Understanding the Cross-Talk of Redox Metabolism and Fe-S Cluster Biogenesis in Leishmania Through Systems Biology Approach

Leishmania parasites possess an exceptional oxidant and chemical defense mechanism, involving a very unique small molecular weight thiol, trypanothione (T[SH]2), that helps the parasite to manage its survival inside the host macrophage. The reduced state of T[SH]2 is maintained by NADPH-dependent trypanothione reductase (TryR) by recycling trypanothione disulfide (TS2). Along with its most important role as central reductant, T[SH]2 have also been assumed to regulate the activation of iron-sulfur cluster proteins (Fe/S). Fe/S clusters are versatile cofactors of various proteins and execute a much broader range of essential biological processes viz., TCA cycle, redox homeostasis, etc. Although, several Fe/S cluster proteins and their roles have been identified in Leishmania, some of the components of how T[SH]2 is involved in the regulation of Fe/S proteins remains to be explored. In pursuit of this aim, a systems biology approach was undertaken to get an insight into the overall picture to unravel how T[SH]2 synthesis and reduction is linked with the regulation of Fe/S cluster proteins and controls the redox homeostasis at a larger scale. In the current study, we constructed an in silico kinetic model of T[SH]2 metabolism. T[SH]2 reduction reaction was introduced with a perturbation in the form of its inhibition to predict the overall behavior of the model. The main control of reaction fluxes were exerted by TryR reaction rate that affected almost all the important reactions in the model. It was observed that the model was more sensitive to the perturbation introduced in TryR reaction, 5 to 6-fold. Furthermore, due to inhibition, the T[SH]2 synthesis rate was observed to be gradually decreased by 8 to 14-fold. This has also caused an elevated level of free radicals which apparently affected the activation of Fe/S cluster proteins. The present kinetic model has demonstrated the importance of T[SH]2 in leishmanial cellular redox metabolism. Hence, we suggest that, by designing highly potent and specific inhibitors of TryR enzyme, inhibition of T[SH]2 reduction and overall inhibition of most of the downstream pathways including Fe/S protein activation reactions, can be accomplished

Management of Treatment and Prevention of Acute OP Pesticide Poisoning by Medical Informatics, Telemedicine and Nanomedicine

Acute organophosphorous pesticide (OP) poisoning kills a lot of people each year. Treatment of acute OP poisoning is of very difficult task and is a time taking event. Present day informatics methods (telemedicine), bioinformatics methods (data mining, molecular modeling, docking, cheminformatics), and nanotechnology (nanomedicine) should be applied in combination or separately to combat the rise of death rate due to OP poisoning. Use of informatics method such as Java enabled camera mobiles will enable us early detection of insecticidal poisoning. Even the patients who are severely intoxicated (suicidal attempts) can be diagnosed early. Telemedicine can take care for early diagnosis and early treatment. Simultaneously efforts must be taken with regard to nanotechnology to find lesser toxic compounds (use less dose of nanoparticle mediated compounds: nano-malathion) as insecticides and find better efficacy of lesser dose of compounds for treatment (nano-atropine) of OP poisoning. Nano-apitropine (atropine oxide) may be a better choice for OP poisoning treatment as the anticholinergic agent; apitropine and hyoscyamine have exhibited higher binding affinity than atropine sulfate. Synthesis of insecticides (malathion) with an antidote (atropine, apitropine) in nanoscale range will prevent the lethal effect of insecticides

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Magnetic resonance imaging (MRI) characterization of perianal fistulous disease in a rural based tertiary hospital of North India

BACKGROUND: To diagnose and characterize the perianal fistulous disease using Magnetic resonance imaging (MRI) in a hilly and rural area of North India. MATERIAL AND METHODS: This prospective hospital based study was conducted for a period of one year from April 2014 to April 2015 in the departments of Radiodiagnosis and Surgery of our institute. A total of 50 consecutive patients presenting with perianal fistulous disease fulfilling the inclusion and exclusion criteria were included in the study and taken up for MRI. The perianal fistulae were classified according to St James University hospital classification and tracks were assessed with regard to anatomical plane, length, ramifications, abscess formation, enteric communication, external cutaneous opening, enhancement and suprasphincteric extension. Surgical correlation was done in 31 patients who opted for surgical treatment. Rest of the 19 patients preferred alternative medicine for treatment or chose to postpone their surgery. RESULTS: The disease was much more prevalent in males in comparison to females with male to female ratio of 24:1. Grade 4 was the most common type of fistula (34%) while Grade 5 was the least common type (4%).MRI showed a high sensitivity of 93.7% and positive predictive value (PPV) of 96.7% when correlated with surgical findings. A substantial number of patients (38%) preferred alternative medicine or non surgical form of treatment. CONCLUSIONS: MRI is a very sensitive modality for the evaluation of perianal fistula. In our study group, the disease predominantly affected middle aged men. Ramifications and abscesses were commonly seen, affecting nearly half of the patients and majority of the patients had active fistulous tracks with posteriorly located enteric opening. Overall, transsphincteric fistulae were most common. Significant number of patients avoided surgery or showed preference for non surgical treatment

Efficacy of sofosbuvir and daclatasvir in compensated chronic hepatitis C infection: A single center, open-label and proof of concept study

Aims and objectives: The advent of directly acting agents for the treatment of Hepatitis C infection has forever transformed our understanding and management of viral infections. With over 95 % patients achieving a sustained viral response at 12 weeks with some of these newly inducted agents, the prospect of eradicating the Hepatitis C virus seems like an achievable target, which makes this one of the most important discoveries in modern medicine. We studied the combination of Sofosbuvir and Daclatasvir in patients with chronic hepatitis C infection (Genotype 3) to assess the rates of sustained virological response at 12 weeks. Methods: We studied 67 treatment naive patients with compensated chronic hepatitis C infection (genotype 3). They were all started on Tab Sofosbuvir 400 mg daily and Tab Daclatasvir 60 mg once daily for 12 weeks and followed up for a total of 24 weeks, which includes a treatment duration and observation period of 12 weeks each. The patients were monitored with HCV RNA levels at one, three and six months, with as many evaluations of liver function and routine hemogram

Predictive correlation of adverse clinical outcomes with thrombocytopenia in dengue fever: A single center experience

Background: Dengue fever is the most widely distributed viral infection in the world with more than 100 million people affected. In this study we attempt to study the co-relation between the nadir of the plateletcount and the onset of warning signs (persistent pain abdomen and vomiting, mucocutaneous bleed or clinical fluid accumulations). A positive co-relation in between these two elements could help predict onset of shock and third spacing and facilitate prognostication and early intervention. Methods: We studied 82 patients with a diagnosis of dengue fever, the basis of which was clinical signs and symptoms with a positive NS1 antigen test. The nadir of thrombocytopenia and rise in transaminases were studied along with onset of various warning signs. Results: The nadir of thrombocytopenia correlates with onset of warning signs such as clinical fluid accumulation (two tailed P value &lt;0.002) and mucosal bleed (two tailed P value &lt;0.001). However, the rising value of transaminases does not co-relate statistically with onset of warning signs in Dengue fever. Conclusions: The age of patients ranged from 18 to 60 with 23 out of 83 (27.7%) being in the 30-40 years age group

Evolution of Intrinsic and Magnetic Field-Induced Magnetic Anisotropies in Strongly Phase-Separated Manganite Thin Films

Single crystalline thin film ( 100 nm) of La0.18Pr0.40Ca0.42MnO3 is grown on (001) oriented LaAlO3 substrates and the evolution of anisotropy associated with the supercooling behaviour of the magnetic liquid is studied as a function of temperature and magnetic field. The angle-dependent magnetization measurements ascertain that the easy magnetic axis lies in the plane of the film while the hard axis is along the plane normal. The ratio of the easy and hard axes magnetizations (M-|| and M-perpendicular to) measured at 10 K, viz., M-||/M-perpendicular to (10 K) = 2.6, confirms the strongly anisotropic nature of the film. The easy axis ferromagnetic (FM) transition temperature (T-C) is smaller than that along the hard axis. The giant hysteresis in FCC-FCW M-T, which manifests the magnetic liquid behaviour of the strongly phase-separated manganites is appreciably narrowed along the hard axis. The strain glass state is also less dominant along the easy axis. The analysis of the M-H data brings out that the easy axis remanence (M-r perpendicular to ) shows a nonlinear temperature dependence, while the one corresponding to the hard axis (M-r parallel to) shows a nearly linear behaviour. The coercivity (H-C) follows a law of the type . The value of exponent b similar to 0.5 for single-domain particles, but in the present case, the best fit to the experimental data yields the exponent b approximate to 0.25 for both H-C parallel to perpendicular to and H-C perpendicular to. The smaller value of the exponent is attributed to the non-canonical nature of the ferromagnetic state and the associated strongly phase-separated nature of the LPCMO thin film

Donor-Derived Cell-Free DNA as a Non-Invasive Biomarker for Graft Rejection in Kidney Transplant Recipients: A Prospective Study among the Indian Population

Monitoring graft health and detecting graft rejection is crucial for the success of post-transplantation outcomes. In Western countries, the use of donor-derived cell-free DNA (dd-cfDNA) has gained widespread recognition as a diagnostic tool for kidney transplant recipients. However, the role of dd-cfDNA among the Indian population remains unexplored. The recipients were categorized into two groups: the post-transplant recipient (PTR) group (n = 16) and the random recipient (RR) group (n = 87). Blood samples were collected daily from the PTR group over a 7-day period, whereas the RR group’s samples were obtained at varying intervals. In this study, we used a targeted approach to identify dd-cfDNA, which eliminated the need for genotyping, and is based on the minor allele frequency of SNP assays. In the PTR group, elevated dd-cfDNA% levels were observed immediately after transplantation, but returned to normal levels within five days. Within the RR group, heightened serum creatinine levels were directly proportional to increased dd-cfDNA%. Sixteen recipients were advised to undergo biopsy due to elevated serum creatinine and other pathological markers. Among these sixteen recipients, six experienced antibody-mediated rejection (ABMR), two exhibited graft dysfunctions, two had active graft injury, and six (37.5%) recipients showed no rejection (NR). In cases of biopsy-proven ABMR and NR, recipients displayed a mean ± SD dd-cfDNA% of 2.80 ± 1.77 and 0.30 ± 0.35, respectively. This study found that the selected SNP assays exhibit a high proficiency in identifying donor DNA. This study also supports the use of dd-cfDNA as a routine diagnostic test for kidney transplant recipients, along with biopsies and serum creatinine, to attain better graft monitoring