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The periodic ingestion of a protein-rich blood meal by adult female mosquitoes causes a drastic metabolic change in their innate physiological status, which is referred to as a ‘metabolic switch’. While understanding the neural circuits for host-seeking is modestly attended, how the gut ‘metabolic switch’ modulates brain functions, and resilience to physiological homeostasis, remains unexplored. Here, through a comparative brain RNA-Seq study, we demonstrate that the protein-rich diet induces the expression of brain transcripts related to mitochondrial function and energy metabolism, possibly causing a shift in the brain’s engagement to manage organismal homeostasis. A dynamic mRNA expression pattern of neuro-signaling and neuro-modulatory genes in both the gut and brain likely establishes an active gut–brain communication. The disruption of this communication through decapitation does not affect the modulation of the neuro-modulator receptor genes in the gut. In parallel, an unusual and paramount shift in the level of neurotransmitters (NTs), from the brain to the gut after blood feeding, further supports the idea of the gut’s ability to serve as a ‘second brain’. After blood-feeding, a moderate enrichment of the gut microbial population, and altered immunity in the gut of histamine receptor-silenced mosquitoes, provide initial evidence that the gut-microbiome plays a crucial role in gut–brain–axis communication. Finally, a comparative metagenomics evaluation of the gut microbiome highlighted that blood-feeding enriches the family members of the Morganellaceae and Pseudomonadaceae bacterial communities. The notable observation of a rapid proliferation of Pseudomonas bacterial sp. and tryptophan enrichment in the gut correlates with the suppression of appetite after blood-feeding. Additionally, altered NTs dynamics of naïve and aseptic mosquitoes provide further evidence that gut-endosymbionts are key modulators for the synthesis of major neuroactive molecules. Our data establish a new conceptual understanding of microbiome–gut–brain–axis communication in mosquitoes.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Background & objectives: Attractin, is a large multi-domain protein which has regulatory functions in multiple physiological processes and thus have strong therapeutic potential. In invertebrates, it was first identified as a water-borne protein pheromone that plays important role in chemical communication and coordinates reproductive activities. But its role in mosquitoes/insects remains unknown. Our unexpected discovery of attractin homolog from the olfactory tissue of Anopheles culicifacies mosquito prompted us to investigate the possible role of Ac-attractin (Ac-atrn) in diverse behavioural responses, e.g. feeding, mating and other non-genetic stresses. Methods: A homology search analysis was performed to identify the full length attractin (Ac-atrn) gene of Anopheles culicifacies mosquito. To unravel its molecular function during external and internal stresses, extensive real-time PCR was performed in the neuro-olfactory tissues of the adult mosquitoes as well as in the larval stages. Further, a behavioural assay was conducted to elucidate its role in mosquitoes mating behaviour. Results: The results indicated that Ac-atrn is a 3942 bp long transcript which encodes a 1313 amino acid protein, having multiple domains including CUB, EGF, Keltch, etc, with 80–90% homology to other insect/mosquito homologs. Ac-atrn gene was dominantly expressed in the young larvae and its expression was elevated in response to the fresh food supply in the starved larvae. Cold stress temporarily arrested the expression of Ac-atrn gene. In case of adult mosquitoes, olfactory and brain tissue showed relatively higher expression of Ac-atrn than reproductive organs. Although, starvation did not yield significant changes in olfactory tissues, but aging and nutritional stress modulated Ac-atrn expression in the brain tissue. Furthermore, a circadian rhythm dependent change in the expression of Ac-atrn of virgin and mated mosquitoes (both sexes), indicates that Ac-atrn might also have a pheromone guided role during swarm formation and mating behaviour. Interpretation & conclusion: The relative expression profiling of Ac-atrn gene in the larvae during nutritional and cold stress suggested its possible role in mediating chemical communication towards the food source and in thermal regulation of young larvae. Similarly, it might have crucial regulatory role in the stress management and survival of adult mosquitoes. The results revealed that Ac-atrn gene is a global regulator of many physiological processes in mosquitoes including stress response and mating behaviour and thus might be a potential target to design novel intervention strategy against mosquitoes.

Understanding patients’ genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype–phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease–drug–gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility.

Decoding the molecular basis of host seeking and blood feeding behavioral evolution/adaptation in the adult female mosquitoes may provide an opportunity to design new molecular strategy to disrupt human-mosquito interactions. Although there is a great progress in the field of mosquito olfaction and chemo-detection, little is known about the sex-specific evolution of the specialized olfactory system of adult female mosquitoes that enables them to drive and manage the complex blood-feeding associated behavioral responses. A comprehensive RNA-Seq analysis of prior and post blood meal olfactory system of An. culicifacies mosquito revealed a minor but unique change in the nature and regulation of key olfactory genes that may play a pivotal role in managing diverse behavioral responses. Based on age-dependent transcriptional profiling, we further demonstrated that adult female mosquito's chemosensory system gradually learned and matured to drive the host-seeking and blood feeding behavior at the age of 5–6 days. A time scale expression analysis of Odorant Binding Proteins (OBPs) unravels unique association with a late evening to midnight peak biting time. Blood meal-induced switching of unique sets of OBP genes and Odorant Receptors (Ors) expression coincides with the change in the innate physiological status of the mosquitoes. Blood meal follows up experiments further provide enough evidence that how a synergistic and concurrent action of OBPs-Ors may drive “prior and post blood meal” associated complex behavioral events. A dominant expression of two sensory appendages proteins (SAP-1 & SAP2) in the legs of An. culicifacies suggests that this mosquito species may draw an extra advantage of having more sensitive appendages than An. stephensi, an urban malarial vector in the Indian subcontinents. Finally, our molecular modeling analysis predicts crucial amino acid residues for future functional characterization of the sensory appendages proteins which may play a central role in regulating multiple behaviors of An. culicifacies mosquito.SIGNIFICANCE Evolution and adaptation of blood feeding behavior not only favored the reproductive success of adult female mosquitoes but also make them important disease-transmitting vectors. An environmental exposure after emergence may favor the broadly tuned olfactory system of mosquitoes to drive complex behavioral responses. But, how these olfactory derived genetic factors manage female specific “pre and post” blood meal associated complex behavioral responses are not well known. Our findings suggest that a synergistic action of olfactory factors may govern an innate to prime learning strategy to facilitate rapid blood meal acquisition and downstream behavioral activities. A species-specific transcriptional profiling and an in-silico analysis predict that “sensory appendages protein” may be a unique target to design disorientation strategy against the mosquito Anopheles culicifacies.

Objective: Alpha-ketoglutarate (α-KG) is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP) induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control): Normal Saline, Group II (APAP): A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG): APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) with oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05) reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats.

Understanding the molecular basis of mosquito behavioural complexity plays a central role in designing novel molecular tools to fight against their vector-borne diseases. Although the olfactory system plays an important role in guiding and managing many behavioural responses including feeding and mating, but the sex-specific regulation of olfactory responses remain poorly investigated. From our ongoing transcriptomic data annotation of olfactory tissue of blood fed adult female An. culicifacies mosquitoes; we have identified a 383 bp long unique transcript encoding a Drosophila homolog of the quick-to-court protein. Previously this was shown to regulate courtship behaviour in adult male Drosophila. A comprehensive in silico analysis of the quick-to-court (qtc) gene of An. culicifacies (Ac-qtc) predicts a 1536 bp single copy gene encoding 511 amino acid protein, having a high degree of conservation with other insect homologs. The age-dependent increased expression of putative Ac-qtc correlated with the maturation of the olfactory system, necessary to meet the sex-specific conflicting demand of mating (mate finding) versus host-seeking behavioural responses. Sixteen to eighteen hours of starvation did not alter Ac-qtc expression in both sexes, however, blood feeding significantly modulated its response in the adult female mosquitoes, confirming that it may not be involved in sugar feeding associated behavioural regulation. Finally, a dual behavioural and molecular assay indicated that natural dysregulation of Ac-qtc in the late evening might promote the mating events for successful insemination. We hypothesize that Ac-qtc may play a unique role to regulate the sex-specific conflicting demand of mosquito courtship behaviour versus blood feeding behaviour in the adult female mosquitoes. Further elucidation of this molecular mechanism may provide further information to evaluate Ac-qtc as a key molecular target for mosquito-borne disease management.

Neurological disorders are known to show similar phenotypic manifestations like anxiety, depression, and cognitive impairment. There is a need to identify shared genetic markers and molecular pathways in these diseases, which lead to such comorbid conditions. Our study aims to prioritize novel genetic markers that might increase the susceptibility of patients affected with one neurological disorder to other diseases with similar manifestations. Identification of pathways involving common candidate markers will help in the development of improved diagnosis and treatments strategies for patients affected with neurological disorders. This systems biology study for the first time integratively uses 3D-structural protein interface descriptors and network topological properties that characterize proteins in a neurological protein interaction network, to aid the identification of genes that are previously not known to be shared between these diseases. Results of protein prioritization by machine learning have identified known as well as new genetic markers which might have direct or indirect involvement in several neurological disorders. Important gene hubs have also been identified that provide an evidence for shared molecular pathways in the neurological disease network.

Today it is a challenge for clinicians and researchers to understand the comprehensive relationship between molecular and physical functioning of genes towards the progression of disease. Although genomic advancements have produced significant data to identify the genes involved in many complex diseases but a loop exists since a single gene is not attributable to a particular concept. In our work, we tried to find key neighbours involved in osteoporosis by analysing osteoporosis disease module (interactome) using both experimental and clinical methodologies which may also contain mechanisms that are collective with other disease modules. Our idea was strengthened by the findings of previous GWAS p-value studies wherein the level of gene expression was different in both diseased as well as normal conditions. We thus, constructed a gene-gene and protein-protein interaction network for 104 genes linked with 173 genetic variants (single nucleotide polymorphisms) that revealed significant hub proteins which might be fundamentally linked to disease pathogenesis. We further performed gene ontology and functional enrichment analysis followed by KEGG pathway analysis to analyze and validate the role of these genes for their pathophysiological and functional activities. Our analysis revealed the polymorphism in SOST and LRP5 genes as significant conservative SNPs which might have a substantial role in the onset of osteoporosis and its development.

Vitiligo is characterized by the occurrence of depigmented patches on the skin caused as a result of progressive loss of functional melanocytes. It is a polygenic disorder entailing both genetic and non-genetic factors intricately and as such is not yet clearly understood. Hence, a comprehensive understanding of the entire spectrum of disease susceptibility and pathogenesis remains a challenge. Emerging evidence over the decades underlines the cardinal role of miRNAs in disease development and having a significant role in melanocyte development and survival. Also, identifying the susceptible genes and their variants that influence disease onset is fundamental to unravel the rationale for disease susceptibility. We, therefore, applied a systems biology approach to identify potential miRNAs and their target genes to construct a miRNA-target gene network revealing essential miRNAs that might be significantly related to vitiligo. We further investigated the susceptible genetic variants associated with vitiligo and prioritized a few proteins in our protein-protein interaction network as significant hub proteins. Network-based polypharmacological studies of such hub proteins are helpful in analyzing a large set of disease-associated proteins which might initiate better diagnosis with the feasibility of personalized treatment for vitiligo patients in the future. Our polypharmacogenomic systems analysis highlighted novel drug candidates and drug repositioning candidates for vitiligo. Furthermore, we investigated the pathogenic effect of the plausible single nucleotide polymorphisms (SNPs) using computational platforms and carried out preliminary protein modeling to implicate the role of SNPs in disease pathogenesis. Thus, our analysis unveiled significant findings which may provide an insight of the mechanisms of vitiligo development and progression, thereby, driving the way towards improved therapeutic and diagnostic interventions for vitiligo management.

Mosquitoes are the deadliest animal in the world. Mosquitoes transmit several vector borne disease (VBDs) such as malaria, dengue, chikungunya, zika fever, yellow fever and responsible for a loss of millions of lives annually. Though, suppression of mosquito population by means of chemical insecticides plays a crucial role in controlling vector population. However, fast emergence of insecticide resistance limits the efforts and demanding to design alternative molecular tools to fight against these VBDs. One of the potential strategies may include interfering complex feeding and/or mating behavioural properties. Compared to female mosquito male mosquito have an indirect effect in disease transmission and thus least studied. Males induce several post-mating behavioural changes in females, including the induction of host seeking and blood feeding behavior. Although, a successful mating events are guided by non-genetic circadian rhythm, but how genetic factors manages the sequential events of swarm formation, suitable mate finding and aerial coupling remains poorly investigated. While understanding the complex feeding behaviour of adult An. culicifacies female mosquito, we identified and analyzed a unique transcript (383 bp) from the olfactory system of the blood-fed mosquito, encoding the ‘quick to court’ (QTC) protein. It is a homolog of Drosophila coiled-coil QTC (Q9VMU5) protein and shown to play an important role in driving the male courtship behaviour. A comprehensive in silico analysis predicted a 1536 bp long transcript encoding 511 AA long protein in the mosquito genome. Age dependent and sex specific transcriptional profiling revealed that both male female mosquitoes attain the specific age of adulteration on 5-7 days. Circadian clock dependent Ac-qtc profiling indicated that late evening natural dysregulation of Ac-qtc by unknown mechanism may promote the successful insemination event during active copulation. Together, our findings provide first molecular evidence that Ac-QTC proteins may have dual mode of action in the regulation of cluster of mosquito olfactory genes that are linked to mating success and/or blood feeding in adult female mosquitoes. A sex specific and circadian rhythm dependent comparative RNAseq analysis of neuro-olfactory and reproductive organs may facilitate to identify key molecular factors, regulating complex events of mating behavior in the mosquitoes.

A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.