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Infective endocarditis (IE) is relatively less common in children compared to adults but can result in significant morbidity and mortality. The epidemiology of IE has shifted in recent years, from rheumatic heart disease (less prevalence) to congenital heart disease (increased survival) and an increase in the use of central venous catheters in children with chronic illness. Children with no preexisting cardiac disease can be affected rarely. We present a case of a 13-year-old boy with no cardiac disease, presented with a fever. He had a history of surgery for hypospadias 3 weeks before presentation. He was diagnosed with IE according to modified Duke criteria. The blood cultures grew methicillin-resistant Staphylococci aureus. The case was surgically deferred in view of his clinical condition and was managed medically. We emphasize the importance of having a high index of suspicion for endocarditis in children with fever even without cardiac disease.

Abstract Collection of hematopoietic progenitor cell products [HPC(A)] is deferred if the donor is symptomatic and tests positive for Covid-19. However, donor questionnaires are subjective and may miss minimally symptomatic donors. Alternatively, myalgia associated with Covid-19 infection can be falsely dismissed as an adverse effect of granulocyte stimulating factor (Filgrastim) administered prior to product collection. The likelihood of donors with an underlying acute but minimally symptomatic infection undergoing successful product collection is significant. In these circumstances, it is less known whether Covid-19 infection results in product viremia or alters the clinical outcome of transplant. We aimed to evaluate the above question by studying a donor whose product was collected during acute Covid-19 infection. Aliquots of the product tested negative for SARS-CoV-2 RNA by reverse-transcriptase polymerase chain reaction assay (RT-PCR). Importantly, the donor received an autologous stem cell transplant using the product collected at the time of infection, and their case will be described in this report. We describe one of the very few reports of successful transplant of HPC(A) product collected during acute Covid-19 infection.

Objective: The World Health Organization declared monkeypox (MPX), a global health crisis, in July 2022. Its symptoms include fever, rash, lymphadenopathy, myalgias, and fatigue; there have also been the reports of neurological manifestations and no data on psychiatric manifestations. In our study, we aimed to study neurologic and psychiatric manifestations in MPX patients. Methodology: Our study used the TriNetX database to identify MPX patients along with their age, gender, race, ethnicity, and geographic location data. Using International Classification of Diseases, tenth revision codes for neurological, psychiatric symptoms, and diagnoses, we identified 331 individuals on November 22, 2022, who had neuropsychiatric signs within a month of diagnosis with MPX (n = 1,006). Results: The most common neurological symptom was pain (17.3%) followed by headache (10.3%), while the most frequent psychiatric symptoms were mood disorders (11.9%), emotional issues (10.5%), and anxiety (9.4%). Conclusion: In this study, neuropsychiatric symptoms were present in about one-third of MPX patients. Physicians, neurologists, and psychiatrists should be aware of the potential for neuropsychiatric side effects associated with MPX infection in patients.

Aim: The aim of this study was to find the correlation between different anthropometric parameters of the patient on the length and diameter of the hamstring graft harvested during anterior cruciate ligament (ACL) reconstruction. Materials and Methods: A total of 50 consecutive patients (33 males and 17 females) with ACL deficiency scheduled for reconstruction using hamstring autograft were evaluated prospectively at our institution during the study. Preoperatively, we recorded age, gender, height, weight, and body mass index (BMI). Intraoperative measurements of the final diameter of the graft using sizing tubes calibrated to 1 mm and length of tendon harvested were taken. Correlation coefficient (Pearson’s r) analysis was used. Results: As per the study, height of the patients correlated to graft diameter and length in both Indian men and women (P < 0.001). Although there was no correlation between age, sex, weight, and BMI with graft length and diameter. Conclusion: Anthropometric measurements such as weight, gender, and BMI cannot be used as definitive predictors for the hamstring graft diameter during harvest, but the height of the patients can be taken as a good predictor.

The complexities of User Interface (UI) and User Experience (UX) design are explored in this research paper, along with their respective functions, areas of overlap, and the changing field of customer experience. In the digital age, where technology is developing at a rapid pace, designing innovative and user-focused digital products requires an understanding of the dynamic interplay between UI and UX. This research also examines how emerging trends in the UI/UX field will affect overall customer satisfaction. Additionally, this paper delves into applications of artificial intelligence (AI) in the domains of human-computer interaction (HCI), user experience (UX), and emerging trends in these fields

Introduction: Poor infant feeding practices predispose children to nutritional disorders which may persist into early childhood with life-long consequences. We aimed to find out prevalence of malnutrition among children aged less than six years and to assess infant and young children feeding practices and their impact on malnutrition. Methods: An analytic cross-sectional study was conducted between March 2021 and May 2022 among children up to six years of age registered in the Anganwadi centers of Rajkot district. Using the formula n = Z2pq/e2, a sample size of 504 was estimated, including 10% nonresponders. Samples were drawn using a multistage simple random sampling method. The z scores related to the anthropometric measurements were estimated using the World Health Organization Anthro 2011 software. We reported prevalence of different types of malnutrition and infant and young child feeding practices. A logistic regression was used to identify significant factors for stunting and wasting (P < 0.05). Results: The mean age of the children was 32.43 months (SD 18.7 months). The prevalence of stunting and wasting was found 36.7% and 30.5%, respectively. The prevalence of prelacteal feeding practices was 72.8%. Less than one-fourth (21.4%) of children were exclusively breastfed and 77.9% of the children received complementary feeding at appropriate age. The binary logistic regression model showed that stunted growth was strongly associated with exclusive breastfeeding and complementary foods’ introduction at the appropriate age. Conclusion: As compared to national, state, and district averages, the prevalence of wasting was remarkably higher among children included in the study. In addition, the study underscores the disturbingly high prevalence of prelacteal feeding practices, which can have a detrimental effect on the health of newborns.

This study examines the influence of planting mixture variations on the quality of the percolated water of the rain garden with and without plants. Six planting mixtures in experimental rain gardens have been used. It has been noted that pollutant removal efficiency of RG can exhibit variations based on specific parameters. Notably, RG6, utilizing a planting mix of 75% topsoil and 25% compost, demonstrated the highest performance. These results draw attention to the critical role of the specific planting mixtures in influencing the performance of vital parameters related to pollutant removal. The observation shows that RG5 exhibits exceptional removal efficiency in pH, Total Suspended Solids (TSS), Biological Oxygen Demand (BOD), and Chemical Oxygen Demand (COD), and RG6 performs best in electrical conductivity (EC), Total Dissolved Solids (TDS), Total Nitrogen (TN), and Total Phosphorus (TP) removal. In particular, when analyzing pollutant removal on a surface with Madagascar periwinkle plants, RG6 emerges as the most effective, achieving an impressive efficiency of approximately 49%. For the bare surface, pollutant removal efficiency is 40%. The study outcome will be useful in deciding the composition of the planting mixture, which will keep the rain garden to improve quality and quantitatively hydrological performance, lowering urban flooding magnitude. HIGHLIGHTS The rain garden planting mixture influences pollutant removal efficiency.; The performance of rain garden with plant is superior to a bare rain garden.; The rain garden having a planting mixture of topsoil in the range of 75–80% and compost in the range of 20–25% performance is best.;

The blanket prescription of nitrogen (N) fertilizer often results in irrational fertilization. To address this issue and align the application of nitrogen fertilizers with the crop-specific demand, it is imperative to save nitrogen resources, maximize the uptake and net income, and subside environmental pollution. In this context, a field experiment was carried out in Kumroj, Chitwan, Nepal during 2022 to assess the growth, yield, and profitability of rice production by comparing different precision nitrogen management practices. The study was carried out in a randomized complete block design with seven treatments and three replications. The treatments included decision support tools for nitrogen management such as the Green Seeker (GS), the Soil plant analysis development Development (SPAD) meter, and the Leaf Color Chart (LCC) combined with basal application of nitrogen at 30 kg ha–1 and the Urea briquette Deep Placement (UDP), the Polymer Coated Urea (PCU), and the Recommended Dose of Fertilizers (RDF, 120 kg N ha–1). The growth, yield, yield attributes, and financial data were taken. Precision nitrogen management techniques significantly enhanced rice growth and yield parameters. GS–guided application required the highest nitrogen demand (155 kg ha–1), while SPAD (80 kg ha–1) and UDP (78 kg ha–1) resulted in lower usage. PCU and UDP enhanced plant height, leaf area index, and above–ground dry matter. Higher grain yield (6.64 t ha–1) was attained with LCC, SPAD (6.44 t ha–1), and UDP (6.41 t ha–1) treatments. GS application exhibited the highest straw yield (11.17 t ha–1), while LCC demonstrated the highest benefit–cost ratio (1.96). This study concluded that SPAD and UDP demonstrated the potential to save nitrogen resources, while LCC and UDP were found profitable.

Abstract Background The global COVID-19 pandemic has brought forth multifaceted healthcare challenges, including the emergence of COVID-19-associated mucormycosis (CAM). This study investigates demographics, clinical presentation, endoscopic grading, radiological correlations, treatment modalities, and outcomes of CAM in Central India. Methods A retrospective analysis of 312 CAM patients (April-June 2021). Data included demographics, clinical profiles, endoscopic and radiological findings, laboratory results, and treatments. A novel endoscopic grading system was utilized to assess the severity of mucormycosis lesions. Statistical analysis, including chi-squared tests, was performed. Results Among 312 patients, 65% were male, 82% had comorbidities, and 84% presented with facial swelling. Endoscopic grading correlated with radiological manifestations (p

Abstract Background Cancer patients are vulnerable to infections due to immunosuppression caused by cancer itself and its treatment. The emergence of antimicrobial-resistant bacteria further complicates the treatment of infections and increases the mortality and hospital stays. This study aimed to investigate the microbial spectrum, antimicrobial resistance patterns, risk factors, and their impact on clinical outcomes in these patients. Methods A prospective study was conducted at a tertiary care cancer hospital in Patna, Bihar, India, which included cancer patients aged 18 years and older with positive microbial cultures. Results This study analysed 440 patients, 53% (234) of whom were females, with an average age of 49.27 (± 14.73) years. A total of 541 isolates were identified, among which 48.01% (242) were multidrug resistant (MDR), 29.76% (150) were extensively drug resistant (XDR), and 19.84% (112) were sensitive. This study revealed that patients who underwent surgery, chemotherapy, were hospitalized, had a history of antibiotic exposure, and had severe neutropenia were more susceptible to MDR and XDR infections. The average hospital stays were 16.90 (± 10.23), 18.30 (± 11.14), and 22.83 (± 13.22) days for patients with sensitive, MDR, and XDR infections, respectively. The study also revealed overall 30-day mortality rate of 31.81% (140), whereas the MDR and XDR group exhibited 38.92% and 50.29% rates of 30-day mortality respectively (P

Abstract Stramenopile algae contribute significantly to global primary productivity, and one class, Eustigmatophyceae, is increasingly studied for applications in high-value lipid production. Yet much about their basic biology remains unknown, including the nature of an enigmatic, pigmented globule found in vegetative cells. Here, we present an in-depth examination of this “red body,” focusing on Nannochloropsis oceanica. During the cell cycle, the red body forms adjacent to the plastid, but unexpectedly it is secreted and released with the autosporangial wall following cell division. Shed red bodies contain antioxidant ketocarotenoids, and overexpression of a beta-carotene ketolase results in enlarged red bodies. Infrared spectroscopy indicates long-chain, aliphatic lipids in shed red bodies and cell walls, and UHPLC-HRMS detects a C32 alkyl diol, a potential precursor of algaenan, a recalcitrant cell wall polymer. We propose that the red body transports algaenan precursors from plastid to apoplast to be incorporated into daughter cell walls.

Purpose: Knee osteoarthritis (KOA) is a very common cartilage disorder affecting millions of people globally and is characterized by pain, stiffness, swelling, loss of articular cartilage, and osteophyte formation, resulting in disability. The presently available treatments for KOA are palliative. Hence, there is a need to explore a non-surgical treatment portfolio. Bone marrow aspirate concentrate (BMAC) is one of the predominant attention-drawing managements/treatments for KOA in recent times due to its potential advantages of disease-modifying and regeneration capacities. Principle: This study aimed to evaluate the role of single-injection autologous BMAC as a therapeutic option in the treatment of KOA and evaluate the functional and clinical outcomes of KOA patients. In this study, 132 patients with KOA (Kellgren and Lawrence (KL) grade II and III) were included as per the inclusion criteria. Autologous bone marrow was aspirated and separated, and concentrated bone marrow aspirate was administered into the knee joint of the affected individual. Results: At the end of the 12th month (end of the follow-up period), 95% of patients showed complete pain relief and improvement in joint function, which shows that the results were promising and encouraging. Unpaired t-test results also indicated that the two-tailed p-value is less than 0.0001, and the difference is extremely statistically significant. No adverse effects were observed in the study patients. Conclusions: BMAC therapy has potential, with satisfactory, efficient, and durable results in KL grades II and III in KOA patients. This can be a safe alternative therapy in the treatment of KOA, especially in the early grades of OA. In summary, to the best of our knowledge, this is the first study from India that evaluated BMAC efficacy both subjectively and objectively in KOA (KL-II and KL-III) patients.

Abstract Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell™. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC = 0.62, AUC = 0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell ‘avatars’ capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.

Abstract While TGF-β signaling is essential for microglial function, the cellular source of TGF-β1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-β1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-β1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ plaques and neurofibrillary tangles. Chronic inflammation and synaptic dysfunction lead to disease progression and cognitive decline. Small extracellular vesicles (sEVs) are implicated in AD progression by facilitating the spread of pathological proteins and inflammatory cytokines. This study investigates synaptic dysfunction and neuroinflammation protein markers in plasma-derived sEVs (PsEVs), their association with Amyloid-β and tau pathologies, and their correlation with AD progression. Methods A total of 90 [AD = 35, mild cognitive impairment (MCI) = 25, and healthy age-matched controls (AMC) = 30] participants were recruited. PsEVs were isolated using a chemical precipitation method, and their morphology was characterized by transmission electron microscopy. Using nanoparticle tracking analysis, the size and concentration of PsEVs were determined. Antibody-based validation of PsEVs was done using CD63, CD81, TSG101, and L1CAM antibodies. Synaptic dysfunction and neuroinflammation were evaluated with synaptophysin, TNF-α, IL-1β, and GFAP antibodies. AD-specific markers, amyloid-β (1–42), and p-Tau were examined within PsEVs using Western blot and ELISA. Results Our findings reveal higher concentrations of PsEVs in AD and MCI compared to AMC (p

Abstract The article introduces an innovative approach to global optimization and feature selection (FS) using the RIME algorithm, inspired by RIME-ice formation. The RIME algorithm employs a soft-RIME search strategy and a hard-RIME puncture mechanism, along with an improved positive greedy selection mechanism, to resist getting trapped in local optima and enhance its overall search capabilities. The article also introduces Binary modified RIME (mRIME), a binary adaptation of the RIME algorithm to address the unique challenges posed by FS problems, which typically involve binary search spaces. Four different types of transfer functions (TFs) were selected for FS issues, and their efficacy was investigated for global optimization using CEC2011 and CEC2017 and FS tasks related to disease diagnosis. The results of the proposed mRIME were tested on ten reliable optimization algorithms. The advanced RIME architecture demonstrated superior performance in global optimization and FS tasks, providing an effective solution to complex optimization problems in various domains.

This study presents a method for the inverse analysis of fluid flow problems. The focus is put on accurately determining boundary conditions and characterizing the physical properties of granular media, such as permeability, and fluid components, like viscosity. The primary aim is to deduce either constant pressure head or pressure profiles, given the known velocity field at a steady-state flow through a conduit containing obstacles, including walls, spheres, and grains. The lattice Boltzmann method (LBM) combined with automatic differentiation (AD) (AD-LBM) is employed, with the help of the GPU-capable Taichi programming language. A lightweight tape is used to generate gradients for the entire LBM simulation, enabling end-to-end backpropagation. Our AD-LBM approach accurately estimates the boundary conditions for complex flow paths in porous media, leading to observed steady-state velocity fields and deriving macro-scale permeability and fluid viscosity. The method demonstrates significant advantages in terms of prediction accuracy and computational efficiency, making it a powerful tool for solving inverse fluid flow problems in various applications.

Planetary Health emphasises the sustainability of natural systems for human well-being, linking human health directly with environmental health. This interdisciplinary concept has gained importance as anthropogenic activities have led to climate changes and health impacts. Despite efforts, a cohesive approach to planetary health from local to global levels remains lacking. The present review analysed 24 sources, including grey literature and published studies, identifying 40 interventions aimed at improving planetary health. The majority of research, primarily from the United States, focuses on reducing air pollution and greenhouse gas emissions. Effective strategies highlighted include promoting active transportation, improving diets, increasing physical activity, and engaging with indigenous communities to protect both environmental and human health. However, a significant gap exists in integrating these interventions through a unified informatics tool, which could enhance coordination and implementation of planetary health measures globally. The review underscores the necessity for a more integrated approach and the development of a global database to consolidate and manage planetary health interventions effectively.

Abstract Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation.

Abstract The 2021 tuberculosis (TB) preventive treatment guidelines in India included silicosis as a screening group, yet latent TB infection (LTBI) testing for silica-dust-exposed individuals is underemphasized. Focusing on an estimated 52 million silica-dust-exposed workers, particularly agate-stone workers in Khambhat, Gujarat, our study aims to estimate LTBI prevalence, identify predictors, and gather insights from TB and silicosis experts. Employing a sequential explanatory mixed-methods approach, a cross-sectional study involved 463 agate-stone workers aged ≥ 20 years in Khambhat, using IGRA kits for LTBI testing. In-depth interviews with experts complemented quantitative findings. Among agate-stone workers, 58% tested positive for LTBI, with predictors including longer exposure, type of work, and BCG vaccination. Our findings reveal a nearly double burden of LTBI compared to the general population, particularly in occupations with higher silica dust exposure. Experts advocate for including silica-dust-exposed individuals in high-risk groups for LTBI testing, exploring cost-effective alternatives like improved skin sensitivity tests, and shorter TB preventive treatment regimens to enhance compliance. Future research should explore upfront TB preventive treatment for silica-dust-exposed individuals with high LTBI prevalence and optimal exposure duration. This study underscores the urgent need for policy changes and innovative approaches to TB prevention among silica-dust-exposed populations, impacting global occupational health strategies.

Abstract Introduction Depression is a pervasive mental health condition that affects individuals across various demographic categories, including imprisoned adults. The prevalence of mental health problems among inmates worldwide is considerably higher than in the general population, and it is estimated that 11% of inmates have significant mental disorders, such as anxiety and depression. This study aimed to find out the prevalence of depression and factors associated with it among the prisoners of Gandaki Province, Nepal. Methods A descriptive cross-sectional study was conducted among the inmates in Gandaki Province, Nepal. Data were collected from 223 inmates, who were recruited through systematic random sampling from eight district-level prisons. The Beck Depression Inventory-II was used to measure depression, with the cumulated score dichotomized into depressed and not-depressed categories. Additionally, a structured questionnaire was employed to capture socio-demographic and imprisonment-related variables. Bivariate and multivariable logistic regressions were performed to examine the factors associated with depression. Results Findings revealed that 18.8% of the inmates exhibited symptoms of depression. Inmates with health problems [(adjusted odds ratio (aOR) = 2.39], suicide ideation during imprisonment (aOR = 4.37), and attempted suicide before imprisonment (aOR = 7.97) had a statistically significant relationship with depression. This study revealed a notable prevalence of depression among incarcerated individuals in the Gandaki Province of Nepal. Conclusion The findings imply a crucial need for psychosocial and rehabilitative interventions to enhance inmates’ mental health and overall well-being.

Abstract Background Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied. Methods Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal–Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC. Results There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response. Conclusions Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer. Trial registration NCT02022202 . Registered 20 December 2013.

Cervical cancer (CC) is a key contributor to cancer‐related mortality in several countries. The identification of molecular markers and the underlying mechanism may help improve CC management. We studied the regulation and biological function of the chromosome 14 microRNA cluster (C14MC; miR‐379/miR‐656) in CC. Most C14MC members exhibited considerably lower expression in CC tissues and cell lines in The Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma patient cohorts. Bisulfite Sanger sequencing revealed hypermethylation of the C14MC promoter in CC tissues and cell lines. 5‐aza‐2 deoxy cytidine treatment reactivated expression of the C14MC members. We demonstrated that C14MC is a methylation‐regulated miRNA cluster via artificial methylation and luciferase reporter assays. C14MC downregulation correlated with poor overall survival and may promote metastasis. C14MC activation via the lentiviral‐based CRISPRa approach inhibited growth, proliferation, migration, and invasion; enhanced G2/M arrest; and induced senescence. Post‐transcriptional regulatory network analysis of C14MC transcriptomic data revealed enrichment of key cancer‐related pathways, such as metabolism, the cell cycle, and phosphatidylinositol 3‐kinase (PI3K)–AKT signaling. Reduced cell proliferation, growth, migration, invasion, and senescence correlated with the downregulation of active AKT, MYC, and cyclin E1 (CCNE1) and the overexpression of p16, p21, and p27. We showed that C14MC miRNA activation increases reactive oxygen species (ROS) levels, intracellular Ca2+ levels, and lipid peroxidation rates, and inhibits epithelial–mesenchymal transition (EMT). C14MC targets pyruvate dehydrogenase kinase‐3 (PDK3) according to the luciferase reporter assay. PDK3 is overexpressed in CC and is inversely correlated with C14MC. Both miR‐494‐mimic transfection and C14MC activation inhibited PDK3 expression. Reduced glucose uptake and lactate production, and upregulation of PDK3 upon C14MC activation suggest the potential role of these proteins in metabolic reprogramming. Finally, we showed that C14MC activation may inhibit EMT signaling. Thus, C14MC is a tumor‐suppressive and methylation‐regulated miRNA cluster in CC. Reactivation of C14MC can be useful in the management of CC.

Abstract To date, degraded mangrove ecosystem restoration accomplished worldwide primarily aligns towards rehabilitation with monotypic plantations, while ecological restoration principles are rarely followed in these interventions. However, researchers admit that most of these initiatives' success rate is not appreciable often. An integrative framework of ecological restoration for degraded mangroves where site-specific observations could be scientifically rationalized, with co-located reference pristine mangroves as the target ecosystem to achieve is currently distinctively lacking. Through this experimental scale study, we studied the suitability of site-specific strategies to ecologically restore degraded mangrove patches vis-à-vis the conventional mono-species plantations in a highly vulnerable mangrove ecosystem in Indian Sundarbans. This comprehensive restoration framework was trialed in small discrete degraded mangrove patches spanning ~ 65 ha. Site-specific key restoration components applied are statistically validated through RDA analyses and Bayesian t-tests. 25 quantifiable metrics evaluate the restoration success of a ~ 3 ha degraded mangrove patch with Ridgeline distribution, Kolmogorov–Smirnov (K-S) tests, and Mahalanobis Distance (D2) measure to prove the site’s near-equivalence to pristine reference in multiple ecosystem attributes. This restoration intervention irrevocably establishes the greater potential of this framework in the recovery of ecosystem functions and self-sustenance compared to that of predominant monoculture practices for vulnerable mangroves.

Introduction: Bacterial Meningitis (BM) is a serious health problem worldwide with high mortality and permanent long-term neurological sequelae. Cerebrospinal Fluid (CSF) analysis is the cornerstone for diagnosing BM, but the lack of specificity creates a difficult clinical scenario for initiating proper treatment. Empiric antibiotic use in patients with suspected meningitis at primary care settings decreases the yield of CSF culture and alters CSF cytological and biochemical findings, making it further difficult to diagnose BM. To overcome this difficulty, there is a need for other biochemical markers with higher sensitivity and specificity. Aim: To determine the diagnostic sensitivity and specificity of Procalcitonin (PCT) in serum and CSF in patients with BM and compare its diagnostic accuracy in both sample types. Materials and Methods: A cross-sectional study was conducted in the Department of Internal Medicine at a tertiary care centre in eastern India from September 2018 to August 2020. A total of 82 adult patients with meningitis were recruited as per the protocol, and CSF analysis was done along with estimation of PCT in serum and CSF. Receiver Operating Characteristics (ROC) curve analysis of serum and CSF PCT was used to determine sensitivity and specificity with a 95% confidence interval. Results: Out of the 82 patients recruited, 30 (36.6%) had BM. CSF PCT with a cut-off value of >0.45 ng/mL had a sensitivity of 86.7% and specificity of 92.3%. The sensitivity of serum PCT with a cut-off value of >0.6 ng/mL was 83.3%, and specificity was 86.5%. There was no statistically significant difference in sensitivity and specificity between CSF and serum PCT in patients with BM (p-value=0.7988). Conclusion: Both serum and CSF PCT were found to have high sensitivity and specificity as markers for diagnosing BM without any statistically significant difference between them.

Terminalia arjuna (Roxb) Wight & Arn is a tropical evergreen woody tree endemic to India that grows along river banks and canals. It has a significant medicinal value, particularly for heart disorders, where tree bark is used to treat circulatory ailments. The stiff seed coat is a key impediment to obtaining good and uniform germination, particularly in inert and low-moisture-holding capacity growing media such as coal-burned fly ash. The current study was designed to look into the effect of arbuscular mycorrhizal fungi on seed germination and seedling growth in Terminalia arjuna using fly ash as a growing medium. The 360 seeds were sown in two sets, for each treatment used in mycorrhizae and control without mycorrhiza inoculation. The results showed that seeds germinated with mycorrhiza inoculation had higher germination (77.77%), germination capacity (83.88%), germination energy (19.44%), germination value (24.16%), mean daily germination (9.33 seeds), peak value (2.59), cumulative germination (77.77%), and germination speed (23.40%) than seeds germinated without mycorrhiza inoculation. The use of mycorrhizal fungi in fly ash showed promising results, which could serve as a foundation for fly ash restoration and stability programs utilizing Terminalia arjuna as one of the powerful trees.

Background: Disseminated septicemia and endocarditis are extremely rare complications of Pasteurella infection and are mainly seen in patients with associated major comorbidities. Clinical Description: A 13-year-old boy, who had undergone surgery for congenital heart disease in early childhood, presented with prolonged fever, gross hematuria, and oliguria. The child was found to be conscious and febrile, with tachycardia, pallor, and edema. There was a systolic murmur in the left upper sternal border with hepatosplenomegaly. Management and Outcome: Routine investigations revealed anemia, low serum albumin, and progressively worsening renal functions, with urinalysis showing significant proteinuria and red cells. Serial blood cultures showed growth of Pasteurella multocida. Echocardiography showed vegetation in conduit (homograft) connecting the right ventricle with the pulmonary artery. Despite intravenous antibiotics, the clinical condition did not improve, so the conduit was removed surgically, following which the child recovered. Conclusion: This case creates awareness regarding infective endocarditis in a child being caused by a rare organism P. multocida, involving a surgically created conduit. The case also highlights the importance of timely surgical removal of the source combined with a prolonged course of antibiotics in a successful recovery.

Aim: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension. Methodology: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP

Introduction: Severe trauma-induced blood loss can lead to metabolic acidosis, shock, and death. Identification of abnormalities in the bicarbonate and serum markers may be seen before frank changes in vital signs in the hemorrhaging trauma patient, allowing for earlier lifesaving interventions. In this study the author aimed to evaluate the usefulness of serum bicarbonate and other lab markers as predictors of mortality in trauma patients within 30 days after injury. Methods: This retrospective, propensity-matched cohort study used the TriNetX database, covering approximately 92 million patients from 55 healthcare organizations in the United States, including 3.8 million trauma patients in the last two decades. Trauma patients were included if they had lab measurements available the day of the event. The analysis focused on mortality within 30 days post-trauma in comparison to measured lab markers. Cohorts were formed based on ranges of bicarbonate, lactate, and base excess levels. Results: Before propensity score matching, a total of 1,275,363 trauma patients with same-day bicarbonate, lactate, or base excess labs were identified. A significant difference in mortality was found across various serum bicarbonate lab ranges compared to the standard range of 21–27 milliequivalents per liter (mEq/L), post-propensity score matching. The relative risk of death was 6.806 for bicarbonate ≤5 mEq/L; 8.651 for 6–10; 6.746 for 11–15; 2.822 for 16–20; and 1.015 for bicarbonate ≥28. Serum lactate also displayed significant mortality outcomes when compared to a normal level of ≤2 millimoles per liter. Base excess showed similar significant correlation at different values compared to a normal base excess of −2 to 2 mEq/L. Conclusion: This study, approximately 100 times larger than prior studies, associated lower bicarbonate levels with increased mortality in the trauma patient. While lactate and base excess offer prognostic value, lower bicarbonate values have a higher relative risk of death. The greater predictive value of bicarbonate and accessibility during resuscitations suggests that it may be the superior prognostic marker in trauma.

Most of the building stock in Nepal is based on masonry construction, which includes monumental, administrative, and residential structures. These structures are vulnerable during earthquakes, as evidenced by the massive structural damage, loss of human life, and property damage due to a lack of proper assessment and appropriate strengthening measures. An analysis of the seismic vulnerability of existing old Newari brick masonry buildings in the Pokhara Valley is presented. These buildings were built using indigenous knowledge and technology. The investigation is based on analytical studies, with some material properties obtained from field tests. Proper modeling of a masonry structure is crucial for reliable seismic resistance and structural design. However, modeling a real masonry structure is a challenging and computationally demanding task due to its complicated framework, requiring in-depth knowledge, realistic material properties, and relevant information. The aim of this research is to assess the seismic performance of old Newari masonry buildings using stress level and fragility curves. The research issues are addressed analytically through linear time history analysis using the finite element program-based software Sap 2000 v20. In dynamic analysis, numerical building models were subjected to three synthetic earthquakes. The performance status of the building based on various stress levels is evaluated, and weak regions are identified. The fragility curve of the structure is assessed, considering the ground motion parameters in the locality. The fragility function is plotted with the probability of failure at an interval of 0.10 g. The results of the analysis highlight that the studied structure is vulnerable compared to the codal provisions and standard recommendations.

Objectives: This study investigated factors associated with the retention of people living with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) during the first 3 years of treatment. Methods: A retrospective study using electronic health records was conducted at a tertiary hospital in Jakarta, Indonesia. Adult HIV-positive patients who started ART from 2010 until 2020 were included. A binary logistic regression model was used to identify factors associated with ART retention in the first 3 years. Results: In total, 535 respondents were included in the analysis. The ART retention rates for the first, second, and third years were 83.7%, 79.1%, and 77.2%, respectively. The multivariate analysis revealed a negative association between CD4 count when starting ART and retention. Patients with CD4 counts >200 cells/mL were 0.65 times less likely to have good retention than those with CD4 counts ≤200 cells/mL. The year of starting ART was also significantly associated with retention. Patients who started ART in 2010-2013 or 2014-2016 were less likely to have good retention than those who started ART in 2017-2020, with adjusted odds ratios of 0.52 and 0.40, respectively. Patients who received efavirenz-based therapy were 1.69 times more likely to have good retention than those who received nevirapine (95% confidence interval, 1.05 to 2.72). Conclusions: Our study revealed a decline in ART retention in the third year. The CD4 count, year of enrollment, and an efavirenz-based regimen were significantly associated with retention. Patient engagement has long been a priority in HIV programs, with interventions being implemented to address this issue.

Abstract Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Abstract Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Abstract Ensuring global food security under present and futuristic scenario of climate change accompanied by expanding population is of major concern worldwide. Researchers across the world are focusing on sustainable agronomic practices to combat climate change induced issues like desertification, reduction in crop yield, pest outbreaks, and reduction in soil health. Biochar has demonstrated positive effects on plant growth, development, fruit quality, carbon capture and sequestration. Studies indicate that biochar amendments to soil can enhance soil health, plant growth and development as well as help in combating abiotic stressors. Biochar has several properties that make it an attractive soil amendment, including high porosity, surface area, water-holding capacity, and the ability to increase soil microbiota, which in turn can promote nutrient uptake and reduce soil erosion. Environmentally, biochar’s ability to degrade organic pollutant as well as sequester carbon makes it a very attractive addition to sustainable agriculture. Nonetheless, biochar has also been reported to have potential hazardous impacts on human health associated with possible leakage of toxic elements and particulate matter pollution. However, lack of exhaustive studies that detail all the major aspects of biochar application in agroecosystem impedes decision making on its overall usability in agriculture. There exists a need for comprehensive review that cover all the important aspects of biochar supplementation. This review provides a thorough overview of the multifaceted impacts of biochar, encompassing its positive effects on soil, plant growth, development and environment, while also exploring the limitations along with potential toxic effects associated with its application.

Back ground: The research was carried out with the aim of detecting instances of second-line antiretroviral therapy (ART) failure and exploring the potential of third-line ART treatment for individuals with HIV, incorporating the utilization of HIV viral load (VL) testing. Beginning in 2016-17, individuals living with HIV are directed to government ART centers and ART plus centers for treatment. Patients who have experienced treatment failure with second-line therapy and have been exposed to multiple NRTIs, in accordance with the Indian National ART Guidelines, are referred to the SACEP Clinic for further evaluation. If deemed eligible according to the Indian National 3rd Line ART Guidelines, these patients are enrolled and followed up for the initiation of 3rd Line ART at our center. Throughout the duration of the study, a collective of 55 individuals diagnosed with Human Immunodeficiency Virus (HIV) were identified as potentially experiencing a lack of efficacy with regards to their secondary line antiretroviral therapy (ART). Two patients in the cohort were diagnosed with both HIV and multi drug resistant tuberculosis (MDR-TB). Method: Fifty-four and a half percent of the patient sample was classified as being in WHO stage I, while 32.8% were categorized as being in stage II, and the remaining 12.7% were identified as being in WHO stage IV. Fifty-five patients who were suspected of experiencing second-line treatment failure were transitioned to third-line antiretroviral therapy. Results: All 55 patients underwent VL follow-up, with 53 of them attaining viral suppression within a median period of 6 months. However, two patients were unable to achieve viral suppression. Conclusion: However, this study describes HIV-positive patients who need third-line ART due to probable second-line ART failure.

Abstract Degradation of bromocresol green in alcohol-water solution using ozone micron sized bubbles is reported. A high speed impeller is used to generate micro bubbles of ozone in liquid while ozone is generated using a commercial ozone generator. A 3-level-3-factor Box–Behnken experimental design is used to statistically identify relative importance of the operating parameters studied namely impeller speed, initial concentration of dye and treatment time. Ozone dosage is kept fixed at 4 g/h. Impeller speed is found to be the most dominant factor according to Analysis of Variance (ANOVA) calculations. Kinetics for degradation of bromocresol green in solution is also reported. A second order kinetics is seen to fit the experimental (concentration–time) data, corresponding value of rate constant being 0.0153 L/mg-s. Based on the laboratory scale data a detailed techno-commercial analysis of a scaled up (75 kL/day) plant for ozone based degradation of bromocresol is presented. All relevant economic indicators pertaining to the scaled up plant are reported. A specific treatment cost of Rs. 100/m3 of treated water yields a return on investment (ROI) of 68.77 and discounted payback period of 5 years.

Abstract The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Abstract In this work, we have investigated a new solution for charged anisotropic compact stellar system in the framework of an extended theory of symmetric teleparallel gravity known as f(Q, T) gravity with the non-metricity term Q and the trace T for energy–momentum tensor. We have constructed a complete set of the gravitational field equations for a non-linear function $$f(Q,T)=\alpha Q + \beta (1+Q^{2}) + \lambda T$$ f ( Q , T ) = α Q + β ( 1 + Q 2 ) + λ T with $$\alpha , \beta $$ α , β and $$\lambda $$ λ are dimensionless constant parameters in case of static spherically symmetric space-time. To evaluate the expression of relevant unknown constants interior space-time has been matched with exterior Reissner–Nordstr $$\ddot{\textrm{o}}$$ o ¨ m metric. We have performed a graphical discussion in detail to test the behavior of physical parameters in the interior region of a stellar system like energy density, radial and tangential pressure, anisotropies of matter portion, electric field intensity etc. Also, to check the physical validity of our solutions, we have performed various tests viz., energy conditions, stability, mass–radius relation, surface redshift etc. The hydrostatic equilibrium position of our stellar system has been analysed through the TOV equation. Finally, we have determined that our stellar structure solutions satisfy all required physical conditions for viability and acceptability in the context of some pulsar like neutron stars. So our model can be used to characterise the neutron stars in f(Q, T) modified gravity.

Abstract Objective The study aims to assess current international clinician attitudes, practices and barriers towards fertility assessment and preservation in patients undergoing radical inguinal orchidectomy (RIO) for testicular cancer. Materials and methods An international online survey of urologists and urologists in training who perform RIO for testicular cancer was developed by the British Association of Urological Surgeons (BAUS) Sections of Andrology and Oncology and the British Urology Researchers in Surgical Training (BURST). The recruitment process used social media and the emailing lists of national urological societies. Responses were collected between 10/02/2021 and 31/05/2021 and stored using password‐protected Research Electronic Data Capture (REDCap) database software. The primary outcome was the proportion of urologists who routinely offer semen cryopreservation prior to RIO. The study was reported according to the Checklist for Reporting Results of Internet E‐Surveys platform. Results A total of 393 respondents took part in the online survey; of these, the majority were from the United Kingdom (65.9%), with the remaining international respondents (34.1%) from six different continents, which included 45 different countries. Of the respondents, 57.1% reported that they would routinely offer semen cryopreservation to all patients undergoing RIO for testicular cancer. In addition, 36.0% of urologists routinely performed pre‐operative semen analysis, and 22.1% routinely performed pre‐operative testicular serum hormone profile. Of the respondents, 14.4% performed expedited RIO within 48 h; 31.2% of respondents reported that they considered no delay to RIO to allow for semen cryopreservation to be acceptable. Conclusions A significant proportion of international urologists do not offer pre‐operative fertility assessment and preservation in men undergoing RIO for testicular cancer. Surgery is performed in an expedited fashion within 1 week in the majority of patients. Urologists perceive there to be a lack of access and availability to fertility services, and that delay to RIO to allow for fertility preservation is often not acceptable.

Abstract Suspended sediment concentration prediction is critical for the design of reservoirs, dams, rivers ecosystems, various operations of aquatic resource structure, environmental safety, and water management. In this study, two different machine models, namely the cascade correlation neural network (CCNN) and feedforward neural network (FFNN) were applied to predict daily-suspended sediment concentration (SSC) at Simga and Jondhara stations in Sheonath basin, India. Daily-suspended sediment concentration and discharge data from 2010 to 2015 were collected and used to develop the model to predict suspended sediment concentration. The developed models were evaluated using statistical indices like Nash and Sutcliffe efficiency coefficient (NES), root mean square error (RMSE), Willmott’s index of agreement (WI), and Legates–McCabe’s index (LM), supplemented by a scatter plot, density plots, histograms and Taylor diagram for graphical representation. The developed model was evaluated and compared with CCNN and FFNN. Nine input combinations were explored using different lag-times for discharge (Qt-n) and suspended sediment concentration (St-n) as input variables, with the current suspended sediment concentration as the desired output, to develop CCNN and FFNN models. The CCNN4 model with 4 lagged inputs (St-1, St-2, St-3, St-4) outperformed the other developed models with the lowest RMSE = 95.02 mg/l and the highest NES = 0.0.662, WI = 0.890 and LM = 0.668 for the Jondhara Station while the same CCNN4 model secure as the best with the lowest RMSE = 53.71 mg/l and the highest NES = 0.785, WI = 0.936 and LM = 0.788 for the Simga Station. The result shows the CCNN model was better than the FFNN model for predicting daily-suspended sediment at both stations in the Sheonath basin, India. Overall, CCNN showed better forecasting potential for suspended sediment concentration compared to FFNN at both stations, demonstrating their applicability for hydrological forecasting with complex relationships.

Abstract Extracellular matrix diseases like fibrosis are elusive to diagnose early on, to avoid complete loss of organ function or even cancer progression, making early diagnosis crucial. Imaging the matrix densities of proteins like collagen in fixed tissue sections with suitable stains and labels is a standard for diagnosis and staging. However, fine changes in matrix density are difficult to realize by conventional histological staining and microscopy as the matrix fibrils are finer than the resolving capacity of these microscopes. The dyes further blur the outline of the matrix and add a background that bottlenecks high-precision early diagnosis of matrix diseases. Here we demonstrate the multiple signal classification method-MUSICAL-otherwise a computational super-resolution microscopy technique to precisely estimate matrix density in fixed tissue sections using fibril autofluorescence with image stacks acquired on a conventional epifluorescence microscope. We validated the diagnostic and staging performance of the method in extracted collagen fibrils, mouse skin during repair, and pre-cancers in human oral mucosa. The method enables early high-precision label-free diagnosis of matrix-associated fibrotic diseases without needing additional infrastructure or rigorous clinical training.

Abstract Understanding the functional connectivity between brain regions and its emergent dynamics is a central challenge. Here we present a theory-experiment hybrid approach involving iteration between a minimal computational model and in vivo electrophysiological measurements. Our model not only predicted spontaneous persistent activity (SPA) during Up-Down-State oscillations, but also inactivity (SPI), which has never been reported. These were confirmed in vivo in the membrane potential of neurons, especially from layer 3 of the medial and lateral entorhinal cortices. The data was then used to constrain two free parameters, yielding a unique, experimentally determined model for each neuron. Analytic and computational analysis of the model generated a dozen quantitative predictions about network dynamics, which were all confirmed in vivo to high accuracy. Our technique predicted functional connectivity; e. g. the recurrent excitation is stronger in the medial than lateral entorhinal cortex. This too was confirmed with connectomics data. This technique uncovers how differential cortico-entorhinal dialogue generates SPA and SPI, which could form an energetically efficient working-memory substrate and influence the consolidation of memories during sleep. More broadly, our procedure can reveal the functional connectivity of large networks and a theory of their emergent dynamics.

Abstract Background Populations of the plant pathogenic fungus Verticillium dahliae display a complex and rich genetic diversity, yet the existence of sexual reproduction in the fungus remains contested. As pivotal genes, MAT genes play a crucial role in regulating cell differentiation, morphological development, and mating of compatible cells. However, the functions of the two mating type genes in V. dahliae, VdMAT1-1-1, and VdMAT1-2-1, remain poorly understood. Results In this study, we confirmed that the MAT loci in V. dahliae are highly conserved, including both VdMAT1-1-1 and VdMAT1-2-1 which share high collinearity. The conserved core transcription factor encoded by the two MAT loci may facilitate the regulation of pheromone precursor and pheromone receptor genes by directly binding to their promoter regions. Additionally, peptide activity assays demonstrated that the signal peptide of the pheromone VdPpg1 possessed secretory activity, while VdPpg2, lacked a predicted signal peptide. Chemotactic growth assays revealed that V. dahliae senses and grows towards the pheromones FO-a and FO-α of Fusarium oxysporum, as well as towards VdPpg2 of V. dahliae, but not in response to VdPpg1. The findings herein also revealed that VdMAT1-1-1 and VdMAT1-2-1 regulate vegetative growth, carbon source utilization, and resistance to stressors in V. dahliae, while negatively regulating virulence. Conclusions These findings underscore the potential roles of VdMAT1-1-1 and VdMAT1-2-1 in sexual reproduction and confirm their involvement in various asexual processes of V. dahliae, offering novel insights into the functions of mating type genes in this species.