Game-Theoretic Analysis of Fusion Rules Over Molecular Reporting Channels.

This work adopts a game theoretic approach to analyze the behavior of transmitter nanomachines (TNMs) in a diffusive 3-dimensional (3-D) channel. In order to communicate the local observations about the region of interest (RoI) to a common supervisor nanomachine (SNM), TNMs transmit information-carrying molecules to SNM. For the production of information-carrying molecules, all the TNMs share the common food molecular budget (CFMB). The TNMs apply cooperative and greedy strategic efforts to get their share from the CFMB. In the cooperative case, all the TNMs communicate to SNM as a group, therefore they cooperatively consume the CFMB to increase the group outcome, whereas, in the greedy scenario, all TNMs decide to perform alone and thus greedily consume the CFMB to increase their individual outcomes. The performance is evaluated in terms of the average rate of success, the average probability of error, and the receiver operating characteristic (ROC) of RoI detection. The derived results are verified through Monte-Carlo and particle-based simulations (PBS).

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

Extremely Elevated Prostate-Specific Antigen in Acute Prostatitis: A Case Report.

Elevated prostate-specific antigen (PSA) levels are mostly suggestive of prostate cancer, but they are elevated in non-cancerous prostatic conditions as well. However, extreme levels of PSA as reported here have not been observed in cases other than prostatic cancer so far. Our patient had a significantly elevated PSA of 1,398 ng/mL in acute prostatitis. The purpose of this case report is to review the patient's atypical and rare presentation of extremely high PSA in acute prostatitis in the background of benign prostatic hyperplasia (BPH) and chronic prostatitis.

Implications of Pharmacogenetic Testing for Clopidogrel Therapy in a Tertiary Healthcare Hospital in North India.

Background Clopidogrel hyporesponsiveness with decreased antiplatelet activity is prevalent in percutaneous coronary intervention (PCI) patients due to reduced function polymorphism in the CYP2C19 enzyme gene which results in poor conversion of this prodrug to an active metabolite. However, pharmacogenetic testing is not part of routine clinical practice in India. Methodology In this retrospective observational study, we observed the prevalence of loss of function (LOF) gene variants of CYP2C19 (*2, *3) in 60 patients undergoing PCI with complex anatomies in a tertiary healthcare hospital in North India. We do not have follow-up data for a few patients. However, the treatment regimen was recorded, and the occurrence of any clinical event was monitored for the remaining 52 patients for six months. Results The mean age of the patients was 61.76 ± 10.14 years. We found that 52% of patients carried these LOF mutations, of which 37% were intermediate metabolizers, while 15% were poor metabolizers of clopidogrel. However, out of 52 patients for whom follow-up data were available, 22 (42.3%) were intermediate metabolizers, while six (11.54%) showed genotypes associated with poor metabolism of clopidogrel. Clopidogrel (75 mg BD) was the primary replacement drug in place of ticagrelor (90 mg BD) during follow-up after four weeks (based on the clinician's discretion). Conclusions No major ischemic event was reported during the follow-up of these 52 patients. The intermediate metabolizers' LOF in one copy of the CYP2C19 gene seems to overcome genetic deficiency with the clopidogrel 75 mg BD regime, which is comparable to maintenance with ticagrelor 90 mg BD. This study can be extrapolated to a larger cohort to observe statistically significant differences among various groups.

Left atrial strain predicts improvement in left atrial functions of severe rheumatic mitral stenoses undergoing successful percutaneous transmitral commissurotomy.

AIMS: Chronic rheumatic heart disease (RHD) is prevalent in India. The mitral valve in isolation or combination with the aortic or tricuspid valve is involved in 31.6% and 52.8% of chronic RHD patients, respectively. The left atrium (LA) functions as a reservoir during the cardiac cycle. Therefore, the LA enlargement leads to longitudinal lengthening, measured as a positive strain, permitting the measurement of the longitudinal strain of LA. This study aimed to assess the LA functions using peak atrial longitudinal strain (PALS) in patients with severe rheumatic mitral stenoses (MS) in sinus rhythm who underwent successful percutaneous transvenous mitral commissurotomy (PTMC). MATERIAL AND METHODS: We recruited 56 patients with severe rheumatic MS for the study, of which 06 PTMC procedures were considered unsuccessful. So, 50 patients of chronic severe rheumatic MS in sinus rhythm undergoing PTMC were enrolled in a tertiary care centre of the Armed Forces from August 2017 to May 2019. Patients included in the study were not consecutive, and patients with atrial fibrillation (AF) were excluded. RESULTS: PALS improved post-PTMC (P < .001) in this study, effectively concluding that PALS is impaired in patients with severe symptomatic MS and is acutely enhanced after treatment. CONCLUSIONS: PALS is a good indicator of LA function and may predict the success of PTMC on the rheumatic mitral valve.

Prevalence, Associated Factors, and Impact of Workplace Violence among Physicians.

BACKGROUND: There is a dearth of objective data and studies pertaining to the prevalence and consequences of workplace violence against physicians in Nepal. This study aims to assess the prevalence, associated factors, and implications of workplace violence on Nepalese physicians. METHODS: We conducted a cross-sectional study from March 2021 to August 2021. Nepal Medical Council-certified physicians currently working in Nepal were included in the study. Baseline characteristics, types of violence experienced, patterns, psychosocial impacts, and changes in patient management were collected. RESULTS: Out of 318 responses received, 302 responses met the inclusion criteria and were included in the final analysis. One-hundred and ninety (62.9%) respondents had ever faced workplace violence. Madhesh Province had the highest prevalence (81.5%). Verbal abuse (93.2%) was the most common type of violence encountered. We found a significant association between workplace violence and hours worked each week. We also found an association between workplace violence and years of experience. Our study found a significant increase in stress/depression/anxiety/idea of persecution, sense of defeat, job turnover, and loss of productivity/income with the increase in severity of workplace violence. CONCLUSIONS: Workplace violence is largely prevalent among Nepalese physicians. In the aftermath of workplace violence, a physician can undergo a multitude of adverse psychosocial consequences leading to a further decrease in productivity. More insights through research, formal training, and policy implementation are necessary to overcome this largely ignored problem of the medical fraternity in Nepal.

Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types.

BACKGROUND: SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. COVID-19 disease severity has been associated with some pre-existing conditions and the magnitude of the adaptive immune response to SARS-CoV-2, and a recent genome-wide association study (GWAS) of the risk of critical illness revealed a significant genetic component. To gain insight into how human genetic variation attenuates or exacerbates disease following SARS-CoV-2 infection, we implicated putatively functional COVID risk variants in the cis-regulatory landscapes of human immune cell types with established roles in disease severity and used high-resolution chromatin conformation capture to map these disease-associated elements to their effector genes. RESULTS: This functional genomic approach implicates 16 genes involved in viral replication, the interferon response, and inflammation. Several of these genes (PAXBP1, IFNAR2, OAS1, OAS3, TNFAIP8L1, GART) were differentially expressed in immune cells from patients with severe versus moderate COVID-19 disease, and we demonstrate a previously unappreciated role for GART in T cell-dependent antibody-producing B cell differentiation in a human tonsillar organoid model. CONCLUSIONS: This study offers immunogenetic insight into the basis of COVID-19 disease severity and implicates new targets for therapeutics that limit SARS-CoV-2 infection and its resultant life-threatening inflammation.

Soluble Guanylate Cyclase Stimulators in Heart Failure.

Heart failure has a high global burden of morbidity and mortality. Despite significant advances in medical management of heart failure, the prognosis remains poor. This justifies the search for newer therapeutic agents. Recently, soluble guanylate stimulators have demonstrated favorable results in clinical trials. This article aims to summarize the guanylate cyclase signaling pathway, the role of soluble guanylate cyclase stimulators in heart failure, and data from recent clinical trials of these drugs. We concluded that soluble guanylate cyclase stimulators have significant benefits in reducing hospitalizations in patients with heart failure with reduced ejection fraction that are at high risk of cardiovascular events. There appears to be no benefit of these drugs in patients with heart failure with preserved ejection fraction.

Acute Mycophenolate Mofetil Overdose Managed Conservatively.

Mycophenolate mofetil (MMF) is an immunosuppressant drug widely used in post-transplant patients and the treatment of various inflammatory conditions. It is considered a relatively safe drug with minimal adverse effects. We managed an acute overdose of 19 grams (g) of MMF with a suicidal intention in a 17-year-old female with no significant past medical history. Apart from episodes of mild headaches, she did not develop other symptoms, laboratory abnormalities, or complications.

Serum Metabolic Disturbances Associated with Acute-on-chronic Liver Failure in Patients with Underlying Alcoholic Liver Diseases: An Elaborative NMR-based Metabolomics Study.

OBJECTIVES: Acute-on-chronic liver failure (ACLF), which develops in patients with underlying alcoholic liver disease (ALD), is characterized by acute deterioration of liver function and organ failures are secondary to that. The clear understanding of metabolic pathways perturbed in ALD-ACLF patients can greatly decrease the mortality and morbidity of patients through predicting outcome, guiding treatment, and monitoring response to treatment. The purpose of this study was to investigate the metabolic disturbances associated with ACLF using nuclear magnetic resonance (NMR)-based serum metabolomics approach and further to assess if the serum metabolic alterations are affected by the severity of hepatic impairment. MATERIALS AND METHODS: The serum-metabolic profiles of 40 ALD-ACLF patients were compared to those of 49 age and sex-matched normal-control (NC) subjects making composite use of both multivariate and univariate statistical tests. RESULTS: Compared to NC, the sera of ACLF patients were characterized by significantly decreased serum levels of several amino acids (except methionine and tyrosine), lipid, and membrane metabolites suggesting a kind of nutritional deficiency and disturbed metabolic homeostasis in ACLF. Twelve serum metabolic entities (including BCAA, histidine, alanine, threonine, and glutamine) were found with AUROC (i.e., area under ROC curve) value >0.9 suggesting their potential in clinical diagnosis and surveillance. CONCLUSION: Overall, the study revealed important metabolic changes underlying the pathophysiology of ACLF and those related to disease progression would add value to standard clinical scores of severity to predict outcome and may serve as surrogate endpoints for evaluating treatment response.

On Gradient Descent Optimization in Diffusion-Advection Based 3-D Molecular Cooperative Communication.

This work considers a cooperative communication system in 3-D fluid medium in which the flow of molecules is supported by the drift and the diffusion phenomena. To enhance the system performance, the equal gain combining is used at the destination nanomachine (DN) where the molecular signals arriving from the direct and the cooperative paths are combined together by employing equal weights. Using the gradient descent algorithm, the optimum threshold at DN, and the optimal number of molecules transmitted from source and cooperative nanomachines are obtained. For this purpose, the convex constraints are determined using the closed-form expression for the average probability of error at DN. Finally, the accuracy of the analytical results is validated through the particle/ Monte Carlo-based simulations.

Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.

Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.

Optimal Transmitted Molecules and Decision Threshold for Drift-Induced Diffusive Molecular Channel With Mobile Nanomachines.

We study a drift-induced diffusive mobile molecular communication system where source, destination and cooperative nanomachines follow the one-dimensional Brownian motion. For information exchange from source nanomachine to receiver nanomachine, both direct and decode-forward (DF) relay-assisted cooperative paths are considered. The closed-form expressions for the probabilities of detection and false alarm are derived at the cooperative and destination nanomachines considering the multiple-source interference (MSI) and the inter-symbol-interference (ISI). The closed-form expressions for end-to-end average probability of error, and maximum achievable rate are also obtained. Moreover, to achieve minimum expected probability of error the optimum number of molecules to be transmitted from transmitter and optimal detection threshold in receiver nanomachine are found. The analytical expressions are validated through particle-based and Monte-Carlo simulation methods.

TRAV1-2+ CD8+ T-cells including oligoconal expansions of MAIT cells are enriched in the airways in human tuberculosis.

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2+ semi-invariant TCRα that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2+ CD8+ T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2+ MAIT-consistent TCRα sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial reactivity and phenotypes suggestive of MAIT cell identity. These findings demonstrate enrichment of TRAV1-2+ CD8+ T cells with MAIT or MAIT-like features in the airways during active TB and suggest a role for these cells in the human pulmonary immune response to Mycobacterium tuberculosis.

Circulating Mycobacterium tuberculosis DosR latency antigen-specific, polyfunctional, regulatory IL10+ Th17 CD4 T-cells differentiate latent from active tuberculosis.

The functional heterogeneity of T cell responses to diverse antigens expressed at different stages of Mycobacterium tuberculosis (Mtb) infection, in particular early secreted versus dormancy related latency antigens expressed later, that distinguish subjects with latent (LTBI), pulmonary (PTB) or extrapulmonary (EPTB) tuberculosis remains unclear. Here we show blood central memory CD4 T-cell responses specific to Mtb dormancy related (DosR) latency, but not classical immunodominant secretory antigens, to clearly differentiate LTBI from EPTB and PTB. The polyfunctionality score integrating up to 31 DosR-specific CD4 T-cell functional profiles was significantly higher in LTBI than EPTB or PTB subjects. Further analysis of 256 DosR-specific T-cell functional profiles identified regulatory IL10 + Th17 cells (IL10+IL17A+IL17F+IL22+) to be significantly enriched in LTBI; in contrast to pro-inflammatory Th17 cells (IFNγ+IL17A+/IL10-) in the blood and lung of EPTB and PTB subjects respectively. A blood polyfunctional, Mtb DosR latency antigen specific, regulatory, central memory response is therefore a novel functional component of T-cell immunity in latent TB and potential correlate of protection.

High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells.

Mucosa-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor TRAV1-2 and detect a range of bacteria and fungi through the MHC-like molecule MR1. However, knowledge of the function and phenotype of bacteria-reactive MR1-restricted TRAV1-2(+) MAIT cells from human blood is limited. We broadly characterized the function of MR1-restricted MAIT cells in response to bacteria-infected targets and defined a phenotypic panel to identify these cells in the circulation. We demonstrated that bacteria-reactive MR1-restricted T cells shared effector functions of cytolytic effector CD8(+) T cells. By analysing an extensive panel of phenotypic markers, we determined that CD26 and CD161 were most strongly associated with these T cells. Using FACS to sort phenotypically defined CD8(+) subsets we demonstrated that high expression of CD26 on CD8(+)  TRAV1-2(+) cells identified with high specificity and sensitivity, bacteria-reactive MR1-restricted T cells from human blood. CD161(hi) was also specific for but lacked sensitivity in identifying all bacteria-reactive MR1-restricted T cells, some of which were CD161(dim) . Using cell surface expression of CD8, TRAV1-2, and CD26(hi) in the absence of stimulation we confirm that bacteria-reactive T cells are lacking in the blood of individuals with active tuberculosis and are restored in the blood of individuals undergoing treatment for tuberculosis.

Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands.

Selective recruitment of IFN-γ biased Th1 effector cells at the pathologic site(s) determines the local immunity of tuberculosis (TB). We observed the enrichment of CXCR3, CCR5 and CD11a(high) T cells in the peripheral blood, pleural fluid and bronchoalveolar lavage of TB pleural effusion (TB-PE) and miliary tuberculosis (MTB) patients respectively. CXCR3(+)CCR5(+) T cells were significantly high at the local disease site(s) in both the forms of TB and their frequency was highest among activated lymphocytes in TB-PE. Interestingly, all CCR5(+) cells were invariably positive for CXCR3 but all CXCR3(+) cells did not co-express CCR5 in pleural fluid whereas the situation was reverse in bronchoalveolar lavage. These CXCR3(+)CCR5(+) cells dominantly produced IFN-γ in response to Mycobacterium tuberculosis antigen. In vitro chemotaxis assay indicates dominant role of RANTES and IP-10 in the selective recruitment of CXCR3(+)CCR5(+)cells at the tubercular pathologic sites.

Foxp3+ regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-γ producing T cells.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis-specific IL-10 along with elevation of IFN-γ production, and raising the IFN-γ/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients.

Relationship between xanthophyll cycle and non-photochemical quenching in rice (Oryza sativa L.) plants in response to light stress.

Thirty days old rice plants grown under low and moderate light conditions were transferred to full sunlight to observe the extent of photoinhibitory damage and protective mechanism, and the relationship between xanthophyll cycle and nonphotochemical quenching (qN) under changing light environment. Control plants (low, moderate and sun grown) exhibited similar Fv/Fm ratio, indicating similar photosynthetic efficiency prior to light stress. On exposure to the high light treatment, low light grown plants exhibited faster and higher degree of photoinhibition compared to moderate and high light grown plants. Moderate and high light grown plants showed relatively less photoinhibition and also showed higher qN, indicating better capacity of energy dissipation. Increase in qN in moderate light and sun grown plants was accompanied by conversion of violaxanthin (V) to antheraxanthin (A) and zeaxanthin (Z) indicating operation of Z-dependent thermal dissipation. Rice plants fed with ascorbate (AsA), a stimulator of the de-epoxidation state of V to Z, showed higher Fv/Fm ratio and qN than the plants fed with dithiothreitol (DTT) an inhibitor of xanthophyll cycle. This indicated that an increased amount of energy reached PS II reaction centre, due to absence of A and Z formation, thereby causing greater damage to photosynthesis in DTT fed rice plants. The present data confirmed the relationship between qN and Z in dissipating the excess light energy, thereby protecting plants against photodamage.

Symbiotic interactions between arbuscular mycorrhizal (AM) fungi and male papaya plants: its status, role and implications.

Experiments were conducted to study the arbuscular mycorrhizal (AM) status and its role in P-uptake through assay of root phosphatases activities in four varieties of male Carica papaya L. viz. CO-1, CO-2, Honey Dew and Washington during flowering stages. In the present study, mean total root colonization of AM fungi recorded peak increase in flowering stage-II while mean root phosphatase (acid and alkaline) activities recorded peak increase in flowering stage-I. Unlike root colonization and root phosphatase activities, spore density did not exhibit any definite patterns and recorded a narrow range of fluctuation during different flowering stages of male C. papaya. The study brought out the fact that root colonization and spore density of AM fungi along with root phosphatase activities varied significantly within the four varieties of male C. papaya plants during each flowering stage. The study also recorded consistently higher acid root phosphatase activity than alkaline root phosphatase activity under P-deficient, acidic soil conditions during all flowering stages of male C. papaya plants. Studies revealed that the root colonization of AM fungi influenced root phosphatase activities (acid and alkaline) positively and significantly during all flowering stages of male C. papaya plants. A total of twelve species of AM fungi belonging to five genera viz. Acaulospora, Dentiscutata, Gigaspora, Glomus, and Racocetra were recovered from the rhizosphere of male C. papaya plants.