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

Centrosome serves as the primary site of microtubule organization in a majority of animal cells. These microtubules carry out several significant functions in the cell such as cell division, chromosome segregation, mechanical support and cellular transport. Proteins localized at the centrosome play extensive role in orchestrating the process of microtubule organization, growth and stabilization in space and time. Anomalies in centrosome number, structure and functioning disturb microtubule organization and lead to several human diseases. Advancements in proteomics and microscopy methods have been instrumental in identifying molecular mechanisms pertaining to the microtubule organizing function of centrosomes. This review focuses on the involvement of centrosome as a microtubule nucleating center of the cell. We present the major molecular mechanisms at the centrosome which affect microtubule nucleation and activation. Finally, we discuss human diseases associated with defective microtubule organization resulting from centrosome abnormalities. © 2021, Indian Institute of Science.

World University root node

Journal of the Indian Institute of Science

Centrosome: A Microtubule Nucleating Cellular Machinery

Centrosomes are the major microtubule organizing centers in a large number of animal cells. They are involved in diverse cellular functions like cell division, migration, sensing and motility. Despite being identified more than 100 years ago, they did not receive much attention until recent discoveries suggesting their association with human diseases. Centrosome-related defects have been observed in several human diseases including cancers, brain disorders and ciliopathies. Researchers in the field are trying to understand the relationship between centrosomes and these diseases. Accordingly, this review provides an overview of the current knowledge regarding the role of centrosomes during ciliogenesis and neural stem cell division. The review primarily focuses on the impairment of centrosome number, organization and functioning leading to a wide range of human diseases. Finally, we discuss the scope of targeting centrosomes for therapeutic purposes. © 2020 Elsevier Ltd

Seminars in Cell and Developmental Biology

Centrosome dysfunction in human diseases

Identification of groups of co-expressed or co-regulated genes is critical for exploring the underlying mechanism behind a particular disease like cancer. Condition-specific (disease-specific) gene-expression profiles acquired from different platforms are widely utilized by researchers to get insight into the regulatory mechanism of the disease. Several clustering algorithms are developed using gene expression profiles to identify the group of similar genes. These algorithms are computationally efficient but are not able to capture the functional similarity present between the genes, which is very important from a biological perspective. In this study, an algorithm named CorGO is introduced, that specifically deals with the identification of functionally similar gene-clusters. Two types of relationships are calculated for this purpose. Firstly, the Correlation (Cor) between the genes are captured from the gene-expression data, which helps in deciphering the relationship between genes based on its expression across several diseased samples. Secondly, Gene Ontology (GO)-based semantic similarity information available for the genes is utilized, that helps in adding up biological relevance to the identified gene-clusters. A similarity measure is defined by integrating these two components that help in the identification of homogeneous and functionally similar groups of genes. CorGO is applied to four different types of gene expression profiles of different types of cancer. Gene-clusters identified by CorGO, are further validated by pathway enrichment, disease enrichment, and network analysis. These biological analyses demonstrated significant connectivity and functional relatedness within the genes of the same cluster. A comparative study with commonly used clustering algorithms is also performed to show the efficacy of the proposed method. © 2021, International Association of Scientists in the Interdisciplinary Areas.

Interdisciplinary Sciences: Computational Life Sciences

CorGO: An Integrated Method for Clustering Functionally Similar Genes

Studying respiratory illness-specific microbial signatures and their interaction with other micro-residents could provide a better understanding of lung microbial ecology. Each respiratory illness has a specific disease etiology, however, so far no study has revealed disease—specific microbial markers. The present study was designed to determine disease-specific microbial features and their interactions with other residents in chronic obstructive pulmonary diseases (stable and exacerbated), sarcoidosis, and interstitial lung diseases. Broncho-alveolar lavage samples (n = 43) were analyzed by SSU rRNA gene sequencing to study the alveolar microbiome in these diseases. A predominance of Proteobacteria followed by Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria was observed in all the disease subsets. Shannon diversity was significantly higher in stable COPD when compared to exacerbated chronic obstructive pulmonary disease (ECOPD) (p = 0.0061), and ILD patient samples (p = 0.037). The lung microbiome of the patients with stable COPD was more diverse in comparison to ECOPD and ILD patients (p < 0.001). Lefse analysis identified 40 disease—differentiating microbial features (LDA score (log10) > 4). Species network analysis indicated a significant correlation (p < 0.05) of diseases specific microbial signature with other lung microbiome members. The current study strengthens the proposed hypothesis that each respiratory illness has unique microbial signatures. These microbial signatures could be used as diagnostic markers to differentiate among various respiratory illnesses. © 2021, The Author(s).

Fulltext

Scientific Reports

Comparative analysis of the alveolar microbiome in COPD, ECOPD, Sarcoidosis, and ILD patients to identify respiratory illnesses specific microbial signatures

Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda vasica (AV) aqueous extract on mouse models of acute allergic as well as severe asthma subtypes at physiological, histopathological, and molecular levels. Oral administration of AV extract attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice and alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC (murine IL-8 homologue), and HIF-1a (hypoxia-inducible factor-1a) in severe asthmatic mice. AV inhibits HIF-1a levels through restoration of expression of its negative regulator—PHD2 (prolyl hydroxylase domain-2). Alleviation of hypoxic response mediated by AV is further confirmed in the acute and severe asthma model. AV reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells—evident from bioenergetic profiles and morphological analysis of mitochondria. In silico docking of AV constituents reveal higher negative binding affinity for C and O—glycosides for HIF-1a, IL-6, Janus kinase 1/3, TNF-a, and TGF-b—key players of hypoxia inflammation. This study for the first time provides a molecular basis of action and effect of AV whole extract that is widely used in Ayurveda practice for diverse respiratory ailments. Further, through its effect on hypoxia-induced mitochondrial dysfunction, the study highlights its potential to treat severe steroid-resistant asthma. Copyright © 2021 the American Physiological Society

American Journal of Physiology - Lung Cellular and Molecular Physiology

Adhatoda vasica rescues the hypoxia-dependent severe asthma symptoms and mitochondrial dysfunction

Background: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. Methods: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. Results: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-β1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions. © 2021, The Author(s).

Respiratory Research

Adhatoda Vasica attenuates inflammatory and hypoxic responses in preclinical mouse models: potential for repurposing in COVID-19-like conditions

To elucidate the unknown regulatory mechanisms involved in aluminum (Al)-induced expression of POLYGALACTURONASE-INHIBITING PROTEIN 1 (PGIP1), which is one of the downstream genes of SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) regulating Al-tolerance genes, we conducted a genome-wide association analysis of gene expression levels (eGWAS) of PGIP1 in the shoots under Al stress using 83 Arabidopsis thaliana accessions. The eGWAS, conducted through a mixed linear model, revealed 17 suggestive SNPs across the genome having the association with the expression level variation in PGIP1. The GWAS-detected SNPs were directly located inside transcription factors and other genes involved in stress signaling, which were expressed in response to Al. These candidate genes carried different expression level and amino acid polymorphisms. Among them, three genes encoding NAC domain-containing protein 27 (NAC027), TRX superfamily protein, and R-R-type MYB protein were associated with the suppression of PGIP1 expression in their mutants, and accordingly, the system affected Al tolerance. We also found the involvement of Al-induced endogenous nitric oxide (NO) signaling, which induces NAC027 and R-R-type MYB genes to regulate PGIP1 expression. In this study, we provide genetic evidence that STOP1-independent NO signaling pathway and STOP1-dependent regulation in phosphoinositide (PI) signaling pathway are involved in the regulation of PGIP1 expression under Al stress. Copyright © 2021 Agrahari, Enomoto, Ito, Nakano, Yanase, Watanabe, Sadhukhan, Iuchi, Kobayashi, Panda, Yamamoto, Koyama and Kobayashi.

Frontiers in plant science

Expression GWAS of PGIP1 Identifies STOP1-Dependent and STOP1-Independent Regulation of PGIP1 in Aluminum Stress Signaling in Arabidopsis.

The dinuclear diorganotin sulfide [R2Sn(µ-S)]2 (1) (R = 2-phenylazophenyl) was synthesized by the room temperature reaction of the N → Sn intramolecularly coordinated starting precursor R2SnCl2 and Na2S·9H2O in acetone/methanol (1:1). The molecular structure of 1 was primarily characterized by single crystal X-ray crystallography. Furthermore, 1 was also characterized by other experimental techniques, such as 1H, 13C and 119Sn NMR, ESI-MS, FTIR spectroscopy. Complex 1 crystallized in the monoclinic P21/n space group. Each tin center of complex 1 is pentacoordinated and acquires a distorted trigonal bipyramidal geometry. Time dependent density functional theory (TD-DFT) analysis revealed that the transitions observed in complex 1 are predominantly of the ligand-to-ligand type. Natural bond orbital (NBO) analysis showed that complex 1 consists of three ionic bonds (2Sn-C and Sn-S) and two ligand to metal coordinate bonds (S → Sn and N → Sn). HOMO-LUMO analysis suggested that the HOMO of complex 1 is mainly sulfur based. The complex 1 showed significant bactericidal activity against both gram positive and negative bacteria. © 2021 Elsevier Ltd

Department of Chemistry

Department of Electrical Engineering

Polyhedron

Hemi Labile Intramolecular N → Sn Coordination in a Diorganotin (IV) Sulfide [R2Sn(µ-S)]2 (R = 2-phenylazophenyl) Complex: Synthesis, Structure, DFT-NBO and Antibacterial Studies

The present study was undertaken to evaluate the mechanism for antiParkinsonian effect of resveratrol employing 6-hydroxydopamine (6-OHDA) induced experimental model of Parkinson's disease (PD). Resveratrol treatment significantly protects the PD related pathological markers like level of tyrosine hydroxylase, dopamine and apoptotic proteins (Bax and cleaved caspase-3). Disease pathology involves significantly decreased level of dopamine transporter, synaptophysin and postsynaptic density protein 95 (PSD-95) along with augmented level of vesicular monoamine transporter and considerably affected the dendrite arborization. Such affected neuronal communication was significantly restored with resveratrol treatment. Biochemical alterations include the depleted level of glutathione (GSH), mitochondrial complex-I activity with concomitant increased level of lipid peroxidation, nitrite level and calcium levels, which were also significantly inhibited with resveratrol treatment. Altered calcium level induces the endoplasmic reticulum (ER) stress related signalling and phosphorylated Nuclear factor erythroid 2-related factor 2 (Nrf2), and with resveratrol treatment the level of phosphorylated Nrf2 was further increased. The concurrent depleted level of proteasome activity was observed which was attenuated with resveratrol treatment. Proinflammatory cytokines and activated astrocytes were observed which was inhibited with resveratrol treatment. In conclusion, findings suggested that resveratrol exhibits the interference in neuronal communication, oxidative stress, mitochondrial pathophysiology, ER stress, protein degradation mechanism and inflammatory responses and could be utilize in clinics to treat the PD patients. © 2021 Elsevier Ltd

Food and Chemical Toxicology

Mechanism for antiParkinsonian effect of resveratrol: Involvement of transporters, synaptic proteins, dendrite arborization, biochemical alterations, ER stress and apoptosis

The lifetimes of localized nonlinear modes in both the β-Fermi-Pasta-Ulam-Tsingou (β-FPUT) chain and a cubic β-FPUT lattice are studied as functions of perturbation amplitude, and by extension, the relative strength of the nonlinear interactions compared to the linear part. We first recover the well known result that localized nonlinear excitations (LNEs) produced by a bond squeeze can be reduced to an approximate two-frequency solution and then show that the nonlinear term in the potential can lead to the production of secondary frequencies within the phonon band. This can affect the stability and lifetime of the LNE by facilitating interactions between the LNE and a low energy acoustic background which can be regarded as “noise” in the system. In the one dimensional FPUT chain, the LNE is stabilized by low energy acoustic emissions at early times; in some cases allowing for lifetimes several orders of magnitude larger than the oscillation period. The longest lived LNEs are found to satisfy the parameter dependence Aβ≈1.1 where β is the relative nonlinear strength and A is the displacement amplitude of the center particles in the LNE. In the cubic FPUT lattice, the LNE lifetime T decreases rapidly with increasing amplitude A and is well described by the double log relationship log10log10(T)≈−(0.15±0.01)Aβ+(0.62±0.02). © 2021 Elsevier Ltd