Life Sciences

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Survivin is a lucrative broad-spectrum drug target for different cancer types, including triple negative breast cancer (TNBC). Sepantronium bromide (YM155) is the first of its class of survivin suppressants and was found to be quite effective in pre-clinical models of TNBC. However, in clinical trials when given in combination with docetaxel, YM55 failed to provide any added advantage. To understand if the clinical outcome is due to YM155 being ineffective or due to an inappropriate choice of combination, we need to elucidate its true mode of action. Hence, to explain the unexpected and unexplained observations pertaining to YM155 biology and its mode of action, we developed isogenic pairs of YM155-sensitive and -resistant TNBC cell lines and characterized them in detail by various biochemical assays. We found that YM155 generates reactive oxygen species (ROS) in the mitochondria in addition to the previously discovered redox cycling pathway. Both survivin suppression and DNA damage are secondary effects resulting from the ROS which contribute to the drug's cytotoxic effects on TNBC cells. Indeed, adaptation to both these pathways was important in conferring YM155 resistance. Finally, we uncovered a unique connection between the ROS and control of survivin expression involving a ROS/AKT/FoxO/survivin axis in TNBC cells. Together, by deciphering the true mode of action of YM155, we present a possible explanation for its poor clinical efficacy when used in combination with docetaxel. The results and conclusions presented here provide the information needed to effectively use YM155 in combination therapy. © The Royal Society of Chemistry 2021.

World University root node

(SoNS) School of Natural Sciences

RSC Medicinal Chemistry

Generation of reactive oxygen species is the primary mode of action and cause of survivin suppression by sepantronium bromide (YM155)

Nucleoid-associated proteins (NAPs) or histone-like proteins (HLPs) are DNA-binding proteins present in bacteria that play an important role in nucleoid architecture and gene regulation. NAPs affect bacterial nucleoid organization via DNA bending, bridging, or forming aggregates. EbfC is a nucleoid-associated protein identified first in Borrelia burgdorferi, belonging to YbaB/EbfC family of NAPs capable of binding and altering DNA conformation. YbaB, an ortholog of EbfC found in Escherichia coli and Haemophilus influenzae, also acts as a transcriptional regulator. YbaB has a novel tweezer-like structure and binds DNA as homodimers. The homologs of YbaB are found in almost all bacterial species, suggesting a conserved function, yet the physiological role of YbaB protein in many bacteria is not well understood. In this study, we characterized the YbaB/EbfC family DNA-binding protein in Caulobacter crescentus. C. crescentus has one YbaB/EbfC family gene annotated in the genome (YbaBCc) and it shares 41% sequence identity with YbaB/EbfC family NAPs. Computational modeling revealed tweezer-like structure of YbaBCc, a characteristic of YbaB/EbfC family of NAPs. N-terminal–CFP tagged YbaBCc localized with the nucleoid and is able to compact DNA. Unlike B. burgdorferi EbfC protein, YbaBCc protein is a non-specific DNA-binding protein in C. crescentus. Moreover, YbaBCc shields DNA against enzymatic degradation. Collectively, our findings reveal that YbaBCc is a small histone-like protein and may play a role in bacterial chromosome structuring and gene regulation in C. crescentus. © Copyright © 2021 Pal, Modi, Ravichandran, Yennamalli and Priyadarshini.

Fulltext

Frontiers in Microbiology

DNA-Binding Properties of YbaB, a Putative Nucleoid-Associated Protein From Caulobacter crescentus

In the originally published version of this manuscript, the following disclosures were inadvertently omitted. Carlos L. Arteaga, co-author in this manuscript, receives or has received research grants from Pfizer, Lilly and Takeda; holds minor stock options in Provista; serves or has served in an advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Taiho Oncology, OrigiMed, Puma Biotechnology, Immunomedics, AstraZeneca, Arvinas, and Sanofi; and reports scientific advisory board remuneration from the Susan G. Komen Foundation. None of these relationships are of any relevance to the work published in this manuscript. These details have been corrected only in this corrigendum to preserve the published version of record. © 2021 Oxford University Press. All rights reserved.

Carcinogenesis

Erratum: The H1047R PIK3CA oncogene induces a senescence-like state, pleiotropy and acute HSP90 dependency in HER2+ mammary epithelial cells (Carcinogenesis DOI: 10.1093/carcin/bgz118)

Salinity stress is one of the major constraints for plant growth and yield. The salinity stress response of different genotypes of crop plants may largely be governed by DNA polymorphisms. To determine the molecular genetic factors involved in salinity stress tolerance in chickpea, we performed a whole genome resequencing data analysis of three each of salinity-sensitive and salinity-tolerant genotypes. A total of 6173 single nucleotide polymorphisms and 920 insertions and deletions differentiating the chickpea genotypes with contrasting salinity stress responses were identified. Gene ontology analysis revealed the enrichment of functional terms related to stress response and development among the genes harboring DNA polymorphisms in their promoter and/or coding regions. DNA polymorphisms located within the cis-regulatory motifs of the quantitative trait loci (QTL)-associated and abiotic stress related genes were identified, which may influence salinity stress response via modulating binding affinity of the transcription factors. Several genes including QTL-associated and abiotic stress response related genes harboring DNA polymorphisms exhibited differential expression in response to salinity stress especially at the reproductive stage of development in the salinity-tolerant genotype. Furthermore, effects of non-synonymous DNA polymorphisms on mutational sensitivity and structural integrity of the encoded proteins by the candidate QTL-associated and abiotic stress response related genes were revealed. The results suggest that DNA polymorphisms may determine salinity stress response via influencing differential gene expression in genotype and/or stage-dependent manner. Altogether, we provide a high-quality set of DNA polymorphisms and candidate genes that may govern salinity stress tolerance in chickpea. © 2021 Scandinavian Plant Physiology Society.

Physiologia Plantarum

Discovery of DNA polymorphisms via whole genome resequencing and their functional relevance in salinity stress response in chickpea

Gamma delta (γδ) T cells, especially the Vγ9Vδ2 subtype, have been implicated in cancer therapy and thus have earned the spotlight in the past decade. Although one of the most important properties of γδ T cells is their activation by phosphoantigens, which are intermediates of the Mevalonate and Rohmer pathway of isoprenoid biosynthesis, such as IPP and HDMAPP, respectively, the global effects of such treatments on Vγ9Vδ2 T cells remain elusive. Here, we used the high-throughput transcriptomics approach to elucidate the transcriptional changes in human Vγ9Vδ2 T cells upon HDMAPP, IPP, and anti-CD3 treatments in combination with interleukin 2 (IL2) cytokine stimulation. These activation treatments exhibited a dramatic surge in transcription with distinctly enriched pathways. We further assessed the transcriptional dynamics upon inhibition of Notch signaling coupled with activation treatments. We observed that the metabolic processes are most affected upon Notch inhibition via GSI-X. The key effector genes involved in gamma–delta cytotoxic function were downregulated upon Notch blockade even in combination with activation treatment, suggesting a transcriptional crosstalk between T-cell receptor (TCR) signaling and Notch signaling in Vγ9Vδ2 T cells. Collectively, we demonstrate the effect of the activation of TCR signaling by phosphoantigens or anti-CD3 on the transcriptional status of Vγ9Vδ2 T cells along with IL2 stimulation. We further show that the blockade of Notch signaling antagonistically affects this activation. © Copyright © 2021 Madhok, Bhat, Philip, Sureshbabu, Chiplunkar and Galande.

Frontiers in Immunology

Transcriptome Signature of Vγ9Vδ2 T Cells Treated With Phosphoantigens and Notch Inhibitor Reveals Interplay Between TCR and Notch Signaling Pathways

In the proposed work, we have implemented all logic gates (AND, OR, NOR, NAND, Ex-OR, and Ex-NOR) on a single chip by utilizing the Ti-Diffused lithium niobate (Ti-LiNbO3) based Mach-Zehnder Interferometers. Earlier, many separate photonic devices were developed for individual logic gates. But, proposed gates are highly optimized for high-speed processing combinational circuits by their uniqueness as a single device for all-logic gates. The Beam propagation method (BPM) is acclimated for modeling, study and simulation of the proposed structure. This macrocosmic design can handle immensely colossal combinational circuits with high-speed processing. An insertion loss of 0.83 ​dB and an extinction ratio (ER) of 9.01 ​dB are reported. The simulated results are verified utilizing mathematical computation and MATLAB simulation. © 2021 Elsevier Ltd

Microelectronics Journal

Implementation of highly optimized optical all logic gates on a single chip using Ti-diffused lithium-niobate for high-speed processing in combinational circuits

Background: Biogenesis and function of mitochondria is profoundly dependent on cytosolic translation of mitochondrial pre-proteins and its subsequent translocation and folding inside the organelle. Continuous exposure of non-native precursor proteins, exposure to damaging by-products of oxidative phosphorylation, load of mis-targeted or misfolded proteins from neighbouring compartments and unremitting demand of communication between mitochondrial and nuclear genomes, continuously pose proteotoxic threats to the organelle. Our knowledge of cellular mechanisms to cope up with such impending threat of proteotoxicity to mitochondria, is currently evolving. In recent years, several unique response and survival pathways have been discovered shedding light on cellular strategies to cope with stressed and dysfunctional mitochondria. As mitochondria compulsorily communicate with nucleus, cytosol and endoplasmic reticulum (ER) for its own biogenesis and function and in turn maintain critical cellular processes for survival, any impairment in communication by stressed or dysfunctional mitochondria may end up with fatal consequences. Discussion and implication: In this review, we have discussed about possible sources of mitochondrial proteotoxicity and the recent developments regarding cellular strategies to counter such stress to overcome dysfunctions of the organelle. Mitochondrial communication with neighbouring subcellular compartments like ER and cytosol during proteotoxic stress have been explored. In the context of mitochondrial proteotoxicity, alterations of crucial inter-organelle connections like ER-mitochondria contact sites and its implication on mitochondrial signaling activity like Ca2+ signaling have been dissected. Furthermore, an overview of pathological conditions, mainly neurodegenerative disorders that are known to be associated with mitochondrial proteotoxicity and Ca2+ dysregulation has been presented. © 2020

Mitochondrion

Alterations in inter-organelle crosstalk and Ca2+ signaling through mitochondria during proteotoxic stresses

Ionospheric response during the annular solar eclipse of June 21, 2020, has been examined in terms of the Total Electron Content (TEC) obtained from six Global Positioning System (GPS) receivers positioned in the Chinese-Taiwanese region. We have shown TEC variation from satellites designated by PRNs (Pseudo-Random Noise code) 2, 6, and 19. PRN wise TEC trend was observed to depend upon satellite-pass trajectory to the receiver's location during the eclipse period. A time lag of ~15–30 min is also observed in maximum TEC decrement after the phase of maximum eclipse. Instead of the percentage of eclipse magnitude, a reduction in TEC is seen more for the station for which the orbital track of respective satellites was in closer view relative to receivers for more hours of eclipse window. Additionally, the eclipse day diurnal variations are compared with the pre-eclipse day TEC trend, and observed results show a clear decrease in TEC values at all chosen stations after the eclipse onset then reached the lowest value a few minutes afterward the maximum eclipse phase. © 2021 COSPAR

Advances in Space Research

A study on TEC reduction during the tail phase of the 21st June 2020 annular solar eclipse

In the present study, various solar and atmospheric parameters, namely solar radiation, surface ozone, relative humidity, air temperature, and wind speed, have been studied first time for the annular solar eclipse of June 21, 2020, at seven Indian stations simultaneously. All the seven different stations are selected along the solar eclipse path having the maximum eclipse magnitude of 92% and above. The various atmospheric parameters have shown the change in behavior during the solar eclipse duration. The incoming solar radiation has a maximum 95.97% decrease at Ludhiana at the time of maximum obscuration compared to the previous day. The surface ozone concentration has shown a decrease for all the seven stations during the maximum obscuration period. A maximum of 9.25% decrease in surface temperature has been observed nearly after 30 min of the time of maximum obscuration of the eclipse. Relative humidity started increasing at all the stations and showed an inverse trend from temperature. The wind speed was found to suppress during the maximum solar eclipse which may be attributed to stabilization of atmospheric boundary layer due to cooling. © 2021, Indian Association for the Cultivation of Science.

Indian Journal of Physics

Changes in atmospheric parameters due to annular solar eclipse of June 21, 2020, over India

One of the major barriers in the prevention and control of malaria programs worldwide is the growing emergence of multidrug resistance in Plasmodium parasites, and this necessitates continued efforts to discover and develop effective drug molecules targeting novel proteins essential for parasite survival. In recent years, epigenetic regulators have evolved as an attractive drug target option owing to their crucial role in survival and development of Plasmodium at different stages of its life cycle. PfMYST, a histone acetyltransferase protein, is known to regulate key cellular processes, such as cell cycle progression, DNA damage repair, and antigenic variation, that facilitate parasite growth, adaptation, and survival inside its host. With the aim of assessing the therapeutic potential of PfMYST as a novel drug target, we examined the effect of NU9056 (an HsTIP60 inhibitor) on the rate of parasite growth and survival. In the present study, by using a yeast complementation assay, we established that PfMYST is a true homolog of TIP60 and showed that NU9056 can inhibit PfMYST catalytic activity and kill P. falciparum parasites in culture. Inhibiting the catalytic activity of PfMYST arrests the parasite in the trophozoite stage and inhibits its further transition to the schizont stage, eventually leading to its death. Overall, our study provides proof of concept that PfMYST catalytic activity is essential for parasite growth and survival and that PfMYST can be a potential target for antimalarial therapy. © 2020 American Society for Microbiology. All Rights Reserved.