperature coefficient

Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters

Sterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological functions and a lack of suitable selective probes for their study. Here, we profile fluorescent steroid-based probes across ten STPs, uncovering substantial differences in their selectivity, aiding the retrospective and prospective interpretation of biological results generated with those probes. These results guided the establishment of an STP screening panel combining diverse biophysical assays, enabling the evaluation of 42 steroid-based natural products and derivatives. Combining this with a thorough structural analysis revealed the molecular basis for STP-specific selectivity profiles, leading to the uncovering of several new potent and selective Aster-B inhibitors and supporting the role of this protein in steroidogenesis

Integrating nonindividual patient features in machine learning models of hospital-onset bacteremia

IMPORTANCE: Hospital-onset bacteremia and fungemia (HOB) are common and potentially preventable complications of hospital care. OBJECTIVE: To assess whether nonindividual patient features, which summarize interactions with other patients and health care workers (HCWs), can contribute to predictive and causal machine learning models for HOB. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included adult patients admitted to Barnes-Jewish Hospital, an academic hospital in St Louis, Missouri, in 2021. Analyses were developed between October 2023 and August 2024 and in April 2025. EXPOSURE: Individual patient features were extracted from electronic health records and used to engineer nonpatient features, including interactions with HCWs and direct or indirect (consecutive room occupancy) patient contact. MAIN OUTCOMES AND MEASURES: HOB was defined as a positive blood culture after the third day of hospitalization. Patients who were hospitalized for more than 3 days were considered at risk for the outcome. We developed 3 gradient boosting models: 2 predictive (with patient features only and with both patient and nonpatient features to predict the occurrence of HOB) and 1 causal to test the association of nonpatient features and HOB. Predictive performance is reported using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC), and the results of the causal model are reported as difference in average effects. Sensitivity analyses separated intensive care unit-onset and ward-onset HOB and included a methicillin-resistant Staphylococcus aureus-specific model to adjust for colonization pressure. RESULTS: Among the 52 442 patients, 34 855 (66.5%) had admissions longer than 72 hours and were included for analysis; of these, 556 (1.6%) developed HOB. The median age for the included patients was 60 (IQR, 44-70) years, 50.5% were female, and obesity was the most frequent comorbidity (25.0%). Nonpatient features, such as a prior occupant of the same room receiving antipseudomonal beta-lactams and the mean number of HCWs per day for the 7 days preceding HOB, improved the model\u27s performance (AUROC, 0.88 [95% CI, 0.88-0.89]; AUPRC, 0.20 [95% CI, 0.20-0.22]) compared with the patient-only model (AUROC, 0.85 [95% CI, 0.85-0.86]; AUPRC, 0.13 [95% CI, 0.12-0.14]) (P \u3c  .001). These 2 features were also associated with a higher likelihood of HOB in the causal gradient boosting model. CONCLUSIONS AND RELEVANCE: These findings suggest that nonindividual patient features may contribute to a comprehensive analysis of HOB when integrated with individual patient features in a machine learning model

High-throughput echocardiography-guided induction of myocardial ischemia/reperfusion in mice

BACKGROUND: Mouse models of myocardial ischemia with subsequent heart failure are common approaches to examine heart failure pathology and possible treatment strategies. We sought to establish a high-throughput approach for echocardiography-guided induction of myocardial ischemia/reperfusion (IR) in mice. METHODS: After visualization of the left coronary artery with high-resolution ultrasound imaging and echocardiographic definition of the level of coronary occlusion, the left anterior descending artery was temporarily occluded with 2 micromanipulator-controlled needles. Functional and molecular changes were assessed and compared with commonly performed surgical techniques. RESULTS: Echocardiography-guided induction of myocardial IR enabled standardized induction of myocardial IR injury with subsequent left ventricular remodeling. Incorporation of various quality control measures throughout the procedure ensured a high success rate and the absence of relevant postinterventional mortality in experienced hands. Compared with surgical approaches, echocardiography-guided induction of myocardial IR showed a quicker recovery time and induced a less pronounced inflammatory response characterized by decreased local and systemic neutrophil counts. Notably, infarct size and subsequent post-myocardial infarction cardiac dysfunction were comparable between methods. The novel procedure was successfully implemented at different academic institutions with imaging expertise and demonstrated high interinstitutional reproducibility. CONCLUSIONS: Echocardiography-guided induction of myocardial IR enables high-throughput induction of myocardial IR injury with precise echocardiographic definition of the occlusion level and immediate evaluation of cardiac function during ischemia. The method provides a more clinically relevant assessment of IR sequelae and offers notable animal welfare advantages by eliminating the need for ventilation and thoracotomy, thereby mitigating potential surgery-related confounders