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Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

Abstract Introduction The purpose of this retrospective cohort study was to assess differences in complication rates, early readmission rates, and reasons for readmission following TKA based on discharge destination. Secondarily, we aimed to identify independent risk factors for developing any adverse event (AAE) in the 30-day postoperative period. Methods The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) was filtered using current procedural terminology (CPT) codes to identify patients undergoing TKA from 2015 to 2020. Patients were divided into three cohorts based on discharge destination: home, skilled nursing facility (SNF), or inpatient rehabilitation facility (IRF). Propensity score matching was used to account for confounding variables. Statistical analysis was conducted using one-way analysis of variance (ANOVA), Chi-square tests, and multivariable logistic regression. Results 352,824 patients were initially identified with 303,375 discharged home, 31,635 discharged to SNF, and 17,814 discharged to IRF. Following propensity score matching, there were 5,000 patients in each cohort. Regarding postoperative complications, the home cohort had significantly a lower readmission rate (p = 0.01) and rate of any adverse event (p

Objective Caroverine is an antagonist of non-NMDA and NMDA glutamate receptors. Cochlear synaptic tinnitus arises from a synaptic disturbance of NMDA or non-NMDA receptors on the afferent dendrites of spiral ganglion neurons. This forms a basis for the use of caroverine in the treatment of tinnitus. Hence, the present study was carried out to find the effect of oral caroverine in the treatment of tinnitus. Methodology This quasi-experimental study was carried out on sixty consecutive patients of tinnitus. Thirty patients were given the usual standard of care consisting of Tab. Cinnarizine 25mg twice daily along with fixed dose combination Cap. B-complex and Ginkgo biloba once daily for ninety days and thirty patients were given Cap. Caroverine 40mg, twice daily for ninety days. Outcome assessment was done using the tinnitus case history questionnaire, tinnitus handicap inventory score, and VAS. The data were analyzed using GraphPad Prism Trial Version. A P value ≤ 0.05 was taken as statistically significant. Results There was a significant improvement in the tinnitus case history questionnaire score at 90 days in patients suffering from mild tinnitus when treated with caroverine. There was a larger decrease in the tinnitus handicap inventory score at 90 days of treatment in the caroverine-treated patients. The median VAS showed an improvement in the caroverine-treated group. The overall reduction in tinnitus in the caroverine-treated group was 53.3% with an odds ratio, 95% CI of 0.375 (0.12-1.08). Conclusion Oral caroverine was found to be better than the usual standard of care in reducing mild cochlear synaptic tinnitus. It also improved sensory–neural hearing loss during the treatment period.

Abstract-: Partial shading deteriorates the overall performance of photovoltaic (PV) arrays by reducing the power output. Various shading mitigation strategies have been proposed in the literature with vulnerabilities of limited applications, switches, sensor counts, design, cost, and complexities. In this paper, a multi-string differential power processing (MS-DPP) based voltage equalizer is proposed for power output improvement in the PV arrays during shading. The equalizer is utilized for the series-parallel array which is equipped with a shading detection system achieved from the optimal placement of minimum sensor counts. The technique uses the concept of a switching capacitor that balances the voltage ratio between the modules of individual strings to ensure higher power generation and convex power curves during shading. The system is simulated and validated in MATLAB simulation and further verified on the OPAL-RT 4510 hardware-in-loop FPGA-based real-time platform. The technique is executed on three array sizes and compared with existing techniques under static and dynamic partial shading cases. The analysis shows that MS-DPP enhances the array power output with a conversion efficiency higher than 99 % during shading with lower system size and 98.38 % and 95.05 % reduced counts of switches and sensors than dynamic reconfigurations.

Background The Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition of Sex Selection) Act (PC&PNDT Act), 1994 was enacted to prevent sex determination and female feticide. As a mandatory statutory requirement, All India Institute of Medical Sciences, New Delhi, India has to renew its PC&PNDT license after every 5 years.

Nowadays, nanotechnology is extensively employed in the medical profession. In this study, we used the aqueous extract of the bark of Mitragyna parvifolia to synthesize silver nanoparticles (AgNPs) by microwave-assisted green synthesis. The synthesis of AgNPs was confirmed by visual color change to brown color and characteristic surface plasmon resonance peak at 432 nm. The hydrodynamic diameter of the AgNPs was 171.81 nm having a zeta potential of −24.14 mV; Fourier Transmission Infrared Spectroscopy confirmed the presence of different functional groups on the NP surface; Scanning Electron Microscope and High-Resolution Transmission Electron Microscopy indicated predominantly circular shape of nanoparticle; Selected Area Electron Diffraction and X-ray Diffraction analyses determined the crystalline structure of AgNPs. Energy-Dispersive X-ray indicated the elemental composition and formation of AgNPs. The AgNPs were screened at different concentrations for antioxidant activity, antimicrobial, and anticancer potential in breast cancer cells (MCF-7 and MDA-MB-231). The AgNPs exhibited remarkable antioxidant, antimicrobial, and anticancer activities. The sedative and antinociceptive activities were also tested on Swiss albino mice, which showed mild sedative and very potent antinociceptive activity. However, detailed mechanistic studies are warranted in the future for clinical application of the AgNPs as a biologically active agent as well as a carrier for drug delivery.

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the targeted chromosome, including in preclinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells (NCT03399448), reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.

Solar photovoltaic (PV) power plants’ performance is severely impacted by multi-level irradiances or partial shading, leading to power losses and voltage instability. Also, partial shading adds further complexity to the maximum power point tracking algorithms by introducing numerous peaks in the power curves, resulting in additional losses. Numerous solutions are presented to deal with shading losses, and dynamic reconfiguration is the most effective; however, higher switch count and complex architecture make it impractical in real-world implementation. Hence, this study proposes a low-complexity architecture based on the grouped string voltage balancing approach. This approach utilizes a voltage balancing converter connected to groups of strings to enhance the power output of the array of PV plants, maintain overall system voltage stability, and eliminate the possibility of multiple peaks formation in the power curves. The effectiveness of the proposed approach is tested under numerous static and dynamic partial shadings and analyzed using power curves, power output, losses, efficiencies, and voltage stability. The validation is done by comparing the proposed approach with conventional and advanced architectures for a 32.5 kW system. The results show that the proposed method requires a 50 % reduced switch count than existing techniques, achieves 99.54 % efficiency, and maintains an average voltage stability of 0.01.

Natural sequence variation within mitochondrial DNA (mtDNA) contributes to human phenotypes and may serve as natural genetic markers in human cells for clonal and lineage tracing. We recently developed a single-cell multi-omic approach, called mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq), enabling concomitant high-throughput mtDNA genotyping and accessible chromatin profiling. Specifically, our technique allows the mitochondrial genome-wide inference of mtDNA variant heteroplasmy along with information on cell state and accessible chromatin variation in individual cells. Leveraging somatic mtDNA mutations, our method further enables inference of clonal relationships among native ex vivo-derived human cells not amenable to genetic engineering-based clonal tracing approaches. Here, we provide a step-by-step protocol for the use of mtscATAC-seq, including various cell-processing and flow cytometry workflows, by using primary hematopoietic cells, subsequent single-cell genomic library preparation and sequencing that collectively take ~3-4 days to complete. We discuss experimental and computational data quality control metrics and considerations for the extension to other mammalian tissues. Overall, mtscATAC-seq provides a broadly applicable platform to map clonal relationships between cells in human tissues, investigate fundamental aspects of mitochondrial genetics and enable additional modes of multi-omic discovery.

The present paper analyzes the relationship between perceived public service performance, trust in the government, and citizens' willingness to participate in water governance with insights into broader state–citizen relations. The study is based on a household survey conducted in June 2022 that employed a multistage stratified random sampling within the Greater Visakhapatnam Municipal Corporation limits of Andhra Pradesh, a southern state of India. The analysis reveals that citizens' perception of water service delivery performance positively affects trust in water managers while negatively affecting their willingness to participate in water governance. In contrast, the citizens' trust in water managers positively correlates to their willingness to participate. Moreover, the identified correlations among the three variables elucidate a circular pattern. The intricate circular pattern observed among these three variables complicates the citizen–state relationship. Understanding and navigating this complex web of relationships is crucial for policymakers and researchers seeking to enhance citizen participation and trust in water services. The circular nature of these interactions underscores the need for holistic and integrated approaches in addressing the multifaceted dynamics within the citizen–state relationship. HIGHLIGHTS Investigates the interplay among citizens'perceptions of water service delivery, trust in water managers, and willingness to participate.; Establishes evidence for mutual reciprocity among the three essential aspects of water governance.; Contributes empirically from a city in the Global South.; The study findings are instrumental in contributing to effective water management practices, strengthening the citizen–state relationship.;

Current implant therapy is a frequently employed treatment for individuals who have lost teeth, as it offers functional and biological advantages over old prostheses. Concurrently, active exploration of intervention strategies aims to prevent the progression of peri-implant diseases and manage the existing peri-implant tissue damage. Indian Society of Periodontology has recognized the need for systematic documents to update the everyday clinical practice of general dental practitioners and has provided evidence-based consensus documents, namely good clinical practice recommendations from time to time to raise the oral health-related awareness and standards of oral health-care delivery across the country. The current clinical practice recommendations focused on peri-implant care to bridge the gap between academic theory and clinical practice by compiling evidence-based suggestions for preventing and treating peri-implant diseases. Twenty-eight subject experts across the country prepared these recommendations after a thorough literature review and group discussions. The document has been prepared in three sections covering peri-implant health and maintenance, peri-implant mucositis, and peri-implantitis. It will be a quick and concise reference for oral implant practitioners in patient management. The guidelines provide distinct definitions, signs, and symptoms, treatment required; recall visit specifications for plausible clinical case situations, and home-care recommendations regarding maintaining peri-implant health. The document advocates combined efforts of oral implant practitioners and the population at large with evidence-based, integrated, and comprehensive peri-implant care. By providing accessible, applicable guidance, these guidelines would empower dental professionals to uphold the well-being of implant patients and ensure the long-term success of implant therapy.

Abstract The proposed work contains three major contribution, such as smart data collection, optimized training algorithm and integrating Bayesian approach with split learning to make privacy of the patent data. By integrating consumer electronics device such as wearable devices, and the Internet of Things (IoT) taking THz image, perform EM algorithm as training, used newly proposed slit learning method the technology promises enhanced imaging depth and improved tissue contrast, thereby enabling early and accurate disease detection the breast cancer disease. In our hybrid algorithm, the breast cancer model achieves an accuracy of 97.5 percent over 100 epochs, surpassing the less accurate old models which required a higher number of epochs, such as 165.

Introduction: Acute Coronary Syndrome (ACS) is a term that encompasses various clinical presentations such as ST-Segment Elevation Myocardial Infarction (STEMI), Non STEMI (NSTEMI), or unstable angina. Neutrophil Gelatinase-associated Lipocalin (NGAL), also known as lipocalin-2, belongs to the lipocalin category of extracellular proteins. Recent research indicates that NGAL levels are increased in different cardiac situations, regardless of the presence of acute renal injury. Aim: To compare the levels of serum NGAL and Global Registry of Acute Coronary Events (GRACE) scores between cases with ACS and Angio-negative cases, and to study the correlation of serum NGAL with the GRACE score (clinical severity score) in ACS patients. Materials and Methods: A cross-sectional study was conducted with 128 patients at the Department of Biochemistry, MKCG Medical College and Hospital, Berhampur, Odisha, India, presenting to the Cardiac Emergency Department from November 2020 to August 2021. Coronary Angiograms (CAG) were done to confirm the presence of Coronary Artery Disease (CAD), and patients were grouped accordingly as Group-1 with ACS patients and Group-2 with angiogram-negative cases. Apart from the routine work-up, including serum urea and creatinine, serum electrolytes, fasting blood sugar, lipid profile, and management, all patients underwent determination of serum NGAL levels and GRACE score at admission. The data were analysis using student’s t-test and Pearson’s correlation test. Results: Among the 128 participants (64 cases in Group-1 and 64 cases in Group-2), Group-1 comprised 37 cases of STEMI, 26 cases of NSTEMI, and one case of unstable angina. Serum NGAL levels were significantly elevated in patients with CAG-proven ACS (140.89±56.47 ng/mL) without any renal dysfunction, sepsis, or overt infection compared to patients without CAD on CAG (52.01±18.39 ng/mL) (p

Atypical parathyroid tumor (APT) is a rare neoplasm of the parathyroid gland, which shows atypical cytological or architectural features and lacks definite diagnosis criteria for malignancy. These cases can cause diagnostic challenges owing to their rarity and similarity with thyroid neoplasm on imaging and fine needle aspiration cytology. Also, differentiating APT from giant parathyroid adenoma or parathyroid carcinoma can be challenging based on clinical, imaging or cytological features. A 49-year-old male presented with clinical features of hyperparathyroidism. On laboratory evaluation, his serum calcium and serum parathyroid hormone was elevated. Imaging studies suggested a possibility of left inferior parathyroid neoplasm, and fine needle aspiration cytology showed features suggestive of parathyroid neoplasm. However, exact categorization of parathyroid tumor was difficult in pre-operative work-up. Possibilities of giant parathyroid adenoma as well as parathyroid carcinoma were considered. A final diagnosis of an atypical parathyroid tumor was made after detailed histopathological evaluation given focal capsular invasion but lack of unequivocal evidence of malignancy in the resected specimen. APT is a rare neoplasm of uncertain malignant potential. Knowledge of the radiological and pathological features will be helpful in accurately identifying the lesion and avoiding misdiagnosis.