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Immune-mediated diseases, such as celiac disease, type 1 diabetes or multiple sclerosis, are a clinically heterogeneous group of diseases that share many key genetic triggers. Although the pathogenic mechanisms responsible for the development of immune mediated disorders is not totally understood, high-throughput genomic studies, such as GWAS and Immunochip, performed in the past few years have provided intriguing hints about underlying mechanisms and pathways that lead to disease. More than a hundred gene variants associated with disease susceptibility have been identified through such studies, but the progress toward understanding the underlying mechanisms has been slow. The majority of the identified risk variants are located in non-coding regions of the genome making it difficult to assign a molecular function to the SNPs. However, recent studies have revealed that many of the non-coding regions bearing disease-associated SNPs generate long non-coding RNAs (lncRNAs). LncRNAs have been implicated in several inflammatory diseases, and many of them have been shown to function as regulators of gene expression. Many of the disease associated SNPs located in lncRNAs modify their secondary structure, or influence expression levels, thereby affecting their regulatory function, hence contributing to the development of disease.

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.

Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status. The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively. Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31 genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival. Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC.

Catfishes are globally demanded as human food, angling sport and aquariums keeping thus are highly exploited all over the world. North-East India possess high abundance of catfishes and are equally exploited through decades. The strategies for conservation necessitate understanding the actual species composition, which is hampered due to sporadic descriptions of the species through traditional taxonomy. Therefore, actual catfish diversity in this region is important to be studied through the combined approach of morphological and molecular technique of DNA barcoding. Altogether 75 native catfish specimens were collected from across the North-East India and their morphological features were compared with the taxonomic keys. The detailed taxonomic study identified 25 species belonging to 17 genera and 9 families. The cytochrome oxidase c subunit-I gene fragment were then sequenced from the samples in accordance with the standard DNA barcoding protocols. The sequences were compared with public databases, viz., GenBank and BOLD. Sequences developed in the current study and from databases of the same and related taxa were analyzed to calculate the congeneric and conspecific genetic divergences using Kimura 2-parameter distance model, and a Neighbor Joining tree was created using software MEGA5.1. The DNA barcoding approach delineated 21 distinct species showing 4.33 folds of difference between the nearest congeners. Four species, viz., Amblyceps apangi, Glyptothorax telchitta, G. trilineatus and Erethistes pusillus, showed high conspecific divergence; hence their identification through molecular approach remained inconclusive. On the other hand, the database sequences for three species, viz., Mystus horai, Bagarius yarrelli and Clarias batrachus, appeared mislabeled. The efficiency of DNA barcoding was reaffirmed from its success by easily identifying the major share (84%) of the studied catfish into 21 distinct species. The study contributed 27 new barcodes for 7 species and confirmed the range expansion of 2 important species in NE India.

Epidemiological studies carried out using culture or microscopy in most of the amoebiasis endemic developing countries, yielded confusing results since none of these could differentiate the pathogenic Entamoeba histolytica from the non-pathogenic Entamoeba dispar and Entamoeba moshkovskii. The Northeastern part of India is a hot spot of infection since the climatic conditions are most conducive for the infection and so far no systemic study has been carried out in this region. Following a cross-sectional study designed during the period 2011-2014, a total of 1260 fecal samples collected from the Northeast Indian population were subjected to microscopy, fecal culture and a sensitive and specific DNA dot blot screening assay developed in our laboratory targeting the Entamoeba spp. Further species discrimination using PCR assay performed in microscopy, culture and DNA dot blot screening positive samples showed E. histolytica an overall prevalence rate of 11.1%, 8.0% and 13.7% respectively. In addition, infection rates of nonpathogenic E. dispar and E. moshkovskii were 11.8% (95% CI = 10.2, 13.8) and 7.8% (95% CI = 6.4, 9.4) respectively. The spatial distributions of infection were 18.2% (107/588) of Assam, 11.7% (23/197) of Manipur, 10.2% (21/207) of Meghalaya, and 8.2% (22/268) of Tripura states. Association study of the disease with demographic features suggested poor living condition (OR = 3.21; 95% CI = 1.83, 5.63), previous history of infection in family member (OR = 3.18; 95% CI = 2.09, 4.82) and unhygienic toilet facility (OR = 1.79; 95% CI = 1.28, 2.49) as significant risk factors for amoebiasis. Children in age group <15 yr, participants having lower levels of education, and daily laborers exhibited a higher infection rate. Despite the importance of molecular diagnosis of amoebiasis, molecular epidemiological data based on a large sample size from endemic countries are rarely reported in the literature. Improved and faster method of diagnosis employed here to dissect out the pathogenic from the nonpathogenic species would help the clinicians to prescribe the appropriate anti-amoebic drug.

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRas G12D -driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling. The molecular mechanisms of acinar-to-ductal metaplasia (ADM) in the course of pancreatitis and cancer development are unclear. Here, the authors show that loss of κB-Ras and consequent Ral activation promotes tumour initiation and progression through persistent ADM and enhanced cell proliferation

Esophageal squamous cell carcinoma (ESCC) develops as a result of complex epigenetic, genetic and environmental interactions. Epigenetic changes like, promoter hypermethylation of multiple tumour suppressor genes are frequent events in cancer, and certain habit-related carcinogens are thought to be capable of inducing aberrant methylation. However, the effects of environmental carcinogens depend upon the level of metabolism by carcinogen metabolizing enzymes. As such key interactions between habits related factors and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of genes are likely. However, this remains largely unexplored in ESCC. Here, we studied the interaction of various habits related factors and polymorphism of GSTM1/GSTT1 genes towards inducing promoter hypermethylation of multiple tumour suppressor genes. The study included 112 ESCC cases and 130 age and gender matched controls. Conditional logistic regression was used to calculate odds ratios (OR) and multifactor dimensionality reduction (MDR) was used to explore high order interactions. Tobacco chewing and smoking were the major individual risk factors of ESCC after adjusting for all potential confounding factors. With regards to methylation status, significantly higher methylation frequencies were observed in tobacco chewers than non chewers for all the four genes under study (p<0.01). In logistic regression analysis, betel quid chewing, alcohol consumption and null GSTT1 genotypes imparted maximum risk for ESCC without promoter hypermethylation. Whereas, tobacco chewing, smoking and GSTT1 null variants were the most important risk factors for ESCC with promoter hypermethylation. MDR analysis revealed two predictor models for ESCC with promoter hypermethylation (Tobacco chewing/Smoking/Betel quid chewing/GSTT1 null) and ESCC without promoter hypermethylation (Betel quid chewing/Alcohol/GSTT1) with TBA of 0.69 and 0.75 respectively and CVC of 10/10 in both models. Our study identified a possible interaction between tobacco consumption and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of tumour suppressor genes in ESCC.

The taxonomic validity of Northeast Indian endemic Mahseer species, Tor progeneius and Neolissochilus hexastichus, has been argued repeatedly. This is mainly due to disagreements in recognizing the species based on morphological characters. Consequently, both the species have been concealed for many decades. DNA barcoding has become a promising and an independent technique for accurate species level identification. Therefore, utilization of such technique in association with the traditional morphotaxonomic description can resolve the species dilemma of this important group of sport fishes. Altogether, 28 mahseer specimens including paratypes were studied from different locations in Northeast India, and 24 morphometric characters were measured invariably. The Principal Component Analysis with morphometric data revealed five distinct groups of sample that were taxonomically categorized into 4 species, viz., Tor putitora, T. progeneius, Neolissochilus hexagonolepis and N. hexastichus. Analysis with a dataset of 76 DNA barcode sequences of different mahseer species exhibited that the queries of T. putitora and N. hexagonolepis clustered cohesively with the respective conspecific database sequences maintaining 0.8% maximum K2P divergence. The closest congeneric divergence was 3 times higher than the mean conspecific divergence and was considered as barcode gap. The maximum divergence among the samples of T. progeneius and T. putitora was 0.8% that was much below the barcode gap, indicating them being synonymous. The query sequences of N. hexastichus invariably formed a discrete and a congeneric clade with the database sequences and maintained the interspecific divergence that supported its distinct species status. Notably, N. hexastichus was encountered in a single site and seemed to be under threat. This study substantiated the identification of N. hexastichus to be a true species, and tentatively regarded T. progeneius to be a synonym of T. putitora. It would guide the conservationists to initiate priority conservation of N. hexastichus and T. putitora.

Photofunctional co-crystal engineering strategies based on donor-acceptor π-conjugated system facilitates expedient molecular packing, consistent morphology, and switchable optical properties, conferring synergic ‘structure-property relationship’ for optoelectronic and biological functions. In this work, a series of organic co-crystals were formulated using a twisted aromatic hydrocarbon (TAH) donor and three diverse planar acceptors, resulting in color-tunable solid and aggregated state emission via variable packing and through-space charge-transfer interactions. While, adjusting the strength of acceptors, a structural transformation into hybrid stacking modes ultimately results in color-specific polymorphs, a configurational cis-isomer with very high photoluminescence quantum yield. The cis-isomeric co-crystal exhibits triplet-harvesting thermally activated delayed fluorescence (TADF) characteristics, presenting a key discovery in hydrocarbon-based multicomponent systems. Further, 1D-microrod-shaped co-crystal acts as an efficient photon-transducing optical waveguides, and their excellent dispersibility in water endows efficient cellular internalization with bright cell imaging performances. These salient approaches may open more avenues for the design and applications of TAH based co-crystals. Co-crystals of donor-acceptor functional material pairs give switchable optical properties despite challenging aggregation-caused quenching effects. Here, the authors report several organic co-crystals with thermally-activated delayed fluorescence, waveguiding and bio-imaging application.

Toll-like receptors (TLRs) are innate immune receptors that sense a variety of pathogen-associated molecular patterns (PAMPs) by interacting with them and subsequently initiating signal transduction cascades that elicit immune responses. TLR11 has been shown to interact with two known protein PAMPs: Salmonella and E. coli flagellin FliC and Toxoplasma gondii profilin-like protein. Given the highly divergent biology of these pathogens recognized by TLR11, it is unclear whether common mechanisms are used to recognize these distinct protein PAMPs. Here we show that TLR11 interacts with these two PAMPs using different receptor domains. Furthermore, TLR11 binding to flagellin and profilin exhibits differential dependency on pH and receptor ectodomain cleavage.