Biotechnological Approaches for Metal Recovery from Electronic Wastes.

The disposal of electronic waste (EW) in open landfills has caused several toxic environmental effects. The harmful metallic components released in the environment due to deposition of EW act as hazards for living systems. EW management has been widely studied in recent days across the world. Though, several processes are implemented in extraction, recycling and recovery of heavy metals from the EW, most of them are not effective in recovering the precious metals. Various chemical processes are executed for efficient extraction of precious metals from e-wastes. Though the techniques are easy to process and rapid, however, the chemical leaching also has detrimental environmental consequences. Biological approaches, on the other hand, solves the purpose for efficient and environmentally friendly recovery of precious metals. Thus, both resource recovery as well as remediation can be targeted simultaneously. Biotechnological methods offer sustainable and efficient solutions for metal recovery from electronic wastes, presenting a viable alternative to traditional methods. Continued advancements in this field hold significant promise for addressing the growing e-waste challenge.

Paracetamol mineralization strategy in laboratory scale using Aspergillus niger KCAC.

The emergence of drug resistance, caused due the presence of pharmaceutical contaminant in the environment, highlights the critical need for pharmaceutical drugs management. Pharmaceutical drugs are sourced in wastewater as pharmaceutical industrial effluents, antibiotic misuse, and inappropriate disposal of expired pharmaceuticals, eventually ending up in sewage deposition. In this work, we aimed to degrade paracetamol (APAP) through the mycoremediation approach in laboratory scale. The isolated paracetamol degradation fungal strain, identified as Aspergillus niger KCAC efficiently degraded the drug into non-toxic metabolites. The results demonstrated that 99.6% degradation rate was achieved by Aspergillus niger KCAC. Unique, low-cost, eco-friendly bioformulation of the fungal isolate was prepared during the study using used vegetable cooking oil as substrate. The bioformulation showed extended shelf-life and can be used in future for large-scale application. Thus, this detailed investigation on paracetamol biodegradation may be useful in developing a wastewater treatment system effective against paracetamol-contaminated wastewater.

DNA methylome in pancreatic cancer identified novel promoter hyper-methylation in NPY and FAIM2 genes associated with poor prognosis in Indian patient cohort.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a 5-year survival rate of only 8.5%. In this study we investigated altered DNA methylation associated with PDAC severity and prognosis. METHODS: Methylome data, generated using 450 K bead array, was compared between paired PDAC and normal samples in the TCGA cohort (n = 9) and our Indian cohort (n = 7). The total Indian Cohort (n = 75) was split into cohort 1 (n = 7), cohort 2 (n = 22), cohort 3 (n = 26) and cohort 4 (n = 20).Validation of differential methylation (6 selected CpG loci) and associated gene expression for differentially methylated genes (10 selected gDMs) were carried out in separate validation cohorts, using MSP, RT-PCR and IHC correlations between methylation and gene expression were observed in TCGA, GTEx cohorts and in validation cohorts. Kaplan-Meier survival analysis was done to study differential prognosis, during 2-5 years of follow-up. RESULTS: We identified 156 DMPs, mapped to 91 genes (gDMs), in PDAC; 68 (43.5%) DMPs were found to be differentially methylated both in TCGA cohort and our cohort, with significant concordance at hypo- and hyper-methylated loci. Enrichments of "regulation of ion transport", "Interferon alpha/beta signalling", "morphogenesis and development" and "transcriptional dysregulation" pathways were observed among 91 gDMs. Hyper-methylation of NPY and FAIM2 genes with down-regulated expression in PDAC, were significantly associated with poor prognosis in the Indian patient cohort. CONCLUSIONS: Ethnic variations among populations may determine the altered epigenetic landscape in the PDAC patients of the Indian cohort. Our study identified novel differentially methylated genes (mainly NPY and FAIM2) and also validated the previously identified differentially methylated CpG sites associated with PDAC cancer patient's survival. Comparative analysis of our data with TCGA and CPTAC cohorts showed that both NPY and FAIM2 hyper-methylation and down-regulations can be novel epigenetically regulated genes in the Indian patient population, statistically significantly associated with poor survival and advanced tumour stages.

Microbial application in remediation of heavy metals: an overview.

Heavy metal contamination poses a menacing threat to all living forms in the natural world due to its catastrophic consequences, contributing to environmental pollution. The need for human beings increasing each day along with anthropological activity is contributing directly to the destruction of the environment with the release of a large number of heavy metals into the food chain. These metals can be accumulated in the food chains and are very extremely toxic even at low concentrations. Heavy metals aggregation can deteriorate the healthy ecosystem of the water bodies as well. One of the major concerns is the diminution and administration of the heavy metals aggregating in marine water bodies and lakes. Heavy metals are not degradable and thus tend to remain in the environment for a prolonged time period. Heavy metal aggregation can demonstrate immediate repercussions such as DNA damage, inhibition of respiration and photosynthesis, and rapid reactive oxygen species generation. Conventional or standard chemical and physical methods for remediation of heavy metals are uneconomical and lead to the production of a large magnitude of chemical waste. This shifts the focus and interest towards the utilization of microbes in remediation of heavy metals from the environment which is eco-friendly and economical. To contend with heavy metals, microorganisms have a specific mechanism such as biotransformation, biosorption, and homeostasis. The microbial system is responsive to the toxicity that is created by the heavy metals which are easily water-soluble and available in the environment. The current review article describes the sources and effects of metal ions in the environment followed by bioremediation strategies followed in their remediation. Microbial approaches in remediation of metal ions from extraterrestrial materials are depicted in the paper.

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

Deregulation of H19 is associated with cervical carcinoma.

CACX is one of the most common cancer affecting women world-wide. Here, expression microarray analysis revealed 8 over-expressed transcribed pseudogenes (GBP1P1, HLA-DRB6, HLA-H, SLC6A10P, NAPSB, KRT16P2, PTTG3P and RNF126P1), down-regulated 7 lincRNAs (H19, MIR100HG, MEG3, DIO3OS, HOXA11-AS, CD27-AS1 and EPB41L4A-AS) and 6 snoRNAs (SNORD97, SNORD3A, SNORD3C, SNORD3D, SNORA12 and SCARNA9) as DEncGs (log2 fold-change ≥ ±1.0) in CACX. Consequently, down-regulation of lincRNA MEG3 and over-expression of pseudogenes, GBP1P1 and PTTG3P in the microarray analysis were found concordant with the real-time quantitative PCR results upon validation. Then, Ingenuity® Pathway analysis (IPA®) analysis with deregulated DEncGs identified functionally important gene, H19. Further, validation (n = 52) of expression confirmed frequent downregulation of H19 with significant association with its deletion (LOH) and promoter methylation (n = 128) in CACX. Moreover, clinicopathological analysis found Indian CACX patients (n = 26) with alterations of H19 by deletion or, promoter methylation with concomitant low expression have poor prognosis.

Hepatic transcriptome signature correlated with HOMA-IR explains early nonalcoholic fatty liver disease pathogenesis.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is multistage with heterogeneous outcomes. We studied the influence of insulin resistance (IR) on the hepatic transcriptome of early NAFLD stages, to understand disease development. MATERIALS AND METHODS: In this cross-sectional study, possible clinicopathological risk factors were compared between mild-NAFL (N = 72) and non-alcoholic steatohepatitis (NASH; N = 51) patients. Liver tissue-transcriptome difference was studied between a subset of 25 mild-NAFL and 20 NASH biopsies and validated on another subset of 12 mild-NAFL and 13 NASH biopsies, using RT-PCR. The relationship between IR driven gene expression changes with fibrosis in NASH was investigated. RESULTS: Significantly higher weight (p = 0.005) and elevated levels of HbA1c (p = 0.009), FBG (p = 0.03) and HOMA-IR (p = 0.009) were found in NASH patients. Five differentially expressed genes (DEGs, fold change > 1.5) were identified in NASH-FABP4, FABP5L2, CD24, PRAP1, and SPP1. The DEGs were positively associated with disease severity and HOMA-IR, and were found to be efficient classifiers of mild-NAFL and NASH. Additional 1218 genes identified related to IR (IrCGs), which can classify NASH-with-fibrosis patients separately from mild-NAFL and NASH patients. IrCGs can promote intra-hepatic fat accumulation, dysregulation of the lipid metabolism, lipotoxicity, and activation of cell survival pathways including activation of cell proliferation and differentiation pathways. CONCLUSIONS: Hepatic expression of genes associated with insulin resistance may drive NAFLD development and progression.

Desorption of heavy metals from metal loaded sorbents and e-wastes: A review.

In recent era, with increasing heavy metal pollution, several sorbents are used to remove heavy metals from environment. Application of chemical adsorbents and biosorbents for uptake of heavy metals from soil and waste water is studied thoroughly. Very less attention has been paid to the recovery of heavy metals from sorbents and their reuse. Few researches have been performed to evaluate the recovery of heavy metals from sorbents and regeneration of sorbents for further adsorption processes. This review explains desorption of heavy metals from metal loaded adsorbents and regeneration of adsorbents. Various desorbing eluents and their utilization in desorption of certain metals are compiled along with the techniques and setups followed to achieve better recovery and regeneration rates. The prospect of such eluents in recovery of heavy metals from electronic wastes (e-waste) is scrutinized. This comprehensive study would be advantageous to determine methods and the most suitable desorbents for particular heavy metals for conducting adsorption-desorption cycles.

Noxious ramifications of cosmetic pollutants on gastrointestinal microbiome: A pathway to neurological disorders.

On exposure to cosmetic pollutants, gastrointestinal dysbiosis, which is characterised by a disturbance in the gut microbiota, has come into focus as a possible contributor to the occurrence of neurotoxic consequences. It is normal practice to use personal care products that include parabens, phthalates, sulphates, triclosans/triclocarbans and micro/nano plastics. These substances have been found in a variety of bodily fluids and tissues, demonstrating their systemic dispersion. Being exposed to these cosmetic pollutants has been linked in recent research to neurotoxicity, including cognitive decline and neurodevelopmental problems. A vital part of sustaining gut health and general well-being is the gut flora. Increased intestinal permeability, persistent inflammation, and impaired metabolism may result from disruption of the gut microbial environment, which may in turn contribute to neurotoxicity. The link between gastrointestinal dysbiosis and the neurotoxic effects brought on by cosmetic pollutants may be explained by a number of processes, primarily the gut-brain axis. For the purpose of creating preventative and therapeutic measures, it is crucial to comprehend the intricate interactions involving cosmetic pollutants, gastrointestinal dysbiosis, and neurotoxicity. This review provides an in-depth understanding of the various hazardous cosmetic pollutants and its potential role in the occurrence of neurological disorders via gastrointestinal dysbiosis, providing insights into various described and hypothetical mechanisms regarding the complex toxic effects of these industrial pollutants.

Zebrafish: A trending model for gut-brain axis investigation.

Zebrafish (Danio rerio) has ascended as a pivotal model organism in the realm of gut-brain axis research, principally owing to its high-throughput experimental capabilities and evolutionary alignment with mammals. The inherent transparency of zebrafish embryos facilitates unprecedented real-time imaging, affording unparalleled insights into the intricate dynamics of bidirectional communication between the gut and the brain. Noteworthy are the structural and functional parallels shared between the zebrafish and mammalian gut-brain axis components, rendering zebrafish an invaluable model for probing the molecular and cellular intricacies inherent in this critical physiological interaction. Recent investigations in zebrafish have systematically explored the impact of gut microbiota on neurodevelopment, behaviour, and disease susceptibility, underscoring the model's prowess in unravelling the multifaceted influence of microbial communities in shaping gut-brain interactions. Leveraging the genetic manipulability inherent in zebrafish, researchers have embarked on targeted explorations of specific pathways and molecular mechanisms, providing nuanced insights into the fundamental functioning of the gut-brain axis. This comprehensive review synthesizes pivotal findings and methodological advancements derived from zebrafish-based gut-brain axis research, accentuating the model's potential to significantly advance our understanding of this complex interplay. Furthermore, it underscores the translational significance of these insights, offering promising avenues for the identification of therapeutic targets in neuro-gastroenterological disorders and psychiatric conditions intricately linked with gut-brain interactions.

8-Aminoquinoline derived two Schiff base platforms: Synthesis, characterization, DFT insights, corrosion inhibitor, molecular docking, and pH-dependent antibacterial study.

The current research divulges the synthesis of two new Schiff base (SB) (L NAPH /L O-VAN ) derived from 8-aminoquinoline (8-AMQ) in the presence of 2-hydroxy naphthaldehyde (NAPH) and ortho-vanillin (O-VAN) in CH3OH solvent. They are structurally characterized by spectroscopic methods (IR/Raman/UV-vis/DRS/NMR) and SEM-EDX. SB compounds have a biologically active avenue of azomethine/imine group (H-C=N) that can donate N e's to Mn + ions, showing coordinating flexibility. The -OH and imine (H-C=N) groups are stable in air, light, and alkalis but undergo acidic environments hydrolysis, separating -NH2 and carbonyl compounds. Moreover, buffer solutions with a pH range of 4-6 release aldehyde. Molecular electrostatic potential (MEP), Frontier molecular orbitals (FMO), Fukui function, and Non-linear optical (NLO) were conducted to elucidate SBs chemical potency, optoelectronic significance, and corrosion inhibitor. Accordingly, the calculated ΔE of FMO for L NAPH and L O-VAN is 3.82 and 4.08 eV, ensuring potent biological function. DFT supported the experimental and theoretical IR spectral correlation to enrich better structural insights. NLO-based polarizability (α) and hyperpolarizability (ß) factors successfully explore the potential optoelectronic significance. Molecular docking experiments were simulated against DNA, anti-COVID-19, and E. coli. The potential microbiological activity was screened against the bacterial strains E. coli, Klebsiella, Bacillus, and Pseudomonas sp. based on zone of inhibition and MIC values. These experiments also explored the fact that L NAPH and L O-VAN discourage microbial cell biofilms and corrosion. We extensively covered the as-prepared compounds' pH-dependent bacterial effects.

Associations of cerebrovascular disease and Alzheimer's disease pathology with cognitive decline: Analysis of the National Alzheimer's Coordinating Center Uniform Data Set.

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) often co-occur and may impact specific cognitive domains. This study's goal was to determine effects of CVD and AD burden on cross-sectional and longitudinal executive function (EF) and memory in older adults. Longitudinally followed participants from the National Alzheimer Coordinating Center database (n = 3342) were included. Cognitive outcomes were EF and memory composite scores. Baseline CVD presence was defined by moderate-to-severe white matter hyperintensities or lacunar infarct on MRI. Baseline AD pathology was defined by amyloid positivity via PET or CSF. Linear mixed models examined effects of CVD, AD, and time on cognitive outcomes, controlling for sex, education, baseline age, MoCA score, and total number of study visits. At baseline, CVD associated with lower EF (p < 0.001), while AD associated with lower EF and memory (ps < 0.001). Longitudinally only AD associated with faster declines in memory and EF (ps < 0.001). These results extend our understanding of CVD and AD pathology, highlighting that CVD does not necessarily indicate accelerated decline.

Uracil as a biomarker for spatial pyrimidine metabolism in the development of gingivobuccal oral squamous cell carcinoma.

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.

Targeting cytokine storm as the potential anti-viral therapy: Implications in regulating SARS-CoV-2 pathogenicity.

The latest global pandemic corona virus disease - 2019 (COVID-19) caused by the virus SARS-CoV-2 is still a matter of worrying concern both for the scientific communities and health care organizations. COVID-19 disease is proved to be a highly contagious disease transmitted through respiratory droplets and even close contact with affected individuals. COVID-19 disease is also understood to exhibit diverse symptoms of ranging severities i.e., from mild fatigue to death. Affected individuals' susceptibility to induce immunologic dysregulation phenomena termed 'cytokine storm' seems to be playing the damaging role of escalating the disease manifestation from mild to severe. Cytokine storm in patients with severe symptoms is understood to be characterized by enhanced serum levels of many cytokines including interleukin-1ß, interleukin-6, IP-10/CXCL10, TNF, interferon-γ, MIP-1α, MIP-1ß and VEGF. Since cytokine production in general is the most important antiviral defense response, understanding the COVID-19 associated cytokine storm in particular and differentiating it from the regular cytokine production response becomes crucial in developing an effective therapeutic strategy.This review focuses on the potential targeting of COVID-19 associated cytokine storm and its challenges.

Overexpression of CD73 is associated with recurrence and poor prognosis of gingivobuccal oral cancer as revealed by transcriptome and deep immune profiling of paired tumor and margin tissues.

BACKGROUND: For various cancers, differences in response to treatment and subsequent survival period have been reported to be associated with variation in immune contextures. AIM: We sought to identify whether such association exists in respect of gingivobuccal oral cancer. MATERIALS AND METHODS: We performed deep immune profiling of tumor and margin tissues collected from 46 treatment naïve, Human Papillomavirus (HPV) negative, patients. Each patient was followed for 24 months and prognosis (recurrence/death) noted. Key findings were validated by comparing with TCGA-HNSC cohort data. RESULTS: About 28% of patients showed poor post-treatment prognosis. These patients exhibited a high probability of recurrence even within 1 year and death within 2 years. There was restricted immune cell infiltration in tumor, but not in margin, among these patients. Reduced expression of eight immune-related genes (IRGs) (NT5E, THRA, RBP1, TLR4, ITGA6, BMPR1B, ITGAV, SSTR1) in tumor strongly predicted better quality of prognosis, both in our patient cohort and in TCGA-HNSC cohort. Tumors of patients with better prognosis were associated with (a) lower CD73+ cells with concomitant lower expression level of NT5E/CD73, (b) higher proportions of CD4+ and CD8+ T cells, B cells, NK cells, M1 macrophages, (c) higher %Granzyme+ cells, (d) higher TCR and BCR repertoire diversities. CD73 expression in tumor was associated with low CD8+ and CD4+ T cells, low immune repertoire diversity, and advanced cancer stage. DISCUSSION AND CONCLUSION: High infiltration of anti-tumor immune cells in both tumors and margins results in good prognosis, while in patients with minimal infiltration in tumors in spite of high infiltration in margins results in poor prognosis. Targeted CD73 immune-checkpoint inhibition may improve clinical outcome.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

Deep learning techniques for observing the impact of the global warming from satellite images of water-bodies.

Global warming is a threat to modern human civilization. There are different reasons for speed up the global average temperature. The consequences are catastrophic for human existence. Seafloor rise, drought, flood, wildfire, dry riverbed are some of the consequences. This paper analyzes the changes in boundaries of different water bodies such as fresh-water lakes and glacial lakes. Over time, the area covered by a water body has been varied due to human interventions or natural causes. Here, variants of Detectron2 instance segmentation architectures have been employed to detect a water-body and compute the changes in its area from the time-lapsed images captured over 32 years, that is, 1984 to 2016. The models are validated using water-bodies images taken by the Sentinel-2 Satellite and compared based on the average precision (AP), 99.95 and 94.51 at A P 50 and A P 75 metrics, respectively. In addition, an ensemble approach has also been introduced for the efficient identification of shrinkage or expansion of water bodies.

Exome-wide scan identifies significant association of rs4788084 in IL27 promoter with increase in hepatic fat content among Indians.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic that often progresses to liver cirrhosis and hepatocellular carcinoma. In contrast to most world populations where NAFLD is mostly prevalent among obese, NAFLD among Indians and generally among South and South-East Asians is unique and highly prevalent among individuals who are lean. Genetics of NAFLD in Indian populations is understudied. In this study, we have used an exome-wide approach to identify genetic determinants of hepatic fat content (HFC) in India. METHODS: HFC was measured in 244 participants using Proton magnetic resonance spectroscopy (H1-MRS). Quantitative trait loci (QTL) mapping was done exome-wide, to identify SNPs associated with HFC. The effects of the interaction between adiposity and QTLs on HFC were studied using a regression model. Association of the significant loci with disease severity was studied in 146 NAFLD patients among 244 participants, who underwent liver biopsy. RESULTS: Our study identified 4 significantly associated SNPs (rs738409 and rs2281135 (PNPLA3), rs3761472 (SAMM50), rs17513722 (FAM161A) and rs4788084), with HFC after adjusting for the effects of covariates (p-value < 0.0005). rs738409, rs2281135 (PNPLA3), and rs3761472 (SAMM50) were associated with hepatocyte ballooning, lobular and portal inflammation and non-alcoholic steatohepatitis (NASH) (p-value < 0.05). rs4788048 is an eQTL for IL27 and SULT1A2 genes, both of which are highly expressed in healthy livers and are likely to be involved in NAFLD pathogenesis. CONCLUSIONS: Our study identified the novel association of rs4788084 with HFC, which regulates the expression of IL-27, an immune regulatory gene. We further showed that adiposity affected the HFC, irrespective of the genetic predisposition.

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here, we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.

Rewiring of Metabolic Network in Mycobacterium tuberculosis During Adaptation to Different Stresses.

Metabolic adaptation of Mycobacterium tuberculosis (M. tuberculosis) to microbicidal intracellular environment of host macrophages is fundamental to its pathogenicity. However, an in-depth understanding of metabolic adjustments through key reaction pathways and networks is limited. To understand how such changes occur, we measured the cellular metabolome of M. tuberculosis subjected to four microbicidal stresses using liquid chromatography-mass spectrometric multiple reactions monitoring (LC-MRM/MS). Overall, 87 metabolites were identified. The metabolites best describing the separation between stresses were identified through multivariate analysis. The coupling of the metabolite measurements with existing genome-scale metabolic model, and using constraint-based simulation led to several new concepts and unreported observations in M. tuberculosis; such as (i) the high levels of released ammonia as an adaptive response to acidic stress was due to increased flux through L-asparaginase rather than urease activity; (ii) nutrient starvation-induced anaplerotic pathway for generation of TCA intermediates from phosphoenolpyruvate using phosphoenolpyruvate kinase; (iii) quenching of protons through GABA shunt pathway or sugar alcohols as possible mechanisms of early adaptation to acidic and oxidative stresses; and (iv) usage of alternate cofactors by the same enzyme as a possible mechanism of rewiring metabolic pathways to overcome stresses. Besides providing new leads and important nodes that can be used for designing intervention strategies, the study advocates the strength of applying flux balance analyses coupled with metabolomics to get a global picture of complex metabolic adjustments.