Department of Bioscience & Bioengineering

&ldquo;IIT Jodhpur is committed to impart quality education to facilitate the creation of qualified, competent and responsible human resources to meet the emerging technological challenges of the world. It is working towards creating an equitable learning platform that is positive, accessible and effective in the face of the modern societal and scientific advancements.

Flexibility in curriculum, in all its academic programs, encompassing elements of teaching, research, creativity, innovation and entrepreneurship is the most unique feature of IIT Jodhpur. The Department of Science and Technology (DST), under the National Mission on Cyber Physical Systems, has identified IIT Jodhpur as a Technology &amp; Innovation Hub in the area of Augmented Reality and Virtual Reality. The institute has also been nominated as the coordinator for the Jodhpur City and Knowledge Cluster by the Office of Principal Scientific Adviser, Government of India.

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

Microtubules play a crucial role in maintenance of structure, function, axonal extensions, cargo transport, and polarity of neurons. During neurodegenerative diseases, microtubule structure and function get severely damaged due to destabilization of its major structural proteins. Therefore, design and development of molecules that stabilize these microtubule networks have always been an important strategy for development of potential neurotherapeutic candidates. Toward this venture, we designed and developed a tyrosine rich trisubstituted triazine molecule (TY3) that stabilizes microtubules through close interaction with the taxol binding site. Detailed structural investigations revealed that the phenolic protons are the key interacting partners of tubulin. Interestingly, we found that this molecule is noncytotoxic in PC12 derived neurons, stabilizes microtubules against nocodazole induced depolymerization, and increases expression of acetylated tubulin (Ac-K40), an important marker of tubulin stability. Further, results show that TY3 significantly induces neurite sprouting as compared to the untreated control as well as the two other analogues (TS3 and TF3). It also possesses anti-Aβ fibrillation properties as confirmed by ThT assay, which leads to its neuroprotective effect against amyloidogenic induced toxicity caused through nerve growth factor (NGF) deprivation in PC12 derived neurons. Remarkably, our results reveal that it reduces the expression of TrkA (pY490) associated with NGF deprived amyloidogenesis, which further proves that it is a potent amyloid β inhibitor. Moreover, it promoted the health of the rat primary cortical neurons through higher expression of key neuronal markers such as MAP2 and Tuj1. Finally, we observed that it has good serum stability and has the ability to cross the blood-brain barrier (BBB). Overall, our work indicates the importance of phenolic -OH in promoting neuroprotection and its importance could be implemented in the development of future neurotherapeutics. © 2018 American Chemical Society.

World University root node

ACS Chemical Neuroscience

Power of Tyrosine Assembly in Microtubule Stabilization and Neuroprotection Fueled by Phenol Appendages

The present study was conducted to investigate the effect of salubrinal on nitric oxide mediated endoplasmic reticulum stress signaling and neuronal apoptosis. Rotenone treatment to neuro2a cells caused significantly decreased cell viability, increased cytotoxicity, augmented nitrite levels, increased nitrotyrosine level and augmented level of key ER stress markers (GRP-78, GADD153 and caspase-12). These augmented levels of ER stress markers could be attenuated with pretreatment of nitric oxide synthase inhibitor-aminoguanidine as well as with salubrinal. The rotenone treatment to neuro2a cells also triggered the ER stress induced up regulation of various signaling factors of unfolded protein response involving pPERK, ATF4, p-IRE1α, XBP-1 and ATF-6. Pretreatment of salubrinal significantly attenuated the activation of transmembrane kinases (PERK and IRE1) and ATF6 and restored the rotenone induced altered level of other UPR related signaling factors. Rotenone induced dephosphorylation of eIF2α was also inhibited with salubrinal treatment. Biochemically rotenone treatment to neuro2a cells caused the reactive oxygen species generation, depleted mitochondrial membrane potential and increased intra cellular calcium level which was attenuated with salubrinal treatment. Rotenone treatment to neuro2a cells also caused neuronal apoptosis, DNA fragmentation and chromatin condensation which were attenuated with salubrinal treatment. In conclusion, the findings suggested that rotenone causes the augmented level of nitric oxide which contributes in ER stress and could be inhibited by both aminoguanidine and/or salubrinal treatment. Further, salubrinal treatment attenuates the nitric oxide induced ER stress axis PERK:IRE1α:ATF-6 and inhibits the DNA damage and neuronal apoptosis. © 2019 Elsevier Ltd

Department of Electrical Engineering

Neurochemistry International

Salubrinal attenuates nitric oxide mediated PERK:IRE1α: ATF-6 signaling and DNA damage in neuronal cells

Intracellular mislocalization of TAR DNA-binding protein 43 (TDP-43), a nuclear DNA/RNA-binding protein involved in RNA metabolism, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although the aggregation-prone, TDP-43 C-terminal domain is widely considered as a key component of TDP-43 pathology in ALS, recent studies including ours suggest that TDP-43 N-terminal fragments (TDP-∆C) may also contribute to the motor dysfunction in ALS. However, the specific pathological functions of TDP-43 N-terminal fragments in mice have not been elucidated. Here, we established TDP-∆C knock-in mice missing a part of exon 6 of murine Tardbp gene, which encodes the C-terminal region of TDP-43. Homozygous TDP-∆C mice showed embryonic lethality, indicating that the N-terminal domain of TDP-43 alone is not sufficient for normal development. In contrast, heterozygous TDP-∆C mice developed normally but exhibited age-dependent mild motor dysfunction with a loss of C-boutons, large cholinergic synaptic terminals on spinal α-motor neurons. TDP-∆C protein broadly perturbed gene expression in the spinal cords of aged heterozygous TDP-∆C mice, including downregulation of Notch1 mRNA. Moreover, the level of Notch1 mRNA was suppressed both by TDP-43 depletion and TDP-∆C expression in Neuro2a cells. Decreased Notch1 mRNA expression in aged TDP-∆C mice was associated with the age-dependent motor dysfunction and loss of Akt surviving signal. Our findings indicate that the N-terminal region of TDP-43 derived from TDP-∆C induces the age-dependent motor dysfunction associated with impaired Notch1-Akt axis in mice.

Fulltext

Acta neuropathologica communications

Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway

The present field study was planned with an objective to unravel the mechanisms behind the differential responses of early and late sown wheat cultivars with respect to their defense capacity to scavenge ROS induced under elevated O3 (EO3). Experiments were performed under ambient and elevated levels of O3 (ambient + 20 ppb) to plants inside open-top chambers (OTCs). Ozone concentrations, stomatal flux of O3 and meteorological parameters were measured throughout the experiment. Contents of superoxide radicals ([rad]O2 −) and hydrogen peroxide (H2O2) and their localization, lipid peroxidation, antioxidative enzyme activities, ascorbic acid and total phenolic contents were measured at vegetative and reproductive developmental stages. EO3 exposure induced higher stomatal flux of O3 in early sown cultivars. Higher contents of [rad]O2 −, H2O2 and lipid peroxidation were noticed under EO3 in all the cultivars but the magnitude of increases was higher in late sown cultivars at the reproductive stage. Activities of glutathione reductase (GR) and ascorbate peroxidase (APX) were higher in late sown cultivars under EO3. Ascorbic acid and total phenolic contents were significantly higher in early sown than late sown cultivars under EO3 treatment. The present study concludes that early sown cultivars are more efficient in their defense response due to higher induction of enzymatic and non-enzymatic antioxidants, while the induction of enzymatic antioxidants was more distinct in late sown cultivars. Non-enzymatic linked defense mechanism requires additional metabolic cost than enzymatic defense, making early sown cultivars more susceptible to EO3. Differential response of early and late sown cultivars with respect to antioxidative defense against O3 stress suggests that yield responses are governed by the time of sowing and intrinsic defense responses of the cultivars. In future with rising trend of O3, early sown cultivars are expected to be more vulnerable to oxidative stress compared to late sown cultivars. © 2018 Elsevier B.V.

Science of the Total Environment

ROS production and its detoxification in early and late sown cultivars of wheat under future O3 concentration

Gliomas are the most prevalent primary brain tumors with immense clinical heterogeneity, poor prognosis and survival. The nucleotide-binding domain, and leucine-rich repeat containing receptors (NLRs) and absent-in-melanoma 2 (AIM2) are innate immune receptors crucial for initiation and progression of several cancers. There is a dearth of reports linking NLRs and AIM2 to glioma pathology. NLRs are expressed by cells of innate immunity, including monocytes, macrophages, dendritic cells, endothelial cells, and neutrophils, as well as cells of the adaptive immune system. NLRs are critical regulators of major inflammation, cell death, immune and cancer-associated pathways. We used a data-driven approach to identify NLRs, AIM2 and NLR-associated gene expression and methylation patterns in low grade glioma and glioblastoma, using The Cancer Genome Atlas (TCGA) patient datasets. Since TCGA data is obtained from tumor tissue, comprising of multiple cell populations including glioma cells, endothelial cells and tumor-associated microglia/macrophages we have used multiple cell lines and human brain tissues to identify cell-specific effects. TCGA data mining showed significant differential NLR regulation and strong correlation with survival in different grades of glioma. We report differential expression and methylation of NLRs in glioma, followed by NLRP12 identification as a candidate prognostic marker for glioma progression. We found that Nlrp12 deficient microglia show increased colony formation while Nlrp12 deficient glioma cells show decreased cellular proliferation. Immunohistochemistry of human glioma tissue shows increased NLRP12 expression. Interestingly, microglia show reduced migration towards Nlrp12 deficient glioma cells. © 2019, The Author(s).

Scientific Reports

Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma

The FASEB Journal 33 (S1), 674.3-674.

Macrophage migration inhibitory factor (MIF): A novel therapeutic target against aggressive breast cancer

Cervical cancer is a leading severe malignancy throughout the world. Molecular processes and biomarkers leading to tumor progression in cervical cancer are either unknown or only partially understood. An increasing number of studies have shown that microRNAs play an important role in tumorigenesis so understanding the regulatory mechanism of miRNAs in gene-regulatory network will help elucidate the complex biological processes that occur during malignancy. Identification of microRNA-messengerRNA (miRNA-mRNA) regulatory modules will aid deciphering aberrant transcriptional regulatory network in cervical cancer but is computationally challenging. In this regard, an algorithm, termed as relevant and functionally consistent miRNA-mRNA modules (RFCM3), is proposed. It integrates miRNA and mRNA expression data of cervical cancer for identification of potential miRNA-mRNA modules. It selects a miRNA-mRNA module by maximizing relation of mRNAs with miRNA and functional similarity between selected mRNAs. Later using the knowledge of miRNA-miRNA synergistic network different modules are fused and finally a set of modules are generated containing several miRNAs as well as mRNAs. This type of module explains the underlying biological pathways containing multiple miRNAs and mRNAs. The effectiveness of the proposed approach over other existing methods has been demonstrated on a miRNA and mRNA expression data of cervical cancer with respect to enrichment analyses and other standard metrices. The proposed approach was found to generate more robust, integrated, and functionally enriched miRNA-mRNA modules in cervical cancer. © 2018 IEEE.

IEEE International Conference on Data Mining Workshops, ICDMW

Robust computational method for identification of miRNA-mRNA modules in cervical cancer

Stomach cancer continues to be one of the most common cancer types in the world. Poor prognosis and late detection are major challenges in the diagnosis and treatment of this cancer. Currently, Next-Generation Sequencing (NGS) of genome has revolutionized stomach cancer research by providing multi-view data which can be used for better understanding of the underlying molecular mechanism of this disease. Micro-RNA (miRNA) sequencing data is one such high resolution expression data. MiRNAs are evolutionary conserved, small, non-coding RNAs that play a role in post-transcriptional regulation of gene expression. They are proven to show abnormal expression for a specific biological condition like tumor or age or survival of stomach cancer which makes them potential biomarkers for this cancer type. MiRNA data analysis comes with a challenge of less number of samples as compared to the number of miRNAs. Finding a small set of miRNAs is needed to identify potential biomarkers. In this regard, here, a method for selecting a small subset of miRNAs from the entire miRNA expression data has been proposed that selects miRNAs, common to three different categories of clinical outcomes, viz. condition, age, and survival status. First, three feature selection methods have been used to rank miRNAs individually for different categories. These ranks are then used to compute an ensemble of ranks of each miRNA using adaptive weight method for each category. Second, the top 100 miRNAs from each category have been used to find the miRNAs that are common to all categories. As a result, four miRNAs are found which are validated using classification of subclass under each category, miRNA-Gene-TF network, PPI network, expression analysis using box plots, KEGG pathway and GO enrichment analysis. © 2019 IEEE.

Proceedings of 2019 IEEE Region 10 Symposium, TENSYMP 2019

Identification of Four miRNAs by Analysing Multi-View miRNA-seq Data of Stomach Cancer

Stomach cancer is one of the leading causes of cancer-related deaths worldwide. More than 80% diagnosis of this cancer occur at later stages leading to low 5-year survival rate. This emphasizes the need to have better prognostic techniques for stomach cancer. In this regard, the Next-Generation Sequencing of whole genome and multi-view approach to omics may reveal the underlying molecular complexity of stomach cancer using high throughput expression data of miRNA. Generally, miRNAs are small, non-coding RNAs, which cause downregulation of target mRNAs. They also show differential expression for a specific biological condition like stage or histological type of stomach cancer, highlighting their importance as potential biomarkers. Analyzing miRNA expression data is a challenging task due to the existence of large number of miRNAs and less sample size. A small set of miRNAs will be helpful in designing efficient diagnostic and prognostic tool. In this regard, here a computational framework is proposed that selects different sets of miRNAs for five different categories of clinical outcomes viz. condition, clinical stage, age, histological type, and survival status. First, the miRNAs are ranked using four feature ranking methods. These ranks are used to find an ensemble rank based on adaptive weight. Second, the top 100 miRNAs from each category are used to find the miRNAs that are common to all categories as well as miRNAs that belong to only one category. Finally, the results have been validated quantitatively and through biological significance analysis. © 2019 Elsevier Inc.

Journal of Biomedical Informatics

Genome-wide analysis of multi-view data of miRNA-seq to identify miRNA biomarkers for stomach cancer

Discovery of a nontoxic fluorescent molecular probe to "light up" specific cellular organelles is extremely essential to understand dynamics of intracellular components. Here, we report a new nontoxic mitochondria-targeted linear bithiazole compound, containing trifluoroacetyl terminal groups, which emits intense blue fluorescence and stained mitochondria of various cells. Interestingly, the power of fluorescence is completely off when the bithiazole unit is stapled by a carbonyl bridge. © 2019 American Chemical Society.