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The crumble of financial markets due to the recent crises has wobbled precariousness in the stock market and intensified the returns vulnerability of banking indices. Against this backdrop, this study intends to model the volatility of the Indian Bank Nifty returns using a battery of GARCH specifications. The finding of the present research contributes to the literature in three ways. First, volatility during the sample period, which corresponds to a time of stress (a bear market), is more persistent, with an estimated coefficient of 0.995695. Moreover, when volatility rises, it persists for a long time before returning to the mean in an average of 16 days. Second, for a positive γ, the results insinuate the possibility of an “anti-leverage effect” with a coefficient of 0.139638. Thus, the volatility of the Bank Nifty returns tends to rise in response to positive shocks relative to negative shocks of equal magnitude in India. Finally, the findings demonstrate that EGARCH with Student’s t-distribution offers lower forecast errors in modeling conditional volatility.

Ni-Mn-Ga shape-memory alloys are promising candidates for large strain actuation and magnetocaloric cooling devices. In view of potential small-scale applications, we probe here nanomechanically the stress-induced austenite–martensite transition in single crystalline austenitic thin films as a function of temperature. In 0.5 µm thin films, a marked incipient phase transformation to martensite is observed during nanoindentation, leaving behind pockets of residual martensite after unloading. These nanomechanical instabilities occur irrespective of deformation rate and temperature, are Weibull distributed, and reveal large spatial variations in transformation stress. In contrast, at a larger film thickness of 2 μm fully reversible transformations occur, and mechanical loading remains entirely smooth. Ab-initio simulations demonstrate how an in-plane constraint can considerably increase the martensitic transformation stress, explaining the thickness-dependent nanomechanical behavior. These findings for a shape-memory Heusler alloy give insights into how reduced dimensions and constraints can lead to unexpectedly large transformation stresses that need to be considered in small-scale actuation design.

Abstract Background Haemosuccus pancreaticus (HP), also known as pseudohaemobilia, is defined as upper gastrointestinal tract hemorrhage originating from the pancreatic duct into the duodenum via the ampulla of Vater or major pancreatic papilla. Pseudoaneurysm formation from the splenic artery is a common complication of pancreatitis; however, upper gastrointestinal bleed resulting from rupture of splenic artery pseudoaneurysm into the pancreatic duct is unusual and challenging to diagnose. Case presentation A 26-year-old patient presented with multiple episodes of hematemesis, melena, and intermittent abdominal pain. A contrast-enhanced computed tomography (CECT) scan was performed that demonstrated chronic calcific pancreatitis with a pseudoaneurysm in the splenic artery in close relation to the main pancreatic duct. The patient was immediately shifted for endovascular management, and the pseudoaneurysm was successfully embolized. Post embolization, the patient developed splenic abscess, which was managed by percutaneous catheter drainage. Conclusion Due to its rarity and being challenging to diagnose, the mortality rate of HP is high. A high level of expertise is required to diagnose HP, and it should be considered in all upper gastrointestinal bleed patients associated with acute or chronic pancreatitis. Rapid initial CECT and angiography should be performed to confirm the diagnosis, followed by embolization of the bleeding pseudoaneurysm to eliminate the need for surgery. This case report highlights the challenges in the diagnosis and management of HP.

Arsenic (As) exposure is progressively associated with chronic kidney disease (CKD), a leading public health concern present worldwide. The adverse effect of As exposure on the kidneys of people living in As endemic areas have not been extensively studied. Furthermore, the impact of only prenatal exposure to As on the progression of CKD also has not been fully characterized. In the present study, we examined the effect of prenatal exposure to low doses of As 0.04 and 0.4 mg/kg body weight (0.04 and 0.4 ppm, respectively) on the progression of CKD in male offspring using a Wistar rat model. Interestingly, only prenatal As exposure was sufficient to elevate the expression of profibrotic (TGF-β1) and proinflammatory (IL-1α, MIP-2α, RANTES, and TNF-α) cytokines at 2-day, 12- and 38-week time points in the exposed progeny. Further, alteration in adipogenic factors (ghrelin, leptin, and glucagon) was also observed in 12- and 38-week old male offspring prenatally exposed to As. An altered level of these factors coincides with impaired glucose metabolism and homeostasis accompanied by progressive kidney damage. We observed a significant increase in the deposition of extracellular matrix components and glomerular and tubular damage in the kidneys of 38-week-old male offspring prenatally exposed to As. Furthermore, the overexpression of TGF-β1 in kidneys corresponds with hypermethylation of the TGF-β1 gene-body, indicating a possible involvement of prenatal As exposure-driven epigenetic modulations of TGF-β1 expression. Our study provides evidence that prenatal As exposure to males can adversely affect the immunometabolism of offspring which can promote kidney damage later in life.

Cold stress adversely affects plant growth, development, and yield. Also, the spatial and geographical distribution of plant species is influenced by low temperatures. Cold stress includes chilling and/or freezing temperatures, which trigger entirely different plant responses. Freezing tolerance is acquired via the cold acclimation process, which involves prior exposure to non-lethal low temperatures followed by profound alterations in cell membrane rigidity, transcriptome, compatible solutes, pigments and cold-responsive proteins such as antifreeze proteins. Moreover, epigenetic mechanisms such as DNA methylation, histone modifications, chromatin dynamics and small non-coding RNAs play a crucial role in cold stress adaptation. Here, we provide a recent update on cold-induced signaling and regulatory mechanisms. Emphasis is given to the role of epigenetic mechanisms and antifreeze proteins in imparting cold stress tolerance in plants. Lastly, we discuss genetic manipulation strategies to improve cold tolerance and develop cold-resistant plants.

Boron (B) and Tungsten (W) are often found enriched in high-temperature geothermal waters associated with the development of subduction-related mafic to felsic arc magma. However, knowledge about the sourcing and transportation of these elements from such hydrothermal systems is sparse and ambiguous. Being the only active continental collision site in the world, the Trans-Himalaya offers a unique chance to study how continental collision sources the high boron and tungsten concentrations in geothermal fluids. This study investigated the distribution of trace elements, major cations, and anions in three physicochemically distinct hotspring sites in the Ladakh region. The results were integrated with the existing geochemical and isotopic data to address the research problem more effectively. This study exhibits that the extreme concentrations of boron, sodium, chlorine, potassium, and tungsten in the hotspring waters were primarily governed by magmatic fluid inputs. In addition, this study recorded the highest-ever chlorine and boron concentrations for the Trans-Himalayan hotspring waters. The highest-ever boron and chlorine concentrations in the hotspring waters probably represented an increase in magmatic activity in the deeper source zone.

This work investigates the role of grain size and recrystallization texture in the corrosion behavior of pure iron in 0.1 M sulfuric acid solution. Annealing heat treatment was applied to obtain samples with different average grain sizes (26, 53 and 87 µm). Optical microscopy, X-ray diffraction and electron backscatter diffraction techniques were used to characterize the microstructure. The EBSD data analysis showed ferrite phase with no inclusions and very low geometrically necessary dislocation density, indicating strain-free grains constituting all samples. The crystallographic texture analysis of the samples revealed that the 26 µm grain size sample had a high volume fraction of {111} oriented grains parallel to the sample surface, while other samples exhibited nearly random crystallographic texture. The electrochemical results from potentiodynamic polarization and electrochemical impedance spectroscopy showed a decrease in corrosion resistance from 87 µm to 53 µm grain size sample and then an increase for the 26 µm grain size sample. This increase was attributed to the dominant effect of recrystallization texture on the corrosion behavior of the sample. The cathodic hydrogen evolution reaction kinetics was found to play a decisive role in the corrosion behavior of iron.

Remarkable discoveries over the last two decades have elucidated the autoimmune basis of several, previously poorly understood, neurological disorders. Autoimmune disorders of the nervous system may affect any part of the nervous system, including the brain and spinal cord (central nervous system, CNS) and also the peripheral nerves, neuromuscular junction and skeletal muscle (peripheral nervous system, PNS). This comprehensive overview of this rapidly evolving field presents the factors which may trigger breakdown of self-tolerance and development of autoimmune disease in some individuals. Then the pathophysiological basis and clinical features of autoimmune diseases of the nervous system are outlined, with an emphasis on the features which are important to recognize for accurate clinical diagnosis. Finally the latest therapies for autoimmune CNS and PNS disorders and their mechanisms of action and the most promising research avenues for targeted immunotherapy are discussed.

Solving environmental and social challenges such as climate change requires a shift from our current non-renewable manufacturing model to a sustainable bioeconomy. To lower carbon emissions in the production of fuels and chemicals, plant biomass feedstocks can replace petroleum using microorganisms as biocatalysts. The anaerobic thermophile Clostridium thermocellum is a promising bacterium for bioconversion due to its capability to efficiently degrade lignocellulosic biomass. However, the complex metabolism of C. thermocellum is not fully understood, hindering metabolic engineering to achieve high titers, rates, and yields of targeted molecules. In this study, we developed an updated genome-scale metabolic model of C. thermocellum that accounts for recent metabolic findings, has improved prediction accuracy, and is standard-conformant to ensure easy reproducibility. We illustrated two applications of the developed model. We first formulated a multi-omics integration protocol and used it to understand redox metabolism and potential bottlenecks in biofuel (e.g., ethanol) production in C. thermocellum. Second, we used the metabolic model to design modular cells for efficient production of alcohols and esters with broad applications as flavors, fragrances, solvents, and fuels. The proposed designs not only feature intuitive push-and-pull metabolic engineering strategies, but also present novel manipulations around important central metabolic branch-points. We anticipate the developed genome-scale metabolic model will provide a useful tool for system analysis of C. thermocellum metabolism to fundamentally understand its physiology and guide metabolic engineering strategies to rapidly generate modular production strains for effective biosynthesis of biofuels and biochemicals from lignocellulosic biomass.

Metabolic pathways reflect an organism's chemical repertoire and hence their elucidation and design have been a primary goal in metabolic engineering. Various computational methods have been developed to design novel metabolic pathways while taking into account several prerequisites such as pathway stoichiometry, thermodynamics, host compatibility, and enzyme availability. The choice of the method is often determined by the nature of the metabolites of interest and preferred host organism, along with computational complexity and availability of software tools. In this paper, we review different computational approaches used to design metabolic pathways based on the reaction network representation of the database (i.e., graph or stoichiometric matrix) and the search algorithm (i.e., graph search, flux balance analysis, or retrosynthetic search). We also put forth a systematic workflow that can be implemented in projects requiring pathway design and highlight current limitations and obstacles in computational pathway design.

Abstract Arsenic is globally infamous for inducing immunosuppression associated with prevalence of opportunistic infection in exposed population, although the mechanism remains elusive. In this study, we investigate the effect of arsenic exposure on thymocyte lineage commitment and the involvement of regulatory T cells (Treg) in arsenic-induced immunosuppression. Male Balb/c mice were exposed to 0.038, 0.38 and 3.8 ppm sodium arsenite for 7, 15 and 30 days through oral gavage. Arsenic exposure promoted CD4 lineage commitment in a dose dependent manner supported by the expression of ThPOK in thymus. Arsenic also increased splenic CD4+ T cells and promoted their differentiation into Treg cells. In parallel, arsenic exposure induced immunosuppression characterized by low cytokine secretion from splenocytes and increased susceptibility to Mycobacterium fortuitum (M. fortuitum) infection. Therefore, we linked arsenic-induced rise in Treg cells with suppressed Th1 and Th2 related cytokines, which has been reversed by inhibition of Treg cells in-vivo using wortmannin. Other parameters like body weight, kidney and liver function, histoanatomy of thymus and spleen as well as thymocyte and splenocytes viability were unaltered by arsenic exposure. Taken together our findings indicated that environmentally relevant dose of arsenic enhanced differentiation of Treg cells which in turn induce immunosuppression in experimental animals.

Abstract Background Clostridium thermocellum is a Gram-positive anaerobe with the ability to hydrolyze and metabolize cellulose into biofuels such as ethanol, making it an attractive candidate for consolidated bioprocessing (CBP). At present, metabolic engineering in C. thermocellum is hindered due to the incomplete description of its metabolic repertoire and regulation within a predictive metabolic model. Genome-scale metabolic (GSM) models augmented with kinetic models of metabolism have been shown to be effective at recapitulating perturbed metabolic phenotypes. Results In this effort, we first update a second-generation genome-scale metabolic model (iCth446) for C. thermocellum by correcting cofactor dependencies, restoring elemental and charge balances, and updating GAM and NGAM values to improve phenotype predictions. The iCth446 model is next used as a scaffold to develop a core kinetic model (k-ctherm118) of the C. thermocellum central metabolism using the Ensemble Modeling (EM) paradigm. Model parameterization is carried out by simultaneously imposing fermentation yield data in lactate, malate, acetate, and hydrogen production pathways for 19 measured metabolites spanning a library of 19 distinct single and multiple gene knockout mutants along with 18 intracellular metabolite concentration data for a Δgldh mutant and ten experimentally measured Michaelis–Menten kinetic parameters. Conclusions The k-ctherm118 model captures significant metabolic changes caused by (1) nitrogen limitation leading to increased yields for lactate, pyruvate, and amino acids, and (2) ethanol stress causing an increase in intracellular sugar phosphate concentrations (~1.5-fold) due to upregulation of cofactor pools. Robustness analysis of k-ctherm118 alludes to the presence of a secondary activity of ketol-acid reductoisomerase and possible regulation by valine and/or leucine pool levels. In addition, cross-validation and robustness analysis allude to missing elements in k-ctherm118 and suggest additional experiments to improve kinetic model prediction fidelity. Overall, the study quantitatively assesses the advantages of EM-based kinetic modeling towards improved prediction of C. thermocellum metabolism and develops a predictive kinetic model which can be used to design biofuel-overproducing strains.

Background: Opioid substitution therapy (OST) is an evidence-based intervention for opiate-dependent persons that replaces illicit drug use with medically prescribed, orally administered opiates such as buprenorphine and methadone. OST reduces HIV risk behaviors and harms associated with injecting opioid. Most of the evidence for OST effectiveness has been generated in middle- and high-income countries where programs are mostly located in dedicated health-care settings; evidence regarding the outcomes of OST programs in low-income countries where OST is often provided in grassroots settings such as drop-in centers is limited. Aims and Objectives: To study the sociodemographic variables, HIV ELISA status, HIV risk behavior, comorbid substance use pattern, and required dose of buprenorphine used for treatment of injection drug users (IDUs) attending oral substitution therapy (OST) center at a tertiary health care center. Methodology: A total of IDUs aged 18–60 years who attended the OST center during 1-year period at a government medical college are included in the study. Results: Majority of the IDUs are male with mean age of 32.8 years. The mean dose of buprenorphine used for the substitution was 4.6 mg/day at the start of therapy. Most of the IDUs are of lower educational status and educated up to primary or middle school. 32.50% of the participants who are unemployed are totally dependent on the family. Most common substance abuse among IDU users were tobacco (74.17%), followed by heroine (57.5%). High-risk behavior found among OST clients was unprotected sexual intercourse (19.17%), sharing needle (11.67%), and sexual intercourse with multiple partners (6.67%). HIV ELISA testing showed positive among 2 (1.67%). Conclusion: These findings have relevance to other parts of India and Asia, where injecting drug use is common and is a first step toward filling the gap in knowledge regarding the effectiveness of community-based OST programs delivered in resource-constrained settings.

Lesch-Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase-1. Few reports on behavioral aspects especially self-injurious behavior in LNS patients are available. We report a case of LNS in an 8-year-old male child, who presented with characteristic self-injurious behavior.

Acute muscarinic and nicotinic side effects of organophosphate (OP) poisoning are well known and easily recognized, but neuropsychiatric changes are rarely reported. We are reporting a case of a 22-year-old male who developed psychotic features and motor neuropathy following acute OP poisoning.

Glutathione is one of the major antioxidant defense components present in cells. It is predominantly present as reduced glutathione (GSH) and converted into oxidized glutathione (GSSG) while reducing the free radicals like hydroxyl ions (OH-). For the measurement of GSH and GSSG, o-phthalaldehyde (OPT) has been used as a fluorescent reagent. O-phthalaldehyde has an ability to react specifically with GSH at pH 8 and GSSG at pH 12 respectively. N-ethylmaleimide (NEM) has been used to prevent auto-oxidation of GSH during measurement of GSSG in the present protocol. The original protocol by Hissin and Hilf was developed for glutathione estimation in Rat liver tissue. The present protocol has been standardized following Hissin and Hilf (1976) for the estimation of glutathione in cultured microglial cell lysate but it can also be used for other mammalian cell lysate. In our lab same protocol has been used for the estimation of glutathione in the whole cell lysate of murine neuroblastoma cell, N2a.

Cabergoline, a dopamine agonist agent, is commonly used in the treatment of hyperprolactinemia, Parkinson's disease, restless leg syndrome, and antipsychotic-induced prolactin elevation. It is generally well tolerated as compared to other dopamine agonist agents due to its more selective D2 receptor agonistic effect. We present a case of a 25-year-old female who developed manic episode, following the use of cabergoline for treatment of pituitary microadenoma. We suggest that physicians should carefully screen patients before initiating cabergoline therapy and at-risk patients may benefit from more frequent monitoring and cessation of therapy at the earliest safe juncture.

Peripheral neuropathy secondary to lithium is under-recognized. Most cases of polyneuropathy were reported with lithium intoxication. However, very few cases were reported without lithium toxicity. We present a case of motor neuropathy due to the use of lithium in a 26-year-old male with a therapeutic lithium level.

Obsessive-compulsive disorder (OCD) is one of the most prevalent psychiatric disorders in children and adolescents. The phenomenology of OCD in children and adolescent is strikingly similar to that of adults. But at times, the presentation of OCD may be so atypical or unusual in children and adolescents that may lead to misdiagnosis or delay in diagnosis. We report a case of 10-year-old child who was initially misdiagnosed with schizophrenia, and treated with antipsychotic for 2 months. But once the core symptoms were recognized as obsessions and compulsions and appropriately treated in the line of OCD, the symptoms resolved significantly.

Childhood disintegrative disorder (CDD) is characterized by late onset (>3 years of age) of developmental delays in language, social function and motor skills. Commonly there is no antecedent physical disorder leading to childhood disintegrative disorder. The present case report describes a child who developed childhood disintegrative disorder at the age of 6 years after an episode of chicken pox.

Fahr′s disease (FD) is a rare idiopathic degenerative neurological disorder, which can be present in different heterogeneous manifestations and characterized by bilateral symmetrical cerebral calcification. We present a case of a 55-year-old male who presented with the psychotic feature, bilateral tremors of hand and bilateral symmetrical calcification of basal ganglia. Hence our case suggests that psychiatrists should evaluate the cases of psychosis thoroughly when the age of presentation is atypical, and they should consider the diagnosis of FD when psychosis presents with motor abnormalities.

Electroconvulsive therapy (ECT) is a recognized and effective treatment in adults for several psychiatric disorders. However, the lack of knowledge and experience with the use of ECT among child and adolescent psychiatrists is an obstacle to its appropriate use. Treatment using ECT in children of prepubertal age has been less reported. We present a case of 10-year-old child with a diagnosis of acute and transient psychotic disorder with catatonic features, where we have used ECT successfully.

P-glycoprotein (Pgp, ABCB1) is an ATP-Binding Cassette (ABC) transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell- and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982) with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [(125)I]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C) Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug-binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available for each substrate.

ATP-binding-cassette family membrane proteins play an important role in multidrug resistance. In this study, we investigated BIRB796, an orally active inhibitor of p38 mitogen-activated protein kinase, reversed MDR induced by ABCB1, ABCG2 and ABCC1. Our results showed that BIRB796 could reverse ABCB1-mediated MDR in both the drug selected and transfected ABCB1-overexpressing cell models, but did not enhance the efficacy of substrate-chemotherapeutical agents in ABCC1 or ABCG2 overexpression cells and their parental sensitive cells. Furthermore, BIRB796 increased the intracellular accumulation of the ABCB1 substrates, such as rhodamine 123 and doxorubicin. Moreover, BIRB796 bidirectionally mediated the ATPase activity of ABCB1, stimulating at low concentration, inhibiting at high concentration. However, BIRB796 did not alter the expression of ABCB1 both at protein and mRNA level. The down-regulation of p38 by siRNA neither affected the expression of ABCB1 nor the cytotoxic effect of paclitaxel on KBV200. The binding model of BIRB796 within the large cavity of the transmembrane region of ABCB1 may form the basis for future lead optimization studies. Importantly, BIRB796 also enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBV200 cell xenografts in nude mice. Overall, we conclude that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. These findings may be useful for cancer combinational therapy with BIRB796 in the clinic.

One of the major causes of chemotherapy failure in cancer treatment is multidrug resistance (MDR) which is mediated by the ABCB1/P-glycoprotein. Previously, through the use of an extensive screening process, we found that vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor significantly reverses MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil, another PDE-5 inhibitor. The present study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated MDR. Vardenafil or tadalafil alone, at concentrations up to 20 µM, had no significant toxic effects on any of the cell lines used in this study, regardless of their membrane transporter status. However, vardenafil when used in combination with anticancer substrates of ABCB1, significantly potentiated their cytotoxicity in ABCB1 overexpressing cells in a concentration-dependent manner, and this effect was greater than that of tadalafil. The sensitivity of the parenteral cell lines to cytotoxic anticancer drugs was not significantly altered by vardenafil. The differential effects of vardenafil and tadalafil appear to be specific for the ABCB1 transporter as both vardenafil and tadalafil had no significant effect on the reversal of drug resistance conferred by ABCC1 (MRP1) and ABCG2 (BCRP) transporters. Vardenafil significantly increased the intracellular accumulation of [(3)H]-paclitaxel in the ABCB1 overexpressing KB-C2 cells. In addition, vardenafil significantly stimulated the ATPase activity of ABCB1 and inhibited the photolabeling of ABCB1 with [(125)I]-IAAP. Furthermore, Western blot analysis indicated the incubation of cells with either vardenafil or tadalafil for 72 h did not alter ABCB1 protein expression. Overall, our results suggest that vardenafil reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1.