Study of the Inflammatory and Fibrotic Pathology in the Gut Following Microcystin Exposure Under Conditions of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic with increased risks of chronic inflammation in obese and elderly population. It has become a major public health concern due to the unavailability of proper therapeutic approaches. NAFLD is a condition of the liver involving wide spectrum of events including accumulation of fat in the liver and inflammation, which can progress to a fibrotic and cirrhotic phenotype, often termed as non-alcoholic steatohepatitis (NASH). In this backdrop, exposure to environmental toxins from harmful algal blooms could prove detrimental to the overweight, obese or elderly population. NAFLD not only affects the liver but also can have ectopic manifestations to distal organs like kidney, intestines and the brain. In this study, I have examined the role of the toxin Microcystin-LR which is released by cyanobacterial blooms in the coastal waters, and the molecular mechanisms involved in exacerbating the conditions of NAFLD in an individual. I observed that exposure to microcystin in NAFLD mice altered the gut microbiome, induced intestinal inflammation, tight junction protein disruption and fibrosis. It was found that microcystin could lead to the formation of NLRP3 inflammasome through the activation of the NADPH oxidase 2 pathway and generation of reactive oxygen species leading to oxidative stress. Inflammasome activation and increased oxidative stress could lead to the disruption of tight junction proteins, gut leaching and portal endotoxemia. I also explored the effect of overproduction of lactate from pathogenic bacteria due to microcystin exposure on the NAFLD murine intestines. The lactate was found to induce TGFβ downstream signaling pathway involving SMAD proteins, which was again mediated by the NADPH oxidase enzyme. Increased collagen depositon and epithelial to mesenchymal transition was also observed on exposure to microcystin indicating formation of a fibrotic phenotype in the murine small intestine. The inflammation and fibrosis were greatly attenuated in the P47 Phox knockout mice suggesting an important role of the NADPH oxidase enzyme in the molecular mechanisms of the action of microcystin. Similar effects of microcystin exposure were observed on leptin primed transformed rat intestinal epithelial cells. The cells showed inflammatory and fibrotic phenotypes with tight junction protein disruption and extracellular matrix protein deposition as the end points. Also the use of specific inhibitors suggested the mechanism of NADPH oxidase 2 in exacerbating the inflammatory and fibrotic conditions of the intestines in vitro. Along with high inflammation, microcystin exposure in NAFLD also led to uncontrolled levels of IL-18 and IL-17A in murine small intestine which can promote tissue inflammation and also tumor growth. Also, the anti- inflammatory cytokines was observed to decrease in the microcystin exposed group. Thus, my research involves a novel mechanism of studying intestinal diseased pathology due to microcystin exposure and highlights the effects of the toxin under the conditions of non- alcoholic fatty liver disease

Membrane Fusion Induced by Small Molecules and Ions

Membrane fusion is a key event in many biological processes. These processes are controlled by various fusogenic agents of which proteins and peptides from the principal group. The fusion process is characterized by three major steps, namely, inter membrane contact, lipid mixing forming the intermediate step, pore opening and finally mixing of inner contents of the cells/vesicles. These steps are governed by energy barriers, which need to be overcome to complete fusion. Structural reorganization of big molecules like proteins/peptides, supplies the required driving force to overcome the energy barrier of the different intermediate steps. Small molecules/ions do not share this advantage. Hence fusion induced by small molecules/ions is expected to be different from that induced by proteins/peptides. Although several reviews exist on membrane fusion, no recent review is devoted solely to small moleculs/ions induced membrane fusion. Here we intend to present, how a variety of small molecules/ions act as independent fusogens. The detailed mechanism of some are well understood but for many it is still an unanswered question. Clearer understanding of how a particular small molecule can control fusion will open up a vista to use these moleucles instead of proteins/peptides to induce fusion both in vivo and in vitro fusion processes

Effect of horizontal magnetic field on K\"{u}ppers-Lortz instability

We investigate the effect of an external horizontal magnetic field on the K\"{u}ppers-Lortz instability (KLI) in rotating Rayleigh-B\'{e}nard convection of Boussinesq fluids using weakly nonlinear theory along with linear theory. By KLI, we mean the instability where the two-dimensional roll solutions of the system occurring at the onset of convection becomes unstable against the perturbations by rolls oriented at different angle with the previous one as the rotation rate exceeds a critical value. The governing parameters, namely, the Prandtl number ($\mathrm{Pr}$), Taylor number ($\mathrm{Ta}$) and Chandrasekhar number ($\mathrm{Q}$) are varied in the ranges $0.8 \leq \mathrm{Pr} < \infty$, $0 < \mathrm{Ta} \leq 10^4$ and $0 \leq \mathrm{Q} \leq 10^4$ respectively by considering the vanishingly small magnetic Prandtl number limit. In the $\mathrm{Pr}\rightarrow \infty$ limit, magnetic field is found to inhibit the KLI by enhancing the critical Taylor number ($\mathrm{Ta}_c$) for its onset. On the other hand, for finite Prandtl number fluids, KLI is favored for lower $\mathrm{Q}$, and it is inhibited for higher $\mathrm{Q}$. Interestingly, in the finite Prandtl number range both KLI and small angle instability are manifested depending on the Prandtl number. No small angle instability is observed for $\mathrm{Pr} \geq 50$ and the rotation induced KLI is inhibited predominantly by the magnetic field. While, for $\mathrm{Pr} < 50$, along with the K\"{u}ppers-Lortz instability, small angle instability is also observed. However, in this case, KLI is favored for lower $\mathrm{Q}$, while it is inhibited for higher $\mathrm{Q}$.Comment: 13 pages, 13 figure

DESIGN OF DISSOLUTION STUDY PROTOCOL FOR PULMONARY DOSAGE FORMS: CRITERIA FOR SELECTION OF BIO-RELEVANT DISSOLUTION MEDIUM

Pulmonary dosage forms constitute an important route of drug delivery for systemic absorption of drugs in management of respiratory diseases as well as diseases such as diabetes, migraine, osteoporosis, and cancer. Performance of different pulmonary dosage forms is greatly influenced by aerodynamic particle size distribution of inhalable particles, spray pattern, fraction of dose actually deposited on pulmonary epithelium, dissolution of active pharmaceutical ingredient and ultimately absorption across pulmonary barriers. In vitro dissolution study should be designed to predict in vivo performance precisely, providing key information on bioavailability and establishing in vitro-in vivo correlation. To obtain meaningful data from dissolution study, focus should be on composition of dissolution medium, dissolution conditions and dissolution test apparatus. For pulmonary dosage forms, selection of physiologically relevant dissolution medium, mimicking lung fluid (LF) is a challenging task. Attempts are being made to develop bio-relevant dissolution medium to overcome the limitations associated with use of conventional media lacking lung surfactant proteins, or several salts normally present in pleural fluid. Use of simulated LFs can give a better understanding of the release mechanisms and possible in vivo behavior of pulmonary dosage forms thereby enhancing the predictive capability of the dissolution testing. In the review, efforts have been taken to provide comprehensive information on composition, physicochemical characteristics and functions of physiological LF, challenges associated with the design and development of dissolution study protocol for pulmonary dosage forms, criteria for selection of an appropriate bio-relevant dissolution medium, comparative study on various reported bio-relevant dissolution media and dissolution apparatuses employed for in vitro characterization of performance of pulmonary dosage forms

Human Papillomavirus Infections in Pregnant Women and Its Impact on Pregnancy Outcomes: Possible Mechanism of Self-Clearance

Young women are at the maximum risk of Human papillomavirus (HPV) infection which are asymptomatic in a majority of cases and spontaneously get cleared. Women in the age between 20 and 35 years are more active sexually and especially in the developing nations, this age group forms a major cohort among the population of pregnant women. The changed hormonal milieu and immune response during pregnancy might favor presence or persistence of HPV infection, while at the same time natural clearance also takes place during pregnancy with an unknown mechanism. Various HPVs have been reported to be associated with preterm rupture of membranes (PROM), fetal growth restriction (FGR), preeclampsia, placental abnormalities and preterm delivery in several populations. The risk factors involved in the intrauterine environment affects fetal development and thus increase the development risk of specific diseases in adult life as per the hypothesis of the fetal origins of adult disease (FOAD). The structural and molecular changes in the feto-maternal interface support and protect the semiallogeneic fetus from immune-mediated or inflammatory injury. On the other hand, the trophoblast cells of placenta facilitate the replication of HPV and the affliction of placenta and the vaginal infection can directly be associated with pregnancy outcomes. So, to optimize better child health care and reproductive outcomes, HPV screening might help during pregnancy. It is therefore important to understand how the HPV is affecting the early pregnancy and immune cells within the feto-maternal interface are educated for self-clearance to fulfill their biological functions or prevalence to affect the pregnancy outcomes and how the persistence of HR-HPV infection overtime increases the development of cervical cancer risk

High-protein rice in high-yielding background, cv. Naveen.

Not AvailableWhile the developing world is approaching towards food security, nutritional aspects must be addressed properly to combat malnutrition. As the staple food of half of the world’s population, rice is a major source of nutrition and needs to be nutritionally enriched with proteins, micronutrients, etc. With the objective of quantitative and qualitative improvement of grain protein content (GPC) in a popular high-yielding background, ‘Naveen’, we developed backcross popu-lation using high GPC (11%–13%) donor, ARC 10075. The range of GPC in BC3F4 lines was 7.13%–13.6%, estimated through calibrated NIR spectroscopy. Among the population lines, seven having phenotypic similarity with the recurrent parent, Naveen were identified based on high yield coupled with high pro-tein content (10%–12%). Further, elevated levels of glutelin and some of the essential amino acids such as lysine and threonine also indicated the qualitative im-provement of grain protein of these lines. Based on higher GPC and protein yield in multilocational test-ing two high-yielding lines, viz. CR2829-PLN-37 (CR Dhan 310), and CR 2829-PLN-100 (CR Dhan 311/Mukul) in the genetic background of cv. Naveen with an average 10.2% and 10.1% GPC respectively, in polished rice were released at the national and state level respectively. These high-yielding varieties with high GPC can significantly contribute towards better nourishment of millions of underprivileged children depending mainly on rice for their nutrition.Not Availabl

Generation mean analysis of gluten strength in bread wheat (Triticum aestivum): An effective utilization of micro-sedimentation test in early generation progenies

Better bread-making quality is one of the most important targets in the quality improvement programmes of wheat (Triticum aestivum L.). Gluten strength is a major indicator of bread making quality and is measured by various methods such as the SDS-sedimentation test. However, the nature of gene action for gluten strength has not been studied so far. In the present study, generation mean analysis was undertaken to estimate the nature and magnitude of gene effects for gluten strength in two sets of crosses involving contrasting parents using a less known microsedimentation test. Scaling test indicated the involvement of epistasis on the expression of the trait and inadequacy of additive-dominance model. Therefore, both six and five parameter models were used to understand the nature and direction of gene action further. Similar types of gene-action for gluten strength were recorded, albeit with some differences in the direction and magnitude of the effects, in the two sets of crosses. Among the different epistatic components, dominance × dominance effect had the maximum contribution and was acting in the negative direction in both the crosses. Analysis of both the cross combinations using Castle-Wright' equation for 'number of effective genes/blocks' revealed that at least one major gene block besides several minor genes could be involved for the micro-sedimentation volume