SARS-CoV-2 inflammation durably imprints memory CD4 T cells.

Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation.

Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions.

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions.

Multiomics Assessment of the Gut Microbiome in Rare Hyperoxaluric Conditions.

Introduction: Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through the activity of its oxalate-degrading enzymes (ODEs). In this cross-sectional study, we leverage multiomics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome.

Geographic and racial variability in kidney, cardiovascular and safety outcomes with canagliflozin: A secondary analysis of the CREDENCE randomized trial.

Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups.

Materials And Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes.

Mechanism of an Intrinsic Oscillation in Rat Geniculate Interneurons.

Depolarizing current injections produced a rhythmic bursting of action potentials - a bursting oscillation - in a set of local interneurons in the lateral geniculate nucleus (LGN) of rats. The current dynamics underlying this firing pattern have not been determined, though this cell type constitutes an important cellular component of thalamocortical circuitry, and contributes to both pathologic and non-pathologic brain states. We thus investigated the source of the bursting oscillation using pharmacological manipulations in LGN slices and .

Machine Learning Methods Using Artificial Intelligence Deployed on Electronic Health Record Data for Identification and Referral of At-Risk Patients From Primary Care Physicians to Eye Care Specialists: Retrospective, Case-Controlled Study.

Background: Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans suffer from vision loss as a result of undiagnosed or untreated ophthalmic conditions.

Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network.

Distributed hypothalamic-midbrain neural circuits help orchestrate complex behavioral responses during social interactions. Given rapid advances in optical imaging, it is a fundamental question how population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. This paper aims to investigate the correspondence between MFP data and social behaviors.

Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.

Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca release and mitogen-activated protein kinase (MAPK) pathway activation.

Discovery and characterization of dietary antigens in oral tolerance.

Food antigens elicit immune tolerance through the action of regulatory T cells (Tregs) in the intestine. Although antigens that trigger common food allergies are known, the epitopes that mediate tolerance to most foods have not been described. Here, we identified murine T cell receptors specific for maize, wheat, and soy, and used expression cloning to de-orphan their cognate epitopes.

Orco-dependent survival of odorant receptor neurons in ants.

Olfaction is essential for complex social behavior in insects. To discriminate complex social cues, ants evolved an expanded number of () genes. Mutations in the obligate odorant co-receptor gene lead to the loss of ~80% of the antennal lobe glomeruli in the jumping ant .

Premature ventricular complexes after catheter ablation for atrial fibrillation: Accounting for regression to the mean.

Introduction: Prior studies have indicated that the frequency of premature ventricular complexes (PVC) increases after catheter ablation for atrial fibrillation (AF). However, these studies have primarily focused on patients whose PVC burden increased rather than including the full spectrum of outcomes.

Methods And Results: We performed a single-center retrospective cohort study of consecutive patients who underwent first-time AF ablation from 1/2018 to 12/2022 for paroxysmal or persistent AF and had both preablation and postablation rhythm monitoring within 6 months of the procedure.

Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis.

Melanosomal pH is important for the synthesis of melanin as the rate-limiting enzyme, tyrosinase, is very pH-sensitive. The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC-dependent regulation of melanosomal pH were undefined. We now systematically examine four well-characterized melanosomal membrane proteins to determine whether any of them are required for sAC-dependent regulation of melanosomal pH.

Comparing Management Strategies in Patients With Clot-in-Transit.

Background: Clot-in-transit is associated with high mortality, but optimal management strategies remain uncertain. The aim of this study was to compare the outcomes of different treatment strategies in patients with clot-in-transit.

Methods: This is a retrospective study of patients with documented clot-in-transit in the right heart on echocardiography across 2 institutions between January 2020 and October 2023.

Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity.

The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα.

De novo design of proteins housing excitonically coupled chlorophyll special pairs.

Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry.

Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency.

BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress.

PyDesigner v1.0: A Pythonic Implementation of the DESIGNER Pipeline for Diffusion Magnetic Resonance Imaging.

PyDesigner is a Python-based software package based on the original Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline (Dv1) for dMRI preprocessing and tensor estimation. This software is openly provided for non-commercial research and may not be used for clinical care. PyDesigner combines tools from FSL and MRtrix3 to perform denoising, Gibbs ringing correction, eddy current motion correction, brain masking, image smoothing, and Rician bias correction to optimize the estimation of multiple diffusion measures.

ACR Appropriateness Criteria® Pretreatment Evaluation and Follow-Up of Invasive Cancer of the Cervix: 2023 Update.

Cervical cancer is a common gynecological malignancy worldwide. Cervical cancer is staged based on the International Federation of Gynecology and Obstetrics (FIGO) classification system, which was revised in 2018 to incorporate radiologic and pathologic data. Imaging plays an important role in pretreatment assessment including initial staging and treatment response assessment of cervical cancer.

Reduced oxygen extraction fraction in deep cerebral veins associated with cognitive impairment in multiple sclerosis.

Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (SO) in the ICVs.

Proton-coupled transport mechanism of the efflux pump NorA.

Efflux pump antiporters confer drug resistance to bacteria by coupling proton import with the expulsion of antibiotics from the cytoplasm. Despite efforts there remains a lack of understanding as to how acid/base chemistry drives drug efflux. Here, we uncover the proton-coupling mechanism of the Staphylococcus aureus efflux pump NorA by elucidating structures in various protonation states of two essential acidic residues using cryo-EM.

Impact evaluation of invisible intimate partner violence on maternal healthcare utilization in Pakistan.

Introduction: Existing research has shown that intimate partner violence (IPV) may hinder maternal access to healthcare services, thereby affecting maternal and child health. However, current studies have ignored whether emotional intimate partner violence (EV) could negatively affect maternal healthcare use. This study aims to evaluate the impact of invisible IPV on maternal healthcare utilization in Pakistan.

Effects of Elective Revision after Breast Reconstruction on Patient-Reported Outcomes.

Background:  There has been increasing emphasis on patient-reported satisfaction as a measure of surgical outcomes. While previous research has investigated factors influencing patient satisfaction following breast reconstruction, there are few studies on how patient satisfaction is impacted by revision procedures. The purpose of this study was to investigate whether elective revisions following breast reconstruction are significantly associated with changes in patient-reported outcomes and quality of life.

Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes.

The HapImmune platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment.