@article {2373, title = {A regulatory network of microRNAs confers lineage commitment during early developmental trajectories of B and T lymphocytes.}, journal = {Proc Natl Acad Sci U S A}, volume = {118}, year = {2021}, month = {2021 11 16}, abstract = {

The commitment of hematopoietic multipotent progenitors (MPPs) toward a particular lineage involves activation of cell type-specific genes and silencing of genes that promote alternate cell fates. Although the gene expression programs of early-B and early-T lymphocyte development are mutually exclusive, we show that these cell types exhibit significantly correlated microRNA (miRNA) profiles. However, their corresponding miRNA targetomes are distinct and predominated by transcripts associated with natural killer, dendritic cell, and myeloid lineages, suggesting that miRNAs function in a cell-autonomous manner. The combinatorial expression of miRNAs miR-186-5p, miR-128-3p, and miR-330-5p in MPPs significantly attenuates their myeloid differentiation potential due to repression of myeloid-associated transcripts. Depletion of these miRNAs caused a pronounced de-repression of myeloid lineage targets in differentiating early-B and early-T cells, resulting in a mixed-lineage gene expression pattern. De novo motif analysis combined with an assay of promoter activities indicates that B as well as T lineage determinants drive the expression of these miRNAs in lymphoid lineages. Collectively, we present a paradigm that miRNAs are conserved between developing B and T lymphocytes, yet they target distinct sets of promiscuously expressed lineage-inappropriate genes to suppress the alternate cell-fate options. Thus, our studies provide a comprehensive compendium of miRNAs with functional implications for B and T lymphocyte development.

}, keywords = {Animals, B-Lymphocytes, Cell Differentiation, Cell Lineage, Gene Expression, Gene Expression Profiling, Gene Regulatory Networks, Hematopoietic Stem Cells, Mice, MicroRNAs, Myeloid Cells, T-Lymphocytes}, issn = {1091-6490}, doi = {10.1073/pnas.2104297118}, author = {Nikhat, Sameena and Yadavalli, Anurupa D and Prusty, Arpita and Narayan, Priyanka K and Palakodeti, Dasaradhi and Murre, Cornelis and Pongubala, Jagan M R} } @article {2270, title = {Repeated victorious and defeat experiences induce similar apical dendritic spine remodeling in CA1 hippocampus of rats.}, journal = {Behav Brain Res}, volume = {406}, year = {2021}, month = {2021 May 21}, pages = {113243}, abstract = {

In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (\>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20-30 μm) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2021.113243}, author = {Patel, Deepika and Anilkumar, Shobha and Chattarji, Sumantra and de Boer, Sietse F and Buwalda, Bauke} } @article {2372, title = {Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy.}, journal = {J Med Genet}, year = {2021}, month = {2021 Dec 16}, abstract = {

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM.

METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 () gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect.

CONCLUSIONS: Our study demonstrates for the first time that the variants in the gene are associated with HCM, and early detection of the variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of gene variants.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2021-107866}, author = {Jain, Pratul Kumar and Jayappa, Shashank and Sairam, Thiagarajan and Mittal, Anupam and Paul, Sayan and Rao, Vinay J and Chittora, Harshil and Kashyap, Deepak K and Palakodeti, Dasaradhi and Thangaraj, Kumarasamy and Shenthar, Jayaprakash and Koranchery, Rakesh and Rajendran, Ranjith and Alireza, Haghighi and Mohanan, Kurukkanparampil Sreedharan and Rathinavel, Andiappan and Dhandapany, Perundurai S} } @article {2206, title = {Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival.}, journal = {Cancers (Basel)}, volume = {13}, year = {2021}, month = {2021 Jan 30}, abstract = {

Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.

}, issn = {2072-6694}, doi = {10.3390/cancers13030533}, author = {Zaarour, Rania F and Azakir, Bilal and Hajam, Edries Y and Nawafleh, Husam and Zeinelabdin, Nagwa A and Engelsen, Agnete S T and Thiery, J{\'e}rome and Jamora, Colin and Chouaib, Salem} } @article {2150, title = {The Rad53-Spt21 and Tel1 axes couple glucose tolerance to histone dosage and subtelomeric silencing.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 19}, pages = {4154}, abstract = {

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21 on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1 and Rpd3 activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.

}, keywords = {Acetylation, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Damage, DNA Repair, Gene Silencing, Glucose, Histone Deacetylases, Histones, Intracellular Signaling Peptides and Proteins, Mutation, Phosphorylation, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Serine, Telomere, Transcription Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17961-4}, author = {Bruhn, Christopher and Ajazi, Arta and Ferrari, Elisa and Lanz, Michael Charles and Batrin, Renaud and Choudhary, Ramveer and Walvekar, Adhish and Laxman, Sunil and Longhese, Maria Pia and Fabre, Emmanuelle and Smolka, Marcus Bustamente and Foiani, Marco} } @article {2209, title = {Reply to Negri et al.: Air pollution and health impacts on bees: Signs of causation.}, journal = {Proc Natl Acad Sci U S A}, volume = {117}, year = {2020}, month = {2020 10 27}, pages = {26578-26579}, keywords = {Air Pollution, Animals, Bees, Health}, issn = {1091-6490}, doi = {10.1073/pnas.2017972117}, author = {Thimmegowda, Geetha G and Brockmann, Axel and Dhandapany, Perundurai S and Olsson, Shannon B} } @article {2204, title = {Resource plasticity-driven carbon-nitrogen budgeting enables specialization and division of labor in a clonal community.}, journal = {Elife}, volume = {9}, year = {2020}, month = {2020 09 02}, abstract = {

Previously, we found that in glucose-limited colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic or glycolytic states. In that study, threshold amounts of trehalose - a limiting, produced carbon-resource, controls the emergence and self-organization of cells exhibiting the glycolytic state, serving as a carbon source that fuels glycolysis (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential metabolic budgeting. In gluconeogenic cells, aspartate is a carbon source for trehalose production, while in glycolytic cells using trehalose for carbon, aspartate is predominantly a nitrogen source for nucleotide synthesis. This metabolic plasticity of aspartate enables carbon-nitrogen budgeting, thereby driving the biochemical self-organization of distinct cell states. Through this organization, cells in each state exhibit true division of labor, providing growth/survival advantages for the whole community.

}, issn = {2050-084X}, doi = {10.7554/eLife.57609}, author = {Varahan, Sriram and Sinha, Vaibhhav and Walvekar, Adhish and Krishna, Sandeep and Laxman, Sunil} } @article {2253, title = {Rethinking Exosomes: From Cell-to-Cell Courier Services to Individualized Medicines}, journal = {AAPS News magazine}, year = {2020}, month = {06/2020}, author = {Ghate, V and Chaudhari, P and Maxwell, A and Lewis, S and Pahal, S and Vemula PK} } @article {2250, title = {Role of connexins in female reproductive system and endometriosis.}, journal = {J Gynecol Obstet Hum Reprod}, volume = {49}, year = {2020}, month = {2020 Jun}, pages = {101705}, abstract = {

Gap junction form channels between the cells and facilitate the function of cellular cross talk. Connexins, the gap junction proteins play an essential role in female reproductive health and its expression anomalies are correlated with female reproductive disorders like polycystic ovarian syndrome, recurrent miscarriage, pre-term birth and endometriosis. Endometriosis is a chronic gynecologic disorder caused by ectopic endometrial lesions growing outside the uterine cavity. Embryonic implantation is adversely affected in case of endometriosis leading to infertility. Endometriosis also interferes with ovulatory functions, reduces fertilization and impaires blastocyst implantation. There lies a lacunae in understanding of the role of gap junctions protein connexins in endometriosis. Therefore, this study discusses the role of connexins in improving female fertility by taming the processes of oogenesis, germ line development, uterine receptivity, placental growth, implantation, decidualization and concludes by focusing the role of connexins in endometriosis.

}, keywords = {Connexins, Decidua, Embryo Implantation, Endometriosis, Endometrium, Female, Gap Junctions, Genitalia, Female, Humans, Infertility, Female, Oogenesis, Ovulation, Pregnancy, Uterus}, issn = {2468-7847}, doi = {10.1016/j.jogoh.2020.101705}, author = {Kaushik, Tripti and Mishra, Rakesh and Singh, Rakesh K and Bajpai, Surabhi} } @article {2059, title = {The Role of Dynamic miRISC During Neuronal Development.}, journal = {Front Mol Biosci}, volume = {7}, year = {2020}, month = {2020}, pages = {8}, abstract = {

Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

}, issn = {2296-889X}, doi = {10.3389/fmolb.2020.00008}, author = {Nawalpuri, Bharti and Ravindran, Sreenath and Muddashetty, Ravi S} } @article {1990, title = {Relax, Don{\textquoteright}t RAN Translate It.}, journal = {Neuron}, volume = {104}, year = {2019}, month = {2019 Dec 04}, pages = {827-829}, abstract = {

The (GGGGCC)n repeat expansion in C9orf72, which is the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis, is translated through repeat-associated non-AUG (RAN) translation. In this issue of Neuron, Cheng et\ al. (2019) report that the helicase DDX3X, which unwinds (or relaxes) RNA, suppresses RAN translation and toxicity.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2019.11.014}, author = {Wilson, Katherine M and Muralidharan, Bhavana and Isaacs, Adrian M} } @article {1742, title = {The resolution revolution reaches India.}, journal = {Biophys Rev}, year = {2019}, month = {2019 Jul 02}, issn = {1867-2450}, doi = {10.1007/s12551-019-00558-7}, author = {Subramanian, Ramaswamy and Mayor, Satyajit and Vinothkumar, Kutti R} } @article {1842, title = {Rodent models of social stress and neuronal plasticity: Relevance to depressive-like disorders.}, journal = {Behav Brain Res}, volume = {369}, year = {2019}, month = {2019 Sep 02}, pages = {111900}, abstract = {

Exposure to severe or persistent social stress may lead to the development of psychiatric disorders such as anxiety and depression. These mood disorders are associated with structural alterations of neural architecture in limbic brain regions that control emotion, mood and cognition. Structural remodeling may either be a sign of successful adaptation, or of failure to do so. In neuropsychiatric disorders like depression structural remodeling involves apoptosis, reduced neurogenesis, and structural remodeling of neuronal dendrites which most likely reflects the latter. Here we review key findings from animal models of psychosocial stress that have been used to gain insights into the relation between stress-related behavioral disorders like depression and structural plasticity. Specifically, we focus on models having a high face validity like social defeat stress in the resident-intruder paradigm and chronic stress of social subordination in social housing conditions. Moderate to severe social stress appears to stimulate plasticity and neuronal growth in regions of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. A major focus of the current review is to characterize social stress induced structural changes in these brain regions, aiming to provide insight in pathways and factors that underlie behavioral effects of stress and depression.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2019.111900}, author = {Patel, Deepika and Kas, Martien J and Chattarji, Sumantra and Buwalda, Bauke} } @article {1616, title = {Reflections on current Ayurveda research.}, journal = {J Ayurveda Integr Med}, volume = {9}, year = {2018}, month = {2018 Oct - Dec}, pages = {250-251}, abstract = {

The current development in modern biology partnered with technology, better understanding of genes, environment is beginning to allow predicting the state of the human body. Research in Modern science is in transitional state from reverse pharmacology to system approach. It{\textquoteright}s time for Ayurveda to undertake research deep in its own foundational theories and in its interface with modern science. The present environment, lifestyle and nutrition have drastically different from ancient times. There is a need to modernize Ayurveda and make it relevant and contextual in terms of personalized medicine where allopathic medicine is heading. Innovations based on advancements, new treatment regimen, therapeutic approaches are the current needs from Ayurveda to make an impact on global clinical practice. In India, the Ayurveda research needs commitment in leadership and good funding resources for its best run, and for true healthcare.

}, issn = {0975-9476}, doi = {10.1016/j.jaim.2018.11.001}, author = {Ramaswamy, S} } @article {1590, title = {Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus.}, journal = {Behav Brain Res}, volume = {347}, year = {2018}, month = {2018 07 16}, pages = {314-324}, abstract = {

Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear social avoidance behavior one day after the last confrontation. To assess the morphological consequences of repeated social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and social stressors.

}, keywords = {Amygdala, Animals, Atrophy, Avoidance Learning, CA1 Region, Hippocampal, Dendritic Spines, Dominance-Subordination, Male, Neuronal Plasticity, Prefrontal Cortex, Pyramidal Cells, Rats, Wistar, Stress, Psychological}, issn = {1872-7549}, doi = {10.1016/j.bbr.2018.03.034}, author = {Patel, D and Anilkumar, S and Chattarji, S and Buwalda, B} } @article {1151, title = {Rudhira/BCAS3 is essential for mouse development and cardiovascular patterning.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 Apr 04}, pages = {5632}, abstract = {

Rudhira/Breast Carcinoma Amplified Sequence 3 (BCAS3) is a cytoskeletal protein that promotes directional cell migration and angiogenesis in vitro and is implicated in human carcinomas and coronary artery disease. To study the role of Rudhira during development in vivo, we generated the first knockout mouse for rudhira and show that Rudhira is essential for mouse development. Rudhira null embryos die at embryonic day (E) 9.5 accompanied by severe vascular patterning defects in embryonic and extra-embryonic tissues. To identify the molecular processes downstream of rudhira, we analyzed the transcriptome of intact knockout yolk sacs. Genome-wide transcriptome analysis showed that Rudhira functions in angiogenesis and its related processes such as cell adhesion, extracellular matrix organization, peptidase activity and TGFβ signaling. Since Rudhira is also expressed in endothelial cells\ (ECs), we further generated Tie2Cre-mediated endothelial knockout (CKO) of rudhira. CKO embryos survive to E11.5 and similar to the global knockout, display gross vascular patterning defects, showing that endothelial Rudhira is vital for development. Further, Rudhira knockdown ECs in culture fail to sprout in a spheroid-sprouting assay, strongly supporting its role in vascular patterning. Our study identifies an essential role for Rudhira in blood vessel remodeling and provides a mouse model for cardiovascular development.

}, issn = {2045-2322}, doi = {10.1038/s41598-018-24014-w}, author = {Shetty, Ronak and Joshi, Divyesh and Jain, Mamta and Vasudevan, Madavan and Paul, Jasper Chrysolite and Bhat, Ganesh and Banerjee, Poulomi and Abe, Takaya and Kiyonari, Hiroshi and VijayRaghavan, K and Inamdar, Maneesha S} }