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The pace of progress in biomedical research directly depends on techniques that enable the quantitative interrogation of interactions between proteins and other biopolymers, or with their small-molecule ligands. Time-resolved Förster resonance energy transfer (TR-FRET) assay platforms offer high sensitivity and specificity. However, the paucity of accessible and biocompatible luminescent lanthanide complexes, which are essential reagents for TR-FRET-based approaches, and their poor cellular permeability have limited broader adaptation of TR-FRET beyond homogeneous and extracellular assay applications. Here, we report the development of CoraFluors, a new class of macrotricyclic terbium complexes, which are synthetically readily accessible, stable in biological media and exhibit photophysical and physicochemical properties that are desirable for biological studies. We validate the performance of CoraFluors in cell-free systems, identify cell-permeable analogs and demonstrate their utility in the quantitative domain-selective characterization of Keap1 ligands, as well as in isoform-selective target engagement profiling of HDAC1 inhibitors in live cells. CoraFluors, a class of macrocyclic terbium complexes for use in time-resolved FRET, exhibit physicochemical properties desirable for biological studies, including characterization of Keap1 ligands and HDAC1 target engagement profiling in live cells.

Arterial wall damage in Takayasu arteritis (TAK) can progress despite immunosuppressive therapy. Vascular fibrosis is more prominent in TAK than in giant cell arteritis (GCA). The inflamed arterial wall in TAK is infiltrated by M1 macrophages [which secrete interleukin-6 (IL-6)], which transition to M2 macrophages once the inflammation settles. M2 macrophages secrete transforming growth factor beta (TGF-β) and glycoprotein non-metastatic melanoma protein B (GPNMB), both of which can activate fibroblasts in the arterial wall adventitia. Mast cells in the arterial wall of TAK also activate resting adventitial fibroblasts. Th17 lymphocytes play a role in both TAK and GCA. Sub-populations of Th17 lymphocytes, Th17.1 lymphocytes [which secrete interferon gamma (IFN-γ) in addition to interleukin-17 (IL-17)] and programmed cell death 1 (PD1)-expressing Th17 (which secrete TGF-β), have been described in TAK but not in GCA. IL-6 and IL-17 also drive fibroblast activation in the arterial wall. The Th17 and Th1 lymphocytes in TAK demonstrate an activation of mammalian target organ of rapamycin 1 (mTORC1) driven by Notch-1 upregulation. A recent study reported that the enhanced liver fibrosis score (derived from serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and pro-collagen III amino-terminal pro-peptide) had a moderate-to-strong correlation with clinically assessed and angiographically assessed vascular damage. In vitro experiments suggest the potential to target arterial wall fibrosis in TAK with leflunomide, tofacitinib, baricitinib, or mTORC1 inhibitors. Since arterial wall inflammation is followed by fibrosis, a strategy of combining immunosuppressive agents with drugs that have an antifibrotic effect merits exploration in future clinical trials of TAK.

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response. Genome-wide association studies of COVID-19 have identified genetic loci affecting disease severity, but the mechanisms remain to be fully described. Here, the authors use genetically predicted transcriptome, splicing and proteome data to identify potential genes and pathways underlying COVID- 19 severity.

The internalizing spectrum encompasses a subset of psychopathologies characterized by emotional liability, anhedonia, anxiousness, distress, and fear, and includes, among others, diagnoses of major depressive disorder (MDD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). In this review, we describe the vast body of work highlighting a role for sex and gender in the environment, symptom onset, genetic liability, and disorder progression and comorbidities of MDD, GAD, and PTSD. We also point the reader to different language used in diverse fields to describe sexual and gender minorities that may complicate the interpretation of emerging literature from the social sciences, psychiatric and psychological sciences, and genetics. Finally, we identify several gaps in knowledge that we hope serve as launch-points for expanding the scope of psychiatric studies beyond binarized sex-stratification. Despite being under-represented in genomics studies, placing emphasis on inclusion of sexual and gender diverse participants in these works will hopefully improve our understanding of disorder etiology using genetics as one tool to inform how biology (e.g., hormone concentration) and environmental variables (e.g., exposure to traumatic events) contribute to differences in symptom onset, pattern, and long-term trajectory.

Biosurfactants are becoming increasingly popular, but industrial production of biosurfactants is difficult, partly due to high production costs resulting from the need to use expensive substrates. One economically feasible candidate is vegetable oils, which can be directly metabolized without pretreatment. The aim of this work is therefore to investigate the possibility of using vegetable oils for lipopeptide production by Serratia marcescens G8-1. The genetic background of this strain for the production of lipopeptides was investigated using a genomic approach. The biosurfactants were analysed by Ultra-Performance Liquid Chromatography coupled with Electrospray Ionisation Mass Spectrometry. The ability to reduce surface tension was investigated using a tensiometer. The results showed that the best effect in reducing surface tension was achieved by adding waste rapeseed oil. Sunflower and linseed oil also showed good results. Significantly poorer results were obtained when fresh rapeseed oil, sesame oil and pumpkin seed oil were used. The putative gene cluster for cyclic lipopeptides NRPS was identified in the genome of S. marcescens G8-1. The results obtained confirmed that serrawettin W1 is the major biosurfactant produced by S. marcescens G8-1. Of particular interest, the results showed the presence of vinylamycin when rapeseed oil was used.

The strength in nanostructured bainitic steels primarily arises from the fine platelets of bainitic ferrite embedded in carbon-enriched austenite. However, the toughness is dictated by the shape and volume fraction of the retained austenite. Therefore, the exact determination of processing–morphology relationships is necessary to design stronger and tougher bainite. In the current study, the morphology of bainitic ferrite in Fe-0.89C-1.59Si-1.65Mn-0.37Mo-1Co-0.56Al-0.19Cr (wt pct) bainitic steel has been investigated as a function of the prior austenite grain size (AGS). Specimens were austenitized at different temperatures ranging from 900 °C to 1150 °C followed by isothermal transformation at 300 °C. Detailed microstructural characterization has been carried out using scanning electron microscopy and X-ray diffraction. The results showed that the bainitic laths transformed in coarse austenite grains are finer resulting in higher hardness, whereas smaller austenite grains lead to the formation of thicker bainitic laths with a large fraction of blocky type retained austenite resulting in lower hardness.

X‐ray diffraction (XRD) combined with in situ mechanical testing is a powerful, non‐destructive technique that provides valuable information on structural evolution and defect formation during deformation. Unlike many other characterization methods, XRD does not impose constraints on sample dimensions, does not require a vacuum environment, and can be applied to a wide range of materials with periodic structures. However, such experiments present significant challenges due to the need for precise synchronization between independently controlled systems: one managing mechanical loading and the other handling X‐ray measurements. In this work, we report on the successful software‐level integration of a nanoindenter control system directly into the beamline control system. This integration enables full control of both mechanical and diffraction measurements from a single user interface, allowing real‐time synchronization and automation of complex in situ experiments. We demonstrate the capabilities of this setup through uniaxial compression tests on α‐Ti micropillars. Mechanical data from the nanoindenter and XRD patterns were collected simultaneously in an automated mode. Raster scans were performed on the micropillar in its pristine state, at two intermediate deformation stages, and post‐mortem. This approach enabled detailed analysis of mechanical behavior and structural evolution under load, illustrating the effectiveness of the integrated system for advanced in situ studies. This work presents a software‐level integration of nanoindenter control directly into a beamline control system, enabling fully synchronized and automated in situ experiments through unified, real‐time coordination of mechanical loading and X‐ray nanodiffraction measurements.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is significantly associated with risk of depression with various definitions. We compared the rare and common genetic architecture across depression definitions by genetic correlation and showed different genetic relationships between definitions across common and rare variants. In addition, we demonstrated that the effects of rare damaging coding variant burden and polygenic risk score on depression risk are additive. The gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. Our study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders. Despite many common genetic variants being linked to depression, the impact of rare coding variants on depression remains largely unknown. Here, the authors perform a whole-exome sequencing study of depression, providing insights into the rare genetic architecture of depression.

Background Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between genetic risk for complex disease and quantitative physiological measurements collected on large populations. Methods A total of 3075 quantitative lab tests were extracted from Vanderbilt University Medical Center’s (VUMC) EHR system and cleaned for population-level analysis according to our QualityLab protocol. Lab values extracted from BioVU were compared with previous population studies using heritability and genetic correlation analyses. We then tested the hypothesis that polygenic risk scores for biomarkers and complex disease are associated with biomarkers of disease extracted from the EHR. In a proof of concept analyses, we focused on lipids and coronary artery disease (CAD). We cleaned lab traits extracted from the EHR performed lab-wide association scans (LabWAS) of the lipids and CAD polygenic risk scores across 315 heritable lab tests then replicated the pipeline and analyses in the Massachusetts General Brigham Biobank. Results Heritability estimates of lipid values (after cleaning with QualityLab) were comparable to previous reports and polygenic scores for lipids were strongly associated with their referent lipid in a LabWAS. LabWAS of the polygenic score for CAD recapitulated canonical heart disease biomarker profiles including decreased HDL, increased pre-medication LDL, triglycerides, blood glucose, and glycated hemoglobin (HgbA1C) in European and African descent populations. Notably, many of these associations remained even after adjusting for the presence of cardiovascular disease and were replicated in the MGBB. Conclusions Polygenic risk scores can be used to identify biomarkers of complex disease in large-scale EHR-based genomic analyses, providing new avenues for discovery of novel biomarkers and deeper understanding of disease trajectories in pre-symptomatic individuals. We present two methods and associated software, QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a Lab-Wide Association Scan.

Background Physical activity is crucial for maintaining the health and well-being of young adults, particularly in an era characterized by sedentary lifestyles. Objective This study aimed to evaluate leisure-time physical activity levels among university students aged 18–25 years using the Godin Leisure-Time Exercise Questionnaire (GLTEQ), which categorizes physical activity into three levels: strenuous, moderate, and light. Methodology A total of 878 undergraduate and postgraduate students from Garden City University were surveyed during an acculturation program on 28th June 2023. Data were analyzed using descriptive statistics to determine weekly activity scores. Results Mean scores were similar across genders: strenuous (2.55), moderate (3.48), and light (4.45–4.46) activities. The average weekly leisure activity score was 53.81 for males and 53.74 for females. Based on GLTEQ classification, 762 participants (86.8%) were categorized as “Active,” 67 (7.6%) as “Moderately Active,” and 49 (5.6%) as “Insufficiently Active.” Conclusion The findings suggest that the majority of the young adult participants are engaging in adequate levels of physical activity. These baseline values can inform targeted interventions to promote physical activity in similar populations.