Department of Bioscience & Bioengineering

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The sprawling 852-acre IIT Jodhpur campus is a majestic tribute to the deep-rooted diverse cultural heritage of the region. The campus is an architectural masterpiece, which is slated to become an international exemplar of sustainability with net-zero energy, and advanced water and waste management strategies.&rdquo;

IIT Jodhpur

Accumulation of misfolded or aberrant proteins in neuronal cells is linked with neurodegeneration and other pathologies. Which molecular mechanisms fail and cause inappropriate folding of proteins and what is their relationship to cellular toxicity is not well known. How does it happen and what are the probable therapeutic or molecular approaches to counter them are also not clear. Here, we demonstrate that treatment of lanosterol diminishes aberrant proteotoxic aggregation and mitigates their cytotoxicity via induced expression of co-chaperone CHIP and elevated autophagy. The addition of lanosterol not only reduces aggregation of mutant bonafide misfolded proteins but also effectively prevents accumulation of various mutant disease-prone proteotoxic proteins. Finally, we observed that lanosterol mitigates cytotoxicity in cells, mediated by different stress-inducing agents. Taken together, our present results suggest that upregulation of cellular molecular chaperones, primarily using small molecules, can probably offer an efficient therapeutic approach in the future against misfolding of different disease-causing proteins and neurodegenerative disorders. © 2017, Springer Science+Business Media New York.

World University root node

Molecular Neurobiology

Lanosterol Suppresses the Aggregation and Cytotoxicity of Misfolded Proteins Linked with Neurodegenerative Diseases

Neurocysticercosis (NCC) is one of the most neglected tropical diseases among widely endemic neurological diseases. It is caused by cysticerci of Taenia solium. The clinical symptom for the outcome of infection and progression of disease is pleomorphic and its neuro-pathomechanism is still illusive. Identification of host genetic factors and their association with disease susceptibility is one of the most important areas of research towards personalized medicine in the era of omics. Several genes and their allelic variations had been identified to be associated with various neurological disorders; however, the information for parasitic diseases affecting the central nervous system is very limited. Both Th1 and Th2 arms of the immune system are reported to be active at different stages of T. solium infection in the brain. Recently, several papers had been published, where the role of host genetic makeup with NCC had been explored. Increased frequency of HLA-A28, HLA-B63, HLA-B58, TLR 4 Asp299Gly, sICAM-1 gene K469E, GSTM1, and GSTT1 were found to be associated with increased risk of NCC occurrence, while HLA-DQW2 and HLA-A11 were shown to be providing protection from disease. In this review, we have summarized these findings and analyzed the influence of host genetic polymorphism on the susceptibility/resistance of host to NCC. © 2017, Springer Science+Business Media New York.

Molecular Neuro-Pathomechanism of Neurocysticercosis: How Host Genetic Factors Influence Disease Susceptibility

The Zika virus is a rapidly spreading Aedes mosquito-borne sickness, which creates an unanticipated linkage birth deformity and neurological turmoil. This study represents the use of the combinatorial immunoinformatics approach to develop a multiepitope subunit vaccine using the structural and nonstructural proteins of the Zika virus. The designed subunit vaccine consists of cytotoxic T-lymphocyte and helper T-lymphocyte epitopes accompanied by suitable adjuvant and linkers. The presence of humoral immune response specific B-cell epitopes was also confirmed by B-cell epitope mapping among vaccine protein. Further, the vaccine protein was characterized for its allergenicity, antigenicity, and physiochemical parameters and found to be safe and immunogenic. Molecular docking and molecular dynamics studies of the vaccine protein with the toll-like receptor-3 were performed to ensure the binding affinity and stability of their complex. Finally, in silico cloning was performed for the effective expression of vaccine construct in the microbial system (Escherichia coli K12 strain). Aforementioned approaches result in the multiepitope subunit vaccine which may have the ability to induce cellular as well as humoral immune response. Moreover, this study needs the experimental validation to prove the immunogenic and protective behavior of the developed subunit vaccine. © 2018 Wiley Periodicals, Inc., A Wiley Company

Journal of Cellular Biochemistry

Designing B- and T-cell multi-epitope based subunit vaccine using immunoinformatics approach to control Zika virus infection

We report the 5.3-Mbp genome sequence of Bacillus cereus strain TS2, which was isolated from the sediments of a solar saltern in southern India. Genome analysis of B. cereus TS2, a salt-resistant strain, will improve our understanding of how B. cereus, a food pathogen, responds to hyperosmotic stress. © 2018 Shankar et al.

Fulltext

Microbiology Resource Announcements

Genome sequence of a moderately halophilic bacillus cereus strain, TS2, isolated from saltern sediments

Various Bacillus spp. capable of producing enzymes with industrially desirable properties have been isolated from adverse environments. Here, we announce the 3.91-Mbp draft genome sequence of a moderately salt-resistant Bacillus vallismortis strain, TD3, capable of producing several industrially relevant enzymes. Copyright © 2018 Suganthi et al.

Genome sequence of Bacillus vallismortis TD3, a salt-tolerant strain isolated from the sediments of a solar saltern in Tamil Nadu, India

Tropospheric ozone (O3) is a well-known threat to global agricultural production. Wheat (Triticum aestivum L.) is the second most important staple crop in India, although little is known about intra-specific variability of Indian wheat cultivars in terms of their sensitivity against O3. In this study, 14 wheat cultivars widely grown in India were exposed to 30 ppb elevated O3 above ambient level using open top chambers to evaluate their response against O3 stress. Different growth and physiological parameters, foliar injury and grain yield were evaluated to assess the sensitivity of cultivars and classified them on the basis of their cumulative stress response index (CSRI). Due to elevated O3, growth parameters, plant biomass, and photosynthetic rates were negatively affected, whereas variable reductions in yield were observed among the test cultivars. Based on CSRI values, HD 2987, DBW 50, DBW 77, and PBW 550 were classified as O3 sensitive; HD 2967, NIAW 34, HD 3059, PBW 502, HUW 213, and HUW 251 as intermediately sensitive, while HUW12, KUNDAN, HUW 55, and KHARCHIYA 65 were found to be O3-tolerant cultivars. Cultivars released after year 2000 were found to be more sensitive compared to earlier released cultivars. Path analysis approach showed that leaf area, plant biomass, stomatal conductance, net assimilation rate, and absolute growth rate were the most important variables influencing yield under O3 stress. Findings of the current study highlight the importance of assessing differential sensitivity and tolerance of wheat cultivars and response of different traits in developing resistance against elevated O3. © 2018, Springer International Publishing AG, part of Springer Nature.

Environmental Monitoring and Assessment

Assessment of ozone toxicity among 14 Indian wheat cultivars under field conditions: growth and productivity

Amyloids are primarily known for their roles in neurodegenerative disorders, as well as in systemic diseases like diabetes. Evolutionary forces tend to maintain a healthy set of heritable characteristics, while eliminating toxic or unfavourable elements; but amyloids seem to represent an exception to this fundamental concept. In addition to their presence in mammals, amyloids also persist in the proteome of many lower organisms that may be linked with possible roles in survival, which are still unexplored. Herein, we address some unanswered questions regarding amyloids: are these well-structured proteinaceous aggregates a by-product of inefficient folding events, or have they been retained in our protein repertoire for as yet unknown functional roles; and how do protein misfolding and associated disorders originate, despite the presence of protein quality-control systems inside the cells? This review aims to extend our current understanding about the multifaceted useful properties of amyloids and their functional interactions with other molecular pathways in various species; this may provide new insights to identify novel therapeutic strategies for ageing and neurodegenerative diseases. © 2018 Cambridge Philosophical Society

Biological Reviews

Amyloids of multiple species: are they helpful in survival?

Cancer Research 78 (4 Supplement), P1-01-19-P1-

Abstract P1-01-19: The role of S100A7 in microbiota mediated inflammation and breast cancer progression

Transient receptor potential vanilloid type-2 (TRPV2) is an ion channel that is triggered by agonists like cannabidiol (CBD). Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Chemotherapy is still the first line for the treatment of TNBC patients; however, TNBC usually gains rapid resistance and unresponsiveness to chemotherapeutic drugs. In this study, we found that TRPV2 protein is highly up-regulated in TNBC tissues compared to normal breast tissues. We also observed that TNBC and estrogen receptor alpha negative (ERa-) patients with higher TRPV2 expression have significantly higher recurrence free survival compared to patients with lower TRPV2 expression especially those who were treated with chemotherapy. In addition, we showed that TRPV2 overexpression or activation by CBD significantly increased doxorubicin (DOX) uptake and apoptosis in TNBC cells. The induction of DOX uptake was abrogated by TRPV2 blocking or downregulation. In vivo mouse model studies showed that the TNBC tumors derived from CBD+DOX treated mice have significantly reduced weight and increased apoptosis compared to those treated with CBD or DOX alone. Overall, our studies for the first time revealed that TRPV2 might be a good prognostic marker for TNBC and ERa-breast cancer patient especially for those who are treated with chemotherapy. In addition, TRPV2 activation could be a novel therapeutic strategy to enhance the uptake and efficacy of chemotherapy in TNBC patients. © 2018 Impact Journals LLC. All Rights Reserved.

Oncotarget

TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer

Cerebellar ataxias are a group of rare progressive neurodegenerative disorders with an average prevalence ranges from 4.8 to 13.8 in 100,000 individuals. The inherited disorders affect multiple members of the families, or a community that is endogamous or consanguineous. Presence of more than 3000 mutations in different genes with overlapping clinical symptoms, genetic anticipation and pleiotropy, as well as incomplete penetrance and variable expressivity due to modifiers pose challenges in genotype–phenotype correlation. Development of a diagnostic algorithm could reduce the time as well as cost in clinicogenetic diagnostics and also help in reducing the economic and social burden of the disease. In a unique research collaboration spanning over 20 years, we have been able to develop a paradigm for studying cerebellar ataxias in the Indian population which would also be relevant in other rare diseases. This has involved clinical and genetic analysis of thousands of families from diverse Indian populations. The extensive resource on ataxia has led to the development of a clinicogenetic algorithm for cost-effective screening of ataxia and a unique ataxia clinic in the tertiary referral centre in All India Institute of Medical Sciences. Utilizing a population polymorphism scanning approach, we have been able to dissect the mechanisms of repeat instability and expansion in many ataxias, and also identify founders, and trace the mutational histories in the Indian population. This provides information for genetic testing of at—risk as well as protected individuals and populations. To dissect uncharacterized cases which comprises more than 50% of the cases, we have explored the potential of next-generation sequencing technologies coupled with the extensive resource of baseline data generated in-house and other public domains. We have also developed a repository of patient-derived peripheral blood mononuclear cells, lymphoblastoid cell lines and neuronal lineages (derived from iPSCs) for ascribing functionality to novel genes/mutations. Through integrating these technologies, novel genes have been identified that has broadened the diagnostic panel, increased the diagnostic yield to over 75%, helped in ascribing pathogenicity to novel mutations and enabled understanding of disease mechanisms. It has also provided a platform for testing novel molecules for amelioration of pathophysiological phenotypes. This review through a perspective on CAs suggests a generic paradigm from diagnostics to therapeutic interventions for rare disorders in the context of heterogeneous Indian populations. © 2018, Indian Academy of Sciences.