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Shiv Nadar University

(SoNS) School of Natural Sciences

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

Life 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

Let (Formula presented.) be an abelian extension of the Lie superalgebra (Formula presented.). In this article we consider the problems of extending endomorphisms of (Formula presented.) and lifting endomorphisms of (Formula presented.) to certain endomorphisms of (Formula presented.). We connect these problems to the cohomology of (Formula presented.) with coefficients in (Formula presented.) through construction of two exact sequences which are our main results. The first exact sequence is obtained using the Hochschild–Serre spectral sequence corresponding to the above extension while to prove the second we rather take a direct approach. As an application of our results we obtain descriptions of certain automorphism groups of semidirect product Lie superalgebras. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Mathematics

Linear and Multilinear Algebra

Exact sequences in the cohomology of a Lie superalgebra extension

Organic room-temperature phosphorescence (RTP) materials with persistent RTP (PRTP) have attracted huge interest in inks, bioimaging, and photodynamic therapy. However, the design principle to increase the lifetime of organic molecules is underdeveloped. Herein, we show donor(D4)-acceptor(A) molecules (TOEPh, TOCPh, TOMPh, TOF and TOPh) with similar orientation of donor rings in aggregates that cause a large number of noncovalent interactions. We observed that TOEPh, TOCPh, TOMPh and TOF showed PRTP, whereas TOPh showed only phosphorescence emission (φP = 11\%) with no PRTP property at ambient conditions. The spectroscopic and single-crystal X-ray analyses confirm the molecular assembly via J-aggregation with a face-to-face orientation of the donor rings. The crystal structure analysis (TOEPh, TOCPh, TOMPh, TOF) reveals that moderate π···πinteractions (3.706 to 4.065 Å) between the donor rings cause the enhancement of the phosphorescence lifetime (26 to 245 ms), whereas the short phosphorescence lifetime (12 ms) of TOPh was observed because of the absence of π···πinteractions. We found that TOEPh shows a long lifetime (245 ms) as compared to other derivatives because of the presence of ethoxy (-OEt) groups that enables spin-orbit coupling caused by strong lone pair (O)···πinteractions present in the molecule. Utilizing the PRTP feature of TOEPh and the fluorescence emission of TOPh, we have shown data security applications in poly(methyl methacrylate). © 2021 The Authors. Published by American Chemical Society.