Publications by authors named "Priyanka Chakraborty"

29 Publications

  • Page 1 of 1

Calcium signaling induces a partial EMT.

EMBO Rep 2021 Sep 29;22(9):e51872. Epub 2021 Jul 29.

Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.
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http://dx.doi.org/10.15252/embr.202051872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419705PMC
September 2021

Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum.

Comput Struct Biotechnol J 2021 17;19:3842-3851. Epub 2021 Jun 17.

Department of Medicine, Durham, NC, United Kingdom.

Epithelial-mesenchymal plasticity plays a critical role in many solid tumor types as a mediator of metastatic dissemination and treatment resistance. In addition, there is also a growing appreciation that the epithelial/mesenchymal status of a tumor plays a role in immune evasion and immune suppression. A deeper understanding of the immunological features of different tumor types has been facilitated by the availability of large gene expression datasets and the development of methods to deconvolute bulk RNA-Seq data. These resources have generated powerful new ways of characterizing tumors, including classification of immune subtypes based on differential expression of immunological genes. In the present work, we combine scoring algorithms to quantify epithelial-mesenchymal plasticity with immune subtype analysis to understand the relationship between epithelial plasticity and immune subtype across cancers. We find heterogeneity of epithelial-mesenchymal transition (EMT) status both within and between cancer types, with greater heterogeneity in the expression of EMT-related factors than of MET-related factors. We also find that specific immune subtypes have associated EMT scores and differential expression of immune checkpoint markers.
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http://dx.doi.org/10.1016/j.csbj.2021.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283019PMC
June 2021

Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing.

Proc Natl Acad Sci U S A 2021 May;118(19)

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;

The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-β, BMP, Wnt-β-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-β1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-β-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process.
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http://dx.doi.org/10.1073/pnas.2102050118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126782PMC
May 2021

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Center for Theoretical Biological Physics and Departments of Physics and Bioengineering, Northeastern University, Boston, MA 02115, USA.

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.
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http://dx.doi.org/10.3390/cancers13071609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037024PMC
March 2021

Gene expression profiles of inflammatory breast cancer reveal high heterogeneity across the epithelial-hybrid-mesenchymal spectrum.

Transl Oncol 2021 Apr 31;14(4):101026. Epub 2021 Jan 31.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India. Electronic address:

Inflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.
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http://dx.doi.org/10.1016/j.tranon.2021.101026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851345PMC
April 2021

Electrocatalytic Water Oxidation by a Phosphorus-Nitrogen O═PN-Pincer Cobalt Complex.

Inorg Chem 2021 Jan 25;60(2):614-622. Epub 2020 Nov 25.

KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.

Water oxidation is a primary step in natural as well as artificial photosynthesis to convert renewable solar energy into chemical energy/fuels. Electrocatalytic water oxidation to evolve O, utilizing suitable low-cost catalysts and renewable electricity, is of fundamental importance considering contemporary energy and environmental issues, yet it is kinetically challenging owing to the complex multiproton/electron transfer processes. Herein, we report the first cobalt-based pincer catalyst for catalytic water oxidation at neutral pH with high efficiency under electrochemical conditions. Most importantly, ligand (pseudo)aromaticity is identified to play an important role during electrocatalysis. A significant potential jump (∼300 mV) was achieved toward a lower positive value when the aromatized cobalt complex was transformed into a (pseudo)dearomatized cobalt species. The dearomatized species catalyzes the water oxidation reaction to evolve oxygen at a much lower overpotential (∼340 mV) on the basis of the onset potential (at a current density of 0.5 mA/cm) of catalysis at pH 10.5, outperforming other Co-based molecular catalysts reported to date. These observations may provide a new strategy for the judicious design of earth-abundant transition-metal-based water oxidation catalysts.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02376DOI Listing
January 2021

Single-Cell RNA-seq Identifies Cell Subsets in Human Placenta That Highly Expresses Factors Driving Pathogenesis of SARS-CoV-2.

Front Cell Dev Biol 2020 19;8:783. Epub 2020 Aug 19.

Molecular and Cellular Biology Laboratory, ICMR-National Institute for Research in Reproductive Health, Indian Council of Medical Research (ICMR), Mumbai, India.

Infection by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) results in the novel coronavirus disease COVID-19, which has posed a serious threat globally. Infection of SARS-CoV-2 during pregnancy is associated with complications such as preterm labor and premature rupture of membranes, and a proportion of neonates born to infected mothers are also positive for the virus. During pregnancy, the placental barrier protects the fetus from pathogens and ensures healthy development. To predict if the placenta is permissive to SARS-CoV-2, we utilized publicly available single-cell RNA-seq data to identify if the placental cells express the necessary factors required for infection. SARS-CoV-2 binding receptor and the S protein priming protease are co-expressed by a subset of syncytiotrophoblasts (STB) in the first trimester and extravillous trophoblasts (EVT) in the second trimester human placenta. In addition, the non-canonical receptor and other proteases (, and ) are detected in most of the placental cells. Other coronavirus family receptors ( and ) were also expressed in the first and second trimester placental cells. Additionally, the term placenta of multiple species including humans expressed , , and along with the viral S protein proteases. The - and -positive ( + +) placental subsets expressed mRNA for proteins involved in viral budding and replication. These cells also had the mRNA for proteins that physically interact with SARS-CoV-2 in host cells. Further, we discovered unique signatures of genes in + + STBs and EVTs. The + + STBs are highly differentiated cells and express genes involving mitochondrial metabolism and glucose transport. The second trimester + + EVTs are enriched for markers of endovascular trophoblasts. Both these subtypes abundantly expressed genes in the Toll-like receptor pathway. The second trimester EVTs are also enriched for components of the JAK-STAT pathway that drives inflammation. We carried out a systematic review and identified that in 12% of pregnant women with COVID-19, the placenta was infected with SARS-CoV-2, and the virus was detected in STBs. To conclude, herein we have uncovered the cellular targets for SARS-CoV-2 entry and have shown that these cells can potentially drive viremia in the developing human placenta. Our results provide a basic framework toward understanding the paraphernalia involved in SARS-CoV-2 infections in pregnancy.
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http://dx.doi.org/10.3389/fcell.2020.00783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466449PMC
August 2020

Novel mannopyranoside esters as sterol 14α-demethylase inhibitors: Synthesis, PASS predication, molecular docking, and pharmacokinetic studies.

Carbohydr Res 2020 Oct 14;496:108130. Epub 2020 Aug 14.

Bioorganic and Medicinal Chemistry Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chattogram, 4331, Bangladesh.

Direct unimolar one-step valeroylation of methyl α-d-mannopyranoside (MDM) furnished mainly 6-O-valeroate. However, similar reaction catalyzed by DMAP resulted 3,6-di-O-valeroate (21%) and 6-O-valeroate (47%) indicating reactivity sequence as 6-OH>3-OH>2-OH,4-OH. To get potential antimicrobial agents, 6-O-valeroate was converted into four 2,3,4-di-O-acyl esters, and 3,6-di-O-valeroate was converted into 2,4-di-O-acetate. Direct tetra-O-valeroylation of MDM gave a mixture of 2,3,4,6-tetra-O-valeroate and 2,3,6-tri-O-valeroate indicating that the C2-OH is more reactive than the equatorial C4-OH. The activity spectra analysis along with in vitro antimicrobial evaluation clearly indicated that these novel MDM esters had better antifungal activities over antibacterial agents. In this connection, molecular docking indicated that these MDM esters acted as competitive inhibitors of sterol 14α-demethylase (CYP51), an essential enzyme for clinical target to cure several infectious diseases. Furthermore, pharmacokinetic studies revealed that these MDM esters may be worth considering as potent candidates for oral and topical administration. Structure activity relationship (SAR) affirmed that saturated valeric chain (C5) in combination with caprylic (C8) chains was more promising CYP51 inhibitor over conventional antifungal antibiotics.
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http://dx.doi.org/10.1016/j.carres.2020.108130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427576PMC
October 2020

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT.

Oncotarget 2020 Jul 7;11(27):2611-2624. Epub 2020 Jul 7.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.
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http://dx.doi.org/10.18632/oncotarget.27651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343638PMC
July 2020

Molecular and Genomic Characterization of PFAB2: A Non-virulent Strain Isolated from an Indian Hot Spring.

Curr Genomics 2019 Nov;20(7):491-507

1UGC-Center of Advanced Study, Department of Botany, The University of Burdwan, Golapbag, Burdwan, West Bengal, India; 2Molecular Biology and Genetic Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi110067, India; 3Centre of Excellence in Genomics, International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), Patancheru, India; 4Centro de Investigación en Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Posgrado, Universidad Católica del Maule, Talca, Chile; 5Facultad de Ciencias Agrarias y Forestales, Centro de Biotecnología de los Recursos Naturales, Universidad Católica del Maule, Talca, Chile.

Background: Thermophilic bacilli in both aerobic or facultative anaerobic forms have been isolated for over a hundred years from different mesophilic or thermophilic environments as they are potential source of bioactive secondary metabolites. But the taxonomic resolution in the genus at species or at strain level is very challenging for the insufficient divergence of the 16S rRNA genes. One such recurring problem is among , . and . . The disease-causing strains have their characteristic virulence factors coded in two well-known plasmids, namely pXO1 (toxin genes) and pXO2 (capsule genes).

Objective: The present study aimed at the molecular and genomic characterization of a recently reported thermophilic and environmental isolate of , strain PFAB2.

Methods: We performed comparative genomics between the PFAB2 genome and different strains of , along with closely related strains.

Results: The pangenomic analysis suggests that the PFAB2 genome harbors no complete prophage genes. Cluster analysis of Bray-Kurtis similarity resemblance matrix revealed that gene content of PFAB2 is more closely related to other environmental strains of . The secretome analysis and the and pathogenesis experiments corroborate the avirulent phenotype of this strain. The most probable explanation for this phenotype is the apparent absence of plasmids harboring genes for capsule biosynthesis and toxins secretion in the draft genome. Additional features of PFAB2 are good spore-forming and germinating capabilities and rapid replication ability.

Conclusion: The high replication rate in a wide range of temperatures and culture media, the non-pathogenicity, the good spore forming capability and its genomic similarity to the Ames strain together make PFAB2 an interesting model strain for the study of the pathogenic evolution of . .
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http://dx.doi.org/10.2174/1389202920666191203121610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327970PMC
November 2019

Dissecting miRNA facilitated physiology and function in human breast cancer for therapeutic intervention.

Semin Cancer Biol 2021 Jul 1;72:46-64. Epub 2020 Jun 1.

Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, 769008, India. Electronic address:

MicroRNAs (miRNAs) are key epigenomic regulators of biological processes in animals and plants. These small non coding RNAs form a complex networks that regulate cellular function and development. MiRNAs prevent translation by either inactivation or inducing degradation of mRNA, a major concern in post-transcriptional gene regulation. Aberrant regulation of gene expression by miRNAs is frequently observed in cancer. Overexpression of various 'oncomiRs' and silencing of tumor suppressor miRNAs are associated with various types of human cancers, although overall downregulation of miRNA expression is reported as a hallmark of cancer. Modulations of the total pool of cellular miRNA by alteration in genetic and epigenetic factors associated with the biogenesis of miRNA machinery. It also depends on the availability of cellular miRNAs from its store in the organelles which affect tumor development and cancer progression. Here, we have dissected the roles and pathways of various miRNAs during normal cellular and molecular functions as well as during breast cancer progression. Recent research works and prevailing views implicate that there are two major types of miRNAs; (i) intracellular miRNAs and (ii) extracellular miRNAs. Concept, that the functions of intracellular miRNAs are driven by cellular organelles in mammalian cells. Extracellular miRNAs function in cell-cell communication in extracellular spaces and distance cells through circulation. A detailed understanding of organelle driven miRNA function and the precise role of extracellular miRNAs, pre- and post-therapeutic implications of miRNAs in this scenario would open several avenues for further understanding of miRNA function and can be better exploited for the treatment of breast cancers.
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http://dx.doi.org/10.1016/j.semcancer.2020.05.017DOI Listing
July 2021

Choice of Explant for Plant Genetic Transformation.

Methods Mol Biol 2020 ;2124:107-123

Department of Botany, UGC-Center of Advanced Study, The University of Burdwan, Golapbag, West Bengal, India.

Particle bombardment or biolistic transformation is an efficient, versatile method. This method does not need any vector for the gene transfer and is not dependent on the cell type, species, and genotype. The success of any transformation technique depends on the starting experimental materials or the explants. Here, we describe the factors that have influenced the choice of explants in biolistic transformation. Many general factors in the selection of explants in the development of transgenic plants are presented here. Therefore, this chapter provides extensive guidelines regarding the choice of explants for researchers working on various plant genetic transformation techniques.
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http://dx.doi.org/10.1007/978-1-0716-0356-7_5DOI Listing
February 2021

Comparative Study of Transcriptomics-Based Scoring Metrics for the Epithelial-Hybrid-Mesenchymal Spectrum.

Front Bioeng Biotechnol 2020 20;8:220. Epub 2020 Mar 20.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India.

The Epithelial-mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade the immune system. Recent , , and evidence indicates that EMT is not an all-or-none process; instead, cells can stably acquire one or more hybrid epithelial/mesenchymal (E/M) phenotypes which often can be more aggressive than purely E or M cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells can undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR)-based metric was capable of distinguishing between "pure" individual hybrid E/M vs. mixtures of E and M cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: (a) it uses a small number of predictors to calculate the EMT score and (b) it can predict from the transcriptomic signature of a population whether it is comprised of "pure" hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.
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http://dx.doi.org/10.3389/fbioe.2020.00220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100584PMC
March 2020

Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD.

J Clin Med 2020 Mar 22;9(3). Epub 2020 Mar 22.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decoded the emergent dynamics of underlying gene regulatory networks that were identified to drive the initiation and the progression of NAFLD. We developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a "hybrid" adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.
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http://dx.doi.org/10.3390/jcm9030870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141525PMC
March 2020

A mechanism for epithelial-mesenchymal heterogeneity in a population of cancer cells.

PLoS Comput Biol 2020 02 10;16(2):e1007619. Epub 2020 Feb 10.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India.

Epithelial-mesenchymal heterogeneity implies that cells within the same tumor can exhibit different phenotypes-epithelial, mesenchymal, or one or more hybrid epithelial-mesenchymal phenotypes. This behavior has been reported across cancer types, both in vitro and in vivo, and implicated in multiple processes associated with metastatic aggressiveness including immune evasion, collective dissemination of tumor cells, and emergence of cancer cell subpopulations with stem cell-like properties. However, the ability of a population of cancer cells to generate, maintain, and propagate this heterogeneity has remained a mystifying feature. Here, we used a computational modeling approach to show that epithelial-mesenchymal heterogeneity can emerge from the noise in the partitioning of biomolecules (such as RNAs and proteins) among daughter cells during the division of a cancer cell. Our model captures the experimentally observed temporal changes in the fractions of different phenotypes in a population of murine prostate cancer cells, and describes the hysteresis in the population-level dynamics of epithelial-mesenchymal plasticity. The model is further able to predict how factors known to promote a hybrid epithelial-mesenchymal phenotype can alter the phenotypic composition of a population. Finally, we used the model to probe the implications of phenotypic heterogeneity and plasticity for different therapeutic regimens and found that co-targeting of epithelial and mesenchymal cells is likely to be the most effective strategy for restricting tumor growth. By connecting the dynamics of an intracellular circuit to the phenotypic composition of a population, our study serves as a first step towards understanding the generation and maintenance of non-genetic heterogeneity in a population of cancer cells, and towards the therapeutic targeting of phenotypic heterogeneity and plasticity in cancer cell populations.
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http://dx.doi.org/10.1371/journal.pcbi.1007619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034928PMC
February 2020

Synthesis, PASS predication, in vitro antimicrobial evaluation and pharmacokinetic study of novel n-octyl glucopyranoside esters.

Carbohydr Res 2019 Nov 10;485:107812. Epub 2019 Sep 10.

Molecular Modeling and Drug Design Laboratory, Bangladesh Council of Scientific & Industrial Research (BCSIR) Laboratories, Chattogram, 4220, Bangladesh.

Octyl β-d-glucopyranoside (OBG), prepared from d-glucose and octan-1-ol employing MW method, was subjected to direct dimolar valeroylation in pyridine at room temperature (25 °C) with valeroyl chloride. This mainly furnished the corresponding 3,6-di-O-valeroate in 57% yield indicating the regioselectivity at C-6 and C-3 positions. For structural elucidation and to get newer glucopyranosides of potential antimicrobial 3,6-di-O-valeroate was further converted into four novel 2,4-di-O-acyl esters reasonably in good yields. Per-O-acetate and per-O-benzoate of OBG were also prepared for SAR study. PASS predication and in vitro antimicrobial studies established them as better antifungal agent than that of antibacterial. SAR study along with AdmetSAR and SwissADME suggested that incorporation of alkanoyl and aromatic ester groups on octyl glucopyranoside core increase antimicrobial potentiality in very low concentration (10 μgmL). Molecular docking revealed that novel 2,4-di-O-tosyl ester and 2,3,4,6-tetra-O-benzoyl ester may act as competitive inhibitors of lanosterol 14-alpha demethylase.
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http://dx.doi.org/10.1016/j.carres.2019.107812DOI Listing
November 2019

CO hydrogenation by phosphorus-nitrogen PNP-pincer iridium hydride complexes: elucidation of the deactivation pathway.

Dalton Trans 2019 Sep 12;48(34):12812-12816. Epub 2019 Aug 12.

KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.

PNP-Ir pincer hydride complexes were synthesized and characterized as catalysts and key intermediates in the direct hydrogenation of CO to formate under mild conditions. The formation of a dearomatized PNP*-Ir(i)-CO species was identified as a plausible key process accountable for the loss of catalytic activity in the CO hydrogenation.
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http://dx.doi.org/10.1039/c9dt01319aDOI Listing
September 2019

α-Alkylation of Ketones with Secondary Alcohols Catalyzed by Well-Defined Cp*Co -Complexes.

ChemSusChem 2019 Aug 26;12(15):3463-3467. Epub 2019 Jun 26.

Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208 016, India.

Although α-alkylation of ketones with primary alcohols by transition-metal catalysis is well-known, the same process with secondary alcohols is arduous and complicated by self-condensation. Herein a well-defined, high-valence cobalt(III)-catalyst was applied for successful α-alkylation of ketones with secondary alcohols. A wide-variety of secondary alcohols, which include cyclic, acyclic, symmetrical, and unsymmetrical compounds, was employed as alkylating agents to produce β-alkyl aryl ketones.
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http://dx.doi.org/10.1002/cssc.201900990DOI Listing
August 2019

studies on bacterial xylanase enzyme: Structural and functional insight.

J Genet Eng Biotechnol 2018 Dec 31;16(2):749-756. Epub 2018 May 31.

UGC-Center of Advanced Study, Department of Botany, The University of Burdwan, Golapbag, Bardhaman 713104, West Bengal, India.

Xylans are the second most abundant form of hemicelluloses and are the second most abundant polysaccharide in nature after cellulose. To degrade xylan, microbes produce mainly xylanase enzyme. Wide range of microorganisms like fungi, bacteria, yeast, marine algae etc. are capable of producing xylanase. Main source of xylanase is fungi but industrial production of bacterial xylanase is low cost, easy downstream process and high production rate. To understand primary, secondary and tertiary structure of xylanase, composition of amino acids, basic physiological characteristics; ., pI, molecular weight, instability index, GRAVY, molar extinction coefficient, secondary structure, presence of functional domain and motifs, phylogenetic tree, salt bridge compositions are determined. study of xylanase focused on 36 different bacterial sources are performed by retrieving FASTA and PDB sequences using RCSB PDB. FASTA and PDB files are proceed further in ExPASy-ProtParam, RAMPAGE, QMEAN, MEME, PSIPRED, InterProScan, MOTIF scan, ERRAT, Peptide cutter, ESBRI and MEGA 7. The instability index range (16.90-38.78) clearly indicates that the protein is highly stable. helix mean value (27.11%) infers the protein is dominated by helix region. The aliphatic index (39.80-90.68) gives information that the protein is highly thermostable, prevalence by alanine amino acid in aliphatic side chain. No transmembrane domain was found in the protein which confirms the enzyme is extracellular in nature. Ancestor chart analysis confirmed that it is a part of carbohydrate metabolic process and more specifically a member of glycoside hydrolase super family.
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http://dx.doi.org/10.1016/j.jgeb.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353727PMC
December 2018

Cobalt-Catalyzed Reductive Alkylation of Amines with Carboxylic Acids.

ChemSusChem 2019 Jul 29;12(13):3089-3093. Epub 2018 Nov 29.

Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208 016, India.

Direct reductive alkylation of amines with carboxylic acid is carried out by using an inexpensive, air-stable cobalt/triphos catalytic system with molecular hydrogen as the reductant. This efficient synthetic method proceeds through reduction and condensation, followed by reduction of the in situ-generated imine into the amine in a green catalytic process.
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http://dx.doi.org/10.1002/cssc.201802144DOI Listing
July 2019

Monomeric nickel hydroxide stabilized by a sterically demanding phosphorus-nitrogen PNP-pincer ligand: synthesis, reactivity and catalysis.

Dalton Trans 2018 Nov;47(45):16057-16065

KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.

A terminal nickel hydroxide complex (PN3P)Ni(OH) (3) bearing the 2nd generation phosphorus-nitrogen PN3P-pincer ligand has been synthesized and structurally characterized. As a nucleophile, 3 reacts with CO to afford the hydroxycarbonyl complex 4, (PN3P)Ni(COOH). 3 can also activate CO2 and CS2 to produce nickel bicarbonate (PN3P)Ni(OCOOH) (5) and bimetallic dithiocarbonate [(PN3P)NiS]2CO (6) respectively, as well as to promote aryl isocyanate and isothiocyanate insertion into the Ni-OH bond to give the corresponding (PN3P)NiEC(O)NHAr complexes (E = O, 7; E = S, 8). In addition, 3 catalyzes the nitrile hydration to various amides with well-defined intermediates (PN3P)Ni-NHC(O)R (R = Me, 9; R = Ph, 10).
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http://dx.doi.org/10.1039/c8dt03403fDOI Listing
November 2018

Structural space of intramolecular peptide disulfides: Analysis of peptide toxins retrieved from venomous peptide databases.

Comput Biol Chem 2017 Jun 15;68:194-203. Epub 2017 Mar 15.

Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi, 585367, Karnataka, India. Electronic address:

Structural space of intramolecular peptide disulfides is the combination of arrangement of even number of cysteine residues in single polypeptide and the disulfide isomers resulting from differential connectivity between cysteine residues. In the current report, we are documenting theoretical analysis and derivation of general formula [2×4] to predict possible distinct cysteine patterns for given 'n' even number of cysteine residues in a sequence. Combined formula of predicting distinct cysteine patterns and different disulfide isomers can be used to deduce the truly available structural space of intramolecular peptide disulfides, which may be used in structural analysis of disulfide rich peptides and proteins. In this report, we have also analyzed cysteine patterns and disulfide connectivities of peptide toxins, which is the largest group of intramolecular peptide disulfide natural products, retrieved from publically available animal toxin databases. Observed 29 distinct cysteine patterns of toxins exhibited 61 unique intramolecular disulfide folds, with limitation of having up to eight cysteine residues in a sequence, compared to theoretically available 170 different cysteine patterns generating 13,946 distinct intramolecular disulfide folds. Database analysis of peptide toxins has also revealed the features of presence of same intramolecular disulfide motif in functionally divergent peptide toxins and adaptation of the same disulfide fold with similar functions in different venomous species. Calculations of relative accessible surface area of cystine and average value of non-cysteine residues in the representative intramolecular disulfide folds of peptide toxins has revealed the feature of poor accessibility of cystine to external agents and their dependency on number of disulfide bonds in the sequence. Implementation of new generation sequencing methods and novel disulfide mapping techniques will unravel hidden diversity of intramolecular disulfide motifs of toxins and current report points to the selection of disulfide motifs in peptide toxins.
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http://dx.doi.org/10.1016/j.compbiolchem.2017.03.004DOI Listing
June 2017

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses.

Toxicology 2016 05 8;357-358:85-96. Epub 2016 Jun 8.

Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India. Electronic address:

Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-κB cascade takes on an alternative role that is correlated with increased immune-suppression.
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http://dx.doi.org/10.1016/j.tox.2016.06.005DOI Listing
May 2016

Magnitude of anthropogenic phosphorus storage in the agricultural production and the waste management systems at the regional and country scales.

Environ Sci Pollut Res Int 2016 Aug 8;23(16):15929-40. Epub 2016 Jun 8.

Business School, University of Glasgow, Scotland, UK.

Based on a systematic review of 17 recent substance flow analyses of phosphorus (P) at the regional and country scales, this study presents an assessment of the magnitude of anthropogenic P storage in the agricultural production and the waste management systems to identify the potential for minimizing unnecessary P storage to reduce the input of P as mineral fertilizer and the loss of P. The assessment indicates that in case of all (6) P flow analyses at the regional scale, the combined mass of annual P storage in the agricultural production and the waste management systems is greater than 50 % of the mass of annual P inflow as mineral fertilizer in the agricultural production system, while this is close to or more than 100 % in case of half of these analyses. At the country scale, in case of the majority (7 out of 11) of analyses, the combined mass of annual P storage in the agricultural production and the waste management systems has been found to be roughly equivalent or greater than 100 % of the mass of annual P inflow as mineral fertilizer in the agricultural production system, while it ranged from 30 to 60 % in the remaining analyses. A simple scenario analysis has revealed that the annual storage of P in this manner over 100 years could result in the accumulation of a massive amount of P in the agricultural production and the waste management systems at both the regional and country scales. This study suggests that sustainable P management initiatives at the regional and country scales should put more emphasis on minimizing unwanted P storage in the agricultural production and the waste management systems.
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http://dx.doi.org/10.1007/s11356-016-6930-8DOI Listing
August 2016

Gold-conjugated green tea nanoparticles for enhanced anti-tumor activities and hepatoprotection--synthesis, characterization and in vitro evaluation.

J Nutr Biochem 2015 Nov 26;26(11):1283-97. Epub 2015 Jul 26.

Department of Physiology, University of Calcutta; UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India. Electronic address:

Green tea (GT)-based chemoprevention has shown promising results in various cancer models. However, the effective dose may not be far from the toxic dose because of inefficient systemic delivery and limited bio-availability of GT polyphenols. We have used GT polyphenols to successfully reduce gold to corresponding gold nanoparticles (NPs) in a single step; a process that fulfils all criteria of green nanotechnology as no "man-made" chemical other than gold acids are used. GT and (-) - epigallocatechin-3-gallate (EGCG) conjugated gold NPs (diameters <50 nm), showed remarkable stability, significantly rapid cellular uptake and excellent in vitro anti-oxidant activities. These NPs were observed to be selectively toxic towards cancer cells (Ehrlich's Ascites Carcinoma and MCF-7) while showing absolutely no lethality towards normal primary mouse hepatocytes. In cancer cells, NPs altered the redox status and limited Nrf2 activation by almost 50%. These NPs significantly decreased nuclear translocation of NF-κB, coupled with decreased phosphorylation of IĸB and down-regulation of NF-κB-dependent anti-apoptotic proteins Bcl2 and Akt in a dose-dependent manner, triggering onset of apoptosis. Culturing normal hepatocytes with tumor-conditioned media prompted apoptosis by increasing reactive oxygen species (ROS) and depleting the anti-oxidant defense mechanism of hepatocytes. Pre-treatment with NPs protected hepatocytes from tumor-induced cellular damage by scavenging excess ROS, increasing the levels of reduced glutathione and anti-oxidant enzymes. There was evidence of decreased Bax/Bcl2 ratio and active Caspase 3 levels in these hepatocytes, indicating apoptosis escape. Nanoformulations of GT-based polyphenols might serve as an operative platform for effective delivery, increased bio-availability, enhanced effects and minimal chemotherapy-associated toxicities.
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http://dx.doi.org/10.1016/j.jnutbio.2015.06.003DOI Listing
November 2015

Analysis of lactate and malate dehydrogenase enzyme profiles of selected major carps of wetland of Calcutta.

J Environ Biol 2012 Jul;33(4):763-7

Department of Zoology, Bethune College, Kolkata--700 006, India.

The East Calcutta Wetland (ECW), a Ramsar site in India, acts as the only sink for both city sewages as well as effluents from the surrounding small-scale industries and is alarmingly polluted with heavy metals. The three best edible major carp species rohu (Labeo rohita,), catla (Catla catla,) and mrigala (Cirrhinus mrigala) were undertaken to monitor lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) by cellulose acetate electrophoresis (CAE) to assess the effects of pollutants, if any. Crude tissue extracts were prepared from brain, eye, heart, skeletal muscle and kidney tissue respectively from each type of fish. No differences were not found in MDH of catla from both sites for all tissues analyzed in this study. Rohu also showed similar mobility for all tissues except for heart tissue which was distinctly different in fishes from ECW site than that of its counterpart from non ECW site. On the other hand, MDH of two tissues of mrigala, eye and muscle respectively showed different migration patterns. LDH profiles for all tissues of three fish species from both the sites were consistently similar, only the expression levels of muscle LDH of mrigala and kidney LDH of rohu varied little.
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July 2012

Characterization of the recent clinical isolates of Indian Kala-azar patients by RAPD-PCR method.

J Parasit Dis 2011 Oct 24;35(2):116-22. Epub 2011 Jun 24.

Department of Zoology, Bethune College, 181, Bidhan Sarani, Kolkata, 700006 India.

Leishmaniasis is one of the most important vector borne diseases caused by kinetoplastid protozoa Leishmania sp. Among all forms of Leishmaniasis, Visceral leishmaniasis (VL) or Kala-azar is the severest form of the illness. VL is characterized by fever, hepatosplenomegaly, anaemia, edema, weight loss and invariably fatal if left untreated. Characterization of Leishmania sp. is extremely necessary to understand the epidemiology, taxonomy and population genetics of the parasites which ultimately helps in designing appropriate drug regimen to combat the disease. In this study, we aimed to type the clinical isolates of Leishmania species collected in the period 2006-2010 from patients (n = 9) diagnosed with Kala-azar and post Kala-azar dermal leishmaniasis (PKDL) by RAPD-PCR method using eight selected primers. Genome of the clinical isolates were amplified and electrophoresed in agarose gel. These were compared with the RAPD PCR profiles of WHO reference strains for L. donovani (DD8) and L. tropica (K27) respectively. We calculated the Jaccard's Similarity Coefficient and found one (study code T5) out of nine isolates as L. tropica while the rest were L. donovani. This pilot study supports the earlier single report claiming that both the species are responsible for Kala-azar in India and it also emphasizes the need for more systematic typing of clinical isolates of Indian Kala-azar.
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http://dx.doi.org/10.1007/s12639-011-0048-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235395PMC
October 2011

Radio-attenuated leishmanial parasites as immunoprophylactic agent against experimental murine visceral leishmaniasis.

Exp Parasitol 2012 Jan 12;130(1):39-47. Epub 2011 Oct 12.

Department of Zoology, Bethune College, 181 Bidhan Sarani, Kolkata 700 006, India.

The present study intends to evaluate the role of radio-attenuated leishmania parasites as immunoprophylactic agents for experimental murine visceral leishmaniasis. BALB/c mice were immunized with gamma (γ)-irradiated Leishmania donovani. A second immunization was given after 15 days of first immunization. After two immunizations, mice were infected with virulent L. donovani promastigotes. Protection against Kala-azar (KA) was estimated from spleen and liver parasitic burden along with the measurement of nitrite and superoxide anion generation by isolation of splenocytes and also by T-lymphocyte helper 1(Th1) and T-lymphocyte helper 2(Th2) cytokines release from the experimental groups. It was observed that BALB/c mice having prior immunization with radio-attenuated parasites showed protection against L. donovani infection through higher expression of Th1 cytokines and suppression of Th2 cytokines along with the generation of protective free radicals. The group of mice without prior priming with radio-attenuated parasites surrendered to the disease. Thus it can be concluded that radio-attenuated L. donovani may be used for.
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http://dx.doi.org/10.1016/j.exppara.2011.10.001DOI Listing
January 2012

Maternal autonomy and low birth weight in India.

J Womens Health (Larchmt) 2011 Sep 18;20(9):1373-82. Epub 2011 Jul 18.

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.

Background: The prevalence of low birth weight (LBW) is a major public health issue in India (30.0%) and is the highest among South-Asian countries. Maternal autonomy or the mother's status in the household indicates her decision-making power with respect to movement, finance, healthcare use, and other household activities. Evidence suggests that autonomy of the mother is significantly associated with the child's nutritional status. Although previous studies in India reported the determinants of LBW, literature on the association between mother's autonomy and birth weight are lacking. This study, therefore, aims to examine the influence of maternal autonomy on birth weight of the newborn.

Methods: The study, a secondary data analysis, examined data from the 2005-2006 National Health and Family Survey (NFHS 3) of India. A maternal autonomy score was created through proximal component factor analysis and categorized as high, medium, and low autonomy levels. The main outcome variable included birth weight of the index child obtained from health cards and mother's recall. Descriptive and logistic regression analyses were performed.

Results: Results from the study indicate that 20.0% of the index children included in the analysis were born at LBW. Low maternal autonomy was an independent predictor of LBW (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.07-1.53, p=0.007) after adjusting for other factors, and medium autonomy level was not significant.

Conclusions: These findings clearly indicate the importance of empowering women in India to combat the high incidence of LBW.
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http://dx.doi.org/10.1089/jwh.2010.2428DOI Listing
September 2011
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