Publications by authors named "Anupam Banerjee"

32 Publications

Estimating Change in Foldability Due to Multipoint Deletions in Protein Structures.

J Chem Inf Model 2020 12 22;60(12):6679-6690. Epub 2020 Nov 22.

Department of Computer Science and Engineering, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.

Insertions/deletions of amino acids in the protein backbone potentially result in altered structural/functional specifications. They can either contribute positively to the evolutionary process or can result in disease conditions. Despite being the second most prevalent form of protein modification, there are no databases or computational frameworks that delineate harmful multipoint deletions (MPD) from beneficial ones. We introduce a positive unlabeled learning-based prediction framework (PROFOUND) that utilizes fold-level attributes, environment-specific properties, and deletion site-specific properties to predict the change in foldability arising from such MPDs, both in the non-loop and loop regions of protein structures. In the absence of any protein structure dataset to study MPDs, we introduce a dataset with 153 MPD instances that lead to native-like folded structures and 7650 unlabeled MPD instances whose effect on the foldability of the corresponding proteins is unknown. PROFOUND on 10-fold cross-validation on our newly introduced dataset reports a recall of 82.2% (86.6%) and a fall out rate (FR) of 14.2% (20.6%), corresponding to MPDs in the protein loop (non-loop) region. The low FR suggests that the foldability in proteins subject to MPDs is not random and necessitates unique specifications of the deleted region. In addition, we find that additional evolutionary attributes contribute to higher recall and lower FR. The first of a kind foldability prediction system owing to MPD instances and the newly introduced dataset will potentially aid in novel protein engineering endeavors.
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http://dx.doi.org/10.1021/acs.jcim.0c00802DOI Listing
December 2020

Ebola Virus VP35 Protein: Modeling of the Tetrameric Structure and an Analysis of Its Interaction with Human PKR.

J Proteome Res 2020 11 18;19(11):4533-4542. Epub 2020 Sep 18.

Department of Computer Science and Engineering, Indian Institute of Technology Kharagpur, West Bengal 721302, India.

The Viral Protein 35 (VP35), a crucial protein of the Zaire Ebolavirus (EBOV), interacts with a plethora of human proteins to cripple the human immune system. Despite its importance, the entire structure of the tetrameric assembly of EBOV VP35 and the means by which it antagonizes the autophosphorylation of the kinase domain of human protein kinase R (PKR) is still elusive. We consult existing structural information to model a tetrameric assembly of the VP35 protein where 93% of the protein is modeled using crystal structure templates. We analyze our modeled tetrameric structure to identify interchain bonding networks and use molecular dynamics simulations and normal-mode analysis to unravel the flexibility and deformability of the different regions of the VP35 protein. We establish that the C-terminal of VP35 (VP35) directly interacts with PKR to prevent it from autophosphorylation. Further, we identify three plausible VP35-PKR complexes with better affinity than the PKR dimer formed during autophosphorylation and use protein design to establish a new stretch in VP35 that interacts with PKR. The proposed tetrameric assembly will aid in better understanding of the VP35 protein, and the reported VP35-PKR complexes along with their interacting sites will help in the shortlisting of small molecule inhibitors.
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http://dx.doi.org/10.1021/acs.jproteome.0c00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640970PMC
November 2020

Estimating the Effect of Single-Point Mutations on Protein Thermodynamic Stability and Analyzing the Mutation Landscape of the p53 Protein.

J Chem Inf Model 2020 06 21;60(6):3315-3323. Epub 2020 May 21.

Department of Computer Science and Engineering, Indian Institute of Technology Kharagpur, West Bengal 721302, India.

Nonsynonymous single-nucleotide polymorphisms often result in altered protein stability while playing crucial roles both in the evolution process and in the development of human diseases. Prediction of change in the thermodynamic stability due to such missense mutations will help in protein engineering endeavors and will contribute to a better understanding of different disease conditions. Here, we develop a machine-learning-based framework, viz., ProTSPoM, to estimate the change in protein thermodynamic stability arising out of single-point mutations (SPMs). ProTSPoM outperforms existing methods on the S2648 and S1925 databases and reports a Pearson correlation coefficient of 0.82 (0.88) and a root-mean-squared-error of 0.92 (1.06) kcal/mol between the predicted and experimental ΔΔ values on the long-established S350 (tumor suppressor p53 protein) data set. Further, we estimate the change in thermodynamic stability for all possible SPMs in the DNA binding domain of the p53 protein. We identify single-nucleotide polymorphisms in p53 which are plausibly detrimental to its structural integrity and interaction affinity with the DNA molecule. ProTSPoM with its reliable estimates and time-efficient prediction is well suited to be integrated with existing protein engineering techniques. The ProTSPoM web server is accessible at http://cosmos.iitkgp.ac.in/ProTSPoM/.
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http://dx.doi.org/10.1021/acs.jcim.0c00256DOI Listing
June 2020

Fire Safety Hazards: How Safe Are Our Hospitals?

Indian J Community Med 2020 Jan-Mar;45(1):104-105

Department of Community Medicine, PDU Government Medical College, Rajkot, Gujarat, India.

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http://dx.doi.org/10.4103/ijcm.IJCM_182_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985949PMC
February 2020

An Evolutionary Profile Guided Greedy Parallel Replica-Exchange Monte Carlo Search Algorithm for Rapid Convergence in Protein Design.

IEEE/ACM Trans Comput Biol Bioinform 2021 Mar-Apr;18(2):489-499. Epub 2021 Apr 8.

Protein design, also known as the inverse protein folding problem, is the identification of a protein sequence that folds into a target protein structure. Protein design is proved as an NP-hard problem. While researchers are working on designing heuristics with an emphasis on new scoring functions, we propose a replica-exchange Monte Carlo (REMC) search algorithm that ensures faster convergence using a greedy strategy. Using biological insights, we construct an evolutionary profile to encode the amino acid variability in different positions of the target protein from its structural homologs. The evolutionary profile guides the REMC search, and the greedy approach confirms appreciable exploration and exploitation of the sequence-structure fitness surface. We allow termination of a simulation trajectory once stagnant situation is detected. A series of sequence and structure level validations establish the goodness of our design. On a benchmark dataset, our algorithm reports an average root-mean-square deviation of 1.21Å between the target and the design proteins when modeled with an existing protein folding software. Besides, our algorithm assures 6.16 times overall speedup. In Molecular Dynamics simulations, we observe that four out of selected five design proteins report better to comparable stability to the corresponding target proteins.
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http://dx.doi.org/10.1109/TCBB.2019.2928809DOI Listing
April 2021

Delineation of crosstalk between HSP27 and MMP-2/MMP-9: A synergistic therapeutic avenue for glioblastoma management.

Biochim Biophys Acta Gen Subj 2019 07 25;1863(7):1196-1209. Epub 2019 Apr 25.

School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India. Electronic address:

Background: Epithelial to mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling, are the two elemental processes promoting glioblastoma (GBM). In the present work we propose a mechanistic modelling of GBM and in process establish a hypothesis elucidating critical crosstalk between heat shock proteins (HSPs) and matrix metalloproteinases (MMPs) with synergistic upregulation of EMT-like process and ECM remodeling.

Methods: The interaction and the precise binding site between the HSP and MMP proteins was assayed computationally, in-vitro and in GBM clinical samples.

Results: A positive crosstalk of HSP27 with MMP-2 and MMP-9 was established in both GBM patient tissues and cell-lines. This association was found to be of prime significance for ECM remodeling and promotion of EMT-like characteristics. In-silico predictions revealed 3 plausible interaction sites of HSP27 interacting with MMP-2 and MMP-9. Site-directed mutagenesis followed by in-vitro immunoprecipitation assay (IP) with 3 mutated recombinant HSP27, confirmed an interface stretch containing residues 29-40 of HSP27 to be a common interaction site for both MMP-2 and MMP-9. This was further validated with in-vitro IP of truncated (sans AA 29-40) recombinant HSP27 with MMP-2 and MMP-9.

Conclusion: The association of HSP27 with MMP-2 and MMP-9 proteins along with the identified interacting stretch has the potential to contribute towards drug development to inhibit GBM infiltration and migration.

General Significance: Current findings provide a novel therapeutic target for GBM opening a new horizon in the field of GBM management.
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http://dx.doi.org/10.1016/j.bbagen.2019.04.015DOI Listing
July 2019

Microscopic investigation of low dimensional magnet ScCuO: combined experimental and ab initio approach.

J Phys Condens Matter 2019 Jun 14;31(24):245802. Epub 2019 Mar 14.

Max Planck Institute for Chemical Physics of Solids, 01187 Dresden, Germany.

ScCuO is a non centro-symmetric oxide comprising of zig-zag chains made up of Cu ions in a distorted square planer coordination. We present here a combined experimental and theoretical investigation on this compound, which is based on magnetization, electron spin resonance (ESR), heat capacity as well as density functional theory (DFT) based calculations. Short range magnetic correlation prior to the long range order at [Formula: see text] K is evidenced by a broad hump like feature ([Formula: see text]43 K) found in the magnetic contribution of the heat capacity as well as by deviations from a regular Curie-Weiss behavior observed in the bulk magnetization and the Cu ESR intensity. The DFT results indicate the existence of ferro-orbital ordering at the Cu-sites, which gives rise to chain like arrangements of Cu ions along the crystallographic b axis. It also signifies complex nature of the spin structure with nonuniform magnetic interactions along the zig-zag chains. The ground state energy is found to be minimum for ferromagnetically coupled spin-dimers along the chains, whereas the adjacent chains are themselves antiferromagnetically coupled. The experimentally observed short range magnetic correlations possibly arise due to this chain like structure.
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http://dx.doi.org/10.1088/1361-648X/ab0fb0DOI Listing
June 2019

Analyzing Change in Protein Stability Associated with Single Point Deletions in a Newly Defined Protein Structure Database.

J Proteome Res 2019 03 18;18(3):1402-1410. Epub 2019 Feb 18.

Department of Structural Biology , Weizmann Institute of Science , Rehovot 76100 , Israel.

Protein backbone alternation due to insertion/deletion or mutation operation often results in a change of fundamental biophysical properties of proteins. The proposed work intends to encode the protein stability changes associated with single point deletions (SPDs) of amino acids in proteins. The encoding will help in the primary screening of detrimental backbone modifications before opting for expensive in vitro experimentations. In the absence of any benchmark database documenting SPDs, we curate a data set containing SPDs that lead to both folded conformations and unfolded state. We differentiate these SPD instances with the help of simple structural and physicochemical features and eventually classify the foldability resulting out of SPDs using a Random Forest classifier and an Elliptic Envelope based outlier detector. Adhering to leave one out cross validation, the accuracy of the Random Forest classifier and the Elliptic Envelope is of 99.4% and 98.1%, respectively. The newly defined database and the delineation of SPD instances based on its resulting foldability provide a head start toward finding a solution to the given problem.
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http://dx.doi.org/10.1021/acs.jproteome.9b00048DOI Listing
March 2019

Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies.

Prog Neurobiol 2019 03 30;174:53-89. Epub 2018 Dec 30.

Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India. Electronic address:

AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.
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http://dx.doi.org/10.1016/j.pneurobio.2018.12.006DOI Listing
March 2019

Hydroxychavicol sensitizes imatinib-resistant chronic myelogenous leukemia cells to TRAIL-induced apoptosis by ROS-mediated IAP downregulation.

Anticancer Drugs 2019 02;30(2):167-178

Department of Life Sciences, Presidency University, Kolkata, West Bengal.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of cytokine superfamily, induces apoptosis in a number of tumor cells through the activation of extrinsic apoptotic pathway but shows little or no cytotoxicity toward normal cells. However some tumor cells are inherently resistant to TRAIL-mediated apoptosis, which needs to be addressed to establish TRAIL as a potential chemotherapeutic drug. In this study, our aim was to manipulate TRAIL-apoptosis pathway by hydroxychavicol (HCH), a polyphenol from Piper betel leaf, for the induction of apoptosis in TRAIL resistant chronic myeloid leukemia cell. When imatinib-resistant K562 cells were treated with HCH, it made these K562 cells sensitive to TRAIL. It was observed that HCH downregulated antiapoptotic proteins XIAP and FLIP, whereas the expression of TRAIL receptors, DR4 and DR5, remains unchanged. Moreover, we observed that reactive oxygen species or ROS played a crucial role in the downregulation of FLIP and XIAP because ROS scavenger significantly reversed the decrease of XIAP, and FLIP. Ubiquitin-proteasome pathway was observed to play a crucial role in the downregulation of XIAP and FLIP, as proteasomal inhibitor MG132 significantly reversed the downregulation of XIAP and FLIP. In conclusion, this study demonstrates the combinatorial treatment of TRAIL and HCH as promising alternative therapeutic approach to treat the imatinib-resistant leukemia, which are also resistant to TRAIL.
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http://dx.doi.org/10.1097/CAD.0000000000000710DOI Listing
February 2019

A Comparative Study of Depression and Associated Risk Factors among Elderly Inmates of Old Age Homes and Community of Rajkot: A Gujarati Version of the Geriatric Depression Scale-Short Form (GDS-G).

Indian J Community Med 2017 Oct-Dec;42(4):204-208

Department of Community Medicine, P. D.U. Government Medical College, Rajkot, Gujarat, India.

Background: The prevalence of depression among elderly people varies across different setups such as old age homes (OAHs), community, and medical clinics.

Aims: The aim of this study was to compare the epidemiological factors pertaining to depression among elderly residents of OAHs and community, using a new Gujarati version of the Geriatric Depression Scale-Short Form (GDS-G).

Settings And Design: A cross-sectional, epidemiological study conducted in an urban setup of Western India.

Materials And Methods: All the eligible 88 elderly residents of all the six OAHs and 180 elderly residents from the same city were administered a pretested semistructured questionnaire having the GDS-G form.

Statistical Analysis: Descriptive statistics, odds ratio, Spearman's rank correlation test.

Results: The elderly of OAHs were more depressed compared to those of community (odds ratio = 1.84; 95% confidence interval = 1.09-3.06). Older age, females, weaker family ties, economic maladies, poorer self-perception of health status, presence of chronic ailments, absence of recreational activity, lack of prayers, impaired sleep, history of addiction emerged as the predictors of depression in both the setups. More health complaints and a later self-perception of visit to a doctor were found among the depressed than the nondepressed in both the setups.

Conclusions: Depressive symptoms were quite high among the elderly in both the setups. Special attention should be given toward health checkups of depressed persons in the OAH and improvement of family ties among depressed persons of the community.
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http://dx.doi.org/10.4103/ijcm.IJCM_181_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682718PMC
November 2017

Functional Studies of CCAAT/Enhancer Binding Protein Site Located Downstream of the Transcriptional Start Site.

Clin Med Insights Pathol 2017 15;10:1179555717694556. Epub 2017 Nov 15.

Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA.

Previous studies have identified a CCAAT/enhancer binding protein (C/EBP) site located downstream of the transcriptional start site (DS3). The role of the DS3 element with respect to HIV-1 transactivation by Tat and viral replication has not been characterized. We have demonstrated that DS3 was a functional C/EBPβ binding site and mutation of this site to the C/EBP knockout DS3-9C variant showed lower HIV-1 long terminal repeat (LTR) transactivation by C/EBPβ. However, it was able to exhibit similar or even higher transcription levels by Tat compared to the parental LTR. C/EBPβ and Tat together further enhanced the transcription level of the parental LAI-LTR and DS3-9C LTR, with higher levels in the DS3-9C LTR. HIV molecular clone viruses carrying the DS3-9C variant LTR demonstrated a decreased replication capacity and delayed rate of replication. These results suggest that DS3 plays a role in virus transcriptional initiation and provides new insight into C/EBP regulation of HIV-1.
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http://dx.doi.org/10.1177/1179555717694556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692137PMC
November 2017

Ebolavirus interferon antagonists-protein interaction perspectives to combat pathogenesis.

Brief Funct Genomics 2018 11;17(6):392-401

Department of Computer Science and Engineering, IIT Kharagpur, India.

Zaire ebolavirus, one of the most pathogenic species of Ebolavirus, is a significant threat to the human community being both highly infectious and lethal. The viral proteins (VPs), specifically VP24 and VP35, antagonize the interferon (IFN) proteins accountable for human immune response. Several efforts have been made to design vaccines and therapeutics drugs. However, the success is not encouraging because of limited knowledge about the binding site information of the VPs. Such limitations stem largely from the highly infectious nature of the virus that requires specialized personnel and biosafety laboratories. As an alternative, computational techniques have also been adopted to improve the success rate of drug discovery. This article elaborates on the interactions between viral and human IFN proteins that lead to IFN antagonism. A computational framework is proposed after evaluating existing computational studies. This protein interaction and protein design-based computational framework identified critical interacting residues of the VP (VP24) responsible for the formation of a stable complex with the human KPNA5 (karyopherin alpha proteins 5). The mutations of those critical residues, as demonstrated in this article, affected the overall stability of the complex because of a sharp decrease in both the number of hydrogen bonds and possible charge-charge interactions. Therefore, we proposed that the framework could be an effective alternative to experimental work for destabilizing interactions between the VPs and human proteins responsible for IFN induction and response.
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http://dx.doi.org/10.1093/bfgp/elx034DOI Listing
November 2018

A soft computing tool for species classification and prediction of glucomannan content in genus.

Eng Life Sci 2017 Dec 11;17(12):1254-1263. Epub 2017 Sep 11.

School of Chemical Engineering The University of New South Wales Sydney Australia.

The proposed work aims at designing a classification system for automatic identification of species, grown as a potential cash crop in many Asian countries, from the DNA fingerprints of genus. Four sets of 48 DNA fingerprints belonging to 37 species of the genus, developed with the help of four different primers are considered for the experiment, with an objective to identify only the fingerprints of the species of interest. A second experimental setup deals with the automatic classification of species containing high amounts of glucomannan from the same set of DNA fingerprints of the genus. For each set of 48 DNA fingerprints generated with a specific primer, the DNA fingerprints are preprocessed to extract a 42 dimensional feature vector which is used to generate a k-Nearest Neighbor based classifier based on the Leave One Out Cross Validation protocol. Final classification based on outputs from individual classifiers constructed with respect to the four different primers is performed according to a n-star consensus strategy. The n-star consensus predicts species with cent per cent accuracy while it predicts species containing glucomannan with a more modest accuracy of 81.25%.
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http://dx.doi.org/10.1002/elsc.201700040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999444PMC
December 2017

A Score-based Performance Assessment of Maternal and Child Health Services Provided by USHA of Rajkot City.

Indian J Community Med 2017 Apr-Jun;42(2):97-101

Department of Community Medicine, PDU Govt. Medical College, Rajkot, India.

Background: Urban Social Health Activists (USHAs) are the grass root health care workers of urban areas. There are 290 USHAs distributed in various Urban Health Centers (UHCs) of Rajkot city.

Objectives: To compare the (i) effectiveness of the training received by the USHAs on their knowledge and counseling skills (ii) knowledge and counseling skills of USHAs on the awareness and utilization of Maternal and Child Health (MCH) care services by their beneficiaries.

Methods: This cross-sectional study involved 32 USHAs and 416 beneficiaries served by the same USHAs. 32 USHAs serving in the same field practice area for more than two years were randomly selected. The beneficiaries were those mothers who had a child between 1-2 years age, and who had availed their antenatal and postnatal services in the same area. A scoring system was used to assess the knowledge and counseling skills of the USHAs and the knowledge and utilization of services by their beneficiaries.

Results: The utilization of health services was significantly more in the beneficiaries who were serviced by USHAs having comparatively better knowledge (72.7% vs. 35.3%) and counseling skills (62.2% vs. 30.6%). The median score for knowledge (41 vs. 30) and counseling skills (20 vs. 16) of the USHAs was found to be more ( < 0.05) in those who had undertaken induction training.

Conclusions: Induction training helped the USHAs to improve their knowledge and counseling skills. Utilization of MCH services was more in those areas served by USHAs having better knowledge and counseling skills.
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http://dx.doi.org/10.4103/0970-0218.205219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427870PMC
May 2017

cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells.

Clin Med Insights Pathol 2017 10;10:1179555717694535. Epub 2017 Mar 10.

Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA.

CD34 hematopoietic progenitor cells have been shown to be susceptible to HIV-1 infection, possibly due to a low-level expression of CXCR4, a coreceptor for HIV-1 entry. Given these observations, we have explored the impact of forskolin on cell surface expression of CXCR4 in a cell line model (TF-1). The elevation of intracellular cyclic adenosine monophosphate (cAMP) by forskolin through adenylyl cyclase (AC) resulted in transcriptional upregulation of CXCR4 with a concomitant increase in replication of the CXCR4-utilizing HIV-1 strain IIIB. Transient expression analyses also demonstrated an increase in CXCR4-, CCR5-, and CXCR4-/CCR5-utilizing HIV-1 (LAI, YU2, and 89.6, respectively) promoter activity. Studies also implicated the protein kinase A (PKA) pathway and the downstream transcription factor CREB-1 in interfacing with cAMP response elements located in the CXCR4 and viral promoter. These observations suggest that the cAMP signaling pathway may serve as a regulator of CXCR4 levels and concomitantly of HIV-1 replication in bone marrow (BM) progenitor cells.
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http://dx.doi.org/10.1177/1179555717694535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398651PMC
March 2017

Design, synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach.

Bioorg Chem 2016 12 11;69:102-120. Epub 2016 Oct 11.

Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India. Electronic address:

A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC 0.60-1.11μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.
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http://dx.doi.org/10.1016/j.bioorg.2016.10.003DOI Listing
December 2016

YY1 Is Required for Germinal Center B Cell Development.

PLoS One 2016 11;11(5):e0155311. Epub 2016 May 11.

Department of Biomedical Sciences, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, Pennsylvania 19104, United States of America.

YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863967PMC
July 2017

Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents.

Eur J Med Chem 2015 Aug 11;101:81-95. Epub 2015 Jun 11.

Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221 005, India. Electronic address:

A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 μM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme.
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http://dx.doi.org/10.1016/j.ejmech.2015.06.020DOI Listing
August 2015

Effect of μ-opioid agonist DAMGO on surface CXCR4 and HIV-1 replication in TF-1 human bone marrow progenitor cells.

BMC Res Notes 2014 Oct 23;7:752. Epub 2014 Oct 23.

Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N, 15th Street, MS# 1013A, Philadelphia, PA 19102, USA.

Background: Approximately one-third of the AIDS cases in the United States have been attributed to the use of injected drugs, frequently involving the abuse of opioids. Consequently, it is critical to address whether opioid use directly contributes to altered susceptibility to HIV-1 beyond the increased risk of exposure. Previous in vitro and in vivo studies addressing the role of μ-opioid agonists in altering levels of the co-receptor CXCR4 and subsequent HIV-1 replication have yielded contrasting results. The bone marrow is believed to be a potential anatomical sanctuary for HIV-1.

Methods: The well-characterized CD34+CD38+ human bone marrow-derived hematopoietic progenitor cell line TF-1 was used as a model to investigate the effects of the μ-opioid receptor-specific peptide DAMGO (D-Ala2,N-Me-Phe4, Gly5-ol-enkephalin) on CXCR4 expression as well as infection of undifferentiated human hematopoietic progenitor cells.

Results: The results revealed the presence of the μ-opioid receptor-1 isoform (MOR-1) on the surface of TF-1 cells. Furthermore, immunostaining revealed that the majority of TF-1 cells co-express MOR-1 and CXCR4, and a subpopulation of these double-positive cells express the two receptors in overlapping membrane domains. Three subpopulations of TF-1 cells were categorized based on their levels of surface CXCR4 expression, defined as non-, low-, and high-expressing. Flow cytometry indicated that treatment with DAMGO resulted in a shift in the relative proportion of CXCR4+ cells to the low-expressing phenotype. This result correlated with a >3-fold reduction in replication of the X4 HIV-1 strain IIIB, indicating a role for the CXCR4 high-expression subpopulation in sustaining infection within this progenitor cell line.

Conclusions: These experiments provide insight into the impact of μ-opioid exposure with respect to inhibition of viral replication in this human TF-1 bone marrow progenitor cell line model.
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http://dx.doi.org/10.1186/1756-0500-7-752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216373PMC
October 2014

Design, synthesis and pharmacological evaluation of N3 aryl/ heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7- dimethoxyquinazolin-4(3H)-ones as potential anticonvulsant agents.

Med Chem 2014 ;10(8):800-9

Department of Pharmaceutics, Indian Institute of Technology (BHU), Varanasi-221 005, India.

Novel N3 aryl/heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7-dimethoxyquinazolin-4(3H)- ones (8a-8l) were synthesized and evaluated for their anticonvulsant activity using various models of epilepsy, such as maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and intracerebroventricular AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The rotarod test has been used to determine the acute neurotoxicity. Further, the serum enzymatic activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed along with histopathological examination of liver. Among all the derivatives, compound 8f displayed significant activity profile based on the overall magnitude of activity and minimum neurotoxicity.
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http://dx.doi.org/10.2174/1573406410666140402152044DOI Listing
June 2015

Modeling Bone Marrow Progenitor Cell Differentiation and Susceptibility to HIV-1 Infection.

MOJ Immunol 2014;1(2):00009-9

Department of Microbiology and Immunology, and Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine Philadelphia, USA.

Human immunodeficiency virus type 1 (HIV-1) infection of the monocytic lineage is involved in the pathologic events associated with AIDS and HIV-1-associated dementia (HAD). Hematopoietic progenitor cells (HPCs) within the bone marrow are refractile to HIV-1 infection, while their progeny of the monocyte-macrophage lineage are susceptible. Previous studies, using phorbol-myristate-acetate (PMA) as a differentiating agent, have suggested that the CD34/CD38 TF-1 cell line may be used as one model to study the differentiation processes of HPCs. In the present study, medium that has been conditioned by PMA-treated TF-1 cells but is devoid of any traces of PMA, was utilized to induce differentiation of TF-1 cells. The conditioned medium (CM) from this bone marrow-derived cell population is enriched with respect to numerous cytokines and induces differentiation and activation of TF-1 cells, as indicated by changes in the expression of CD34, CD38, and CD69 cell surface molecules. Furthermore, treatment with CM was also shown to induce the expression of CCR5 and CXCR4, while maintaining the expression of CD4, which was ultimately correlated with increased susceptibility to HIV-1. Additionally, the activation of the TF-1 cells was shown to lead to increased LTR activity, with specificity protein (Sp) and nuclear factor kappa-light-chain-enhancer of activated B cells) NF-κB factors playing a crucial role in HIV-1 long terminal repeat (LTR)-mediated transcription and possibly overall TF-1 permissivity. Interleukin (IL)-1β, which is elevated in the CM, recapitulates some of the CM effects. In summary, these studies suggest that the TF-1 cell line could serve as a model to study the susceptibility of bone marrow progenitor cells to HIV-1 infection.
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http://dx.doi.org/10.15406/moji.2014.01.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517689PMC
January 2014

Transcriptional repression of Gata3 is essential for early B cell commitment.

Immunity 2013 May 16;38(5):930-42. Epub 2013 May 16.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6082, USA.

The mechanisms underlying the silencing of alternative fate potentials in very early B cell precursors remain unclear. Using gain- and loss-of-function approaches together with a synthetic Zinc-finger polypeptide (6ZFP) engineered to prevent transcription factor binding to a defined cis element, we show that the transcription factor EBF1 promotes B cell lineage commitment by directly repressing expression of the T-cell-lineage-requisite Gata3 gene. Ebf1-deficient lymphoid progenitors exhibited increased T cell lineage potential and elevated Gata3 transcript expression, whereas enforced EBF1 expression inhibited T cell differentiation and caused rapid loss of Gata3 mRNA. Notably, 6ZFP-mediated perturbation of EBF1 binding to a Gata3 regulatory region restored Gata3 expression, abrogated EBF1-driven suppression of T cell differentiation, and prevented B cell differentiation via a GATA3-dependent mechanism. Furthermore, EBF1 binding to Gata3 regulatory sites induced repressive histone modifications across this region. These data identify a transcriptional circuit critical for B cell lineage commitment.
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http://dx.doi.org/10.1016/j.immuni.2013.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664383PMC
May 2013

Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis.

J Neurovirol 2011 Aug 7;17(4):291-302. Epub 2011 Jul 7.

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.

About one third of acquired immunodeficiency syndrome cases in the USA have been attributed to the use of injected addictive drugs, frequently involving opioids like heroin and morphine, establishing them as significant predisposing risk factors for contracting human immunodeficiency virus type 1 (HIV-1). Accumulating evidence from in vitro and in vivo experimental systems indicates that opioids act in concert with HIV-1 proteins to exacerbate dysregulation of neural and immune cell function and survival through diverse molecular mechanisms. In contrast, the impact of opioid exposure and withdrawal on the viral life cycle and HIV-1 disease progression itself is unclear, with conflicting reports emerging from the simian immunodeficiency virus and simian-human immunodeficiency virus infection models. However, these studies suggest a potential role of opioids in elevated viral production. Because human microglia, astrocytes, CD4+ T lymphocytes, and monocyte-derived macrophages express opioid receptors, it is likely that intracellular signaling events triggered by morphine facilitate enhancement of HIV-1 infection in these target cell populations. This review highlights the biochemical changes that accompany prolonged exposure to and withdrawal from morphine that synergize with HIV-1 proteins to disrupt normal cellular physiological functions especially within the central nervous system. More importantly, it collates evidence from epidemiological studies, animal models, and heterologous cell systems to propose a mechanistic link between such physiological adaptations and direct modulation of HIV-1 production. Understanding the opioid-HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids.
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http://dx.doi.org/10.1007/s13365-011-0037-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757547PMC
August 2011

Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway.

Biomed Pharmacother 2011 Jul 30;65(4):293-7. Epub 2011 May 30.

Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N. 15th Street, MS# 1013A, Philadelphia, Pennsylvania 19102, USA.

The cyclic adenosine monophosphate (cAMP)-dependent signaling pathway directs the expression of several genes involved in diverse neuroendocrine, immune, metabolic, and developmental pathways. The primary effectors of this pathway are members of the cAMP response element binding (CREB) family of transcription factors, in particular the CREB-1 and cAMP response element modulator (CREM). Both these genes encode alternative splice variants that serve as activators or repressors in a context- and position-specific manner. Although the β-chemokine receptor CC chemokine receptor 5 (CCR5) has been identified on progenitor cells in the bone marrow, the regulatory mechanisms orchestrating its expression are not fully understood. Previous reports have identified putative cAMP response elements in the CCR5 promoter and have described a suppressive role of cAMP in CCR5 expression. In this study, the CD34+CD4+CCR5+ human bone marrow progenitor cell line TF-1 was used to investigate the detailed kinetics of CCR5 transcription in response to the elevation of intracellular cAMP levels and the underlying molecular events. We hypothesize that CCR5 transcription follows an asymmetrical sinusoidal pattern in TF-1 cells that parallels a protein kinase A-dependent alternating change in the ratio of activator pCREB-1-α,Δ to repressor pCREM-α,β isoforms. However, elevated CCR5 mRNA levels do not correlate with enhancement in infectivity with respect to the R5 human immunodeficiency virus type 1 (HIV-1) strain. Our results lend critical insight into the precise mechanism governing the cAMP-CCR5 axis in progenitor cells and pose interesting questions regarding its functional role in HIV-1 infection.
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http://dx.doi.org/10.1016/j.biopha.2011.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150495PMC
July 2011

Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency virus type 1 subtype C LTR.

Biomed Pharmacother 2010 Dec 25;64(10):672-80. Epub 2010 Sep 25.

Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, USA.

Human immunodeficiency virus type 1 (HIV-1) subtype C, which is most predominant in sub-Saharan Africa as well as in Asia and India, is the most prevalent subtype worldwide. A large number of transcription factor families have been shown to be involved in regulating HIV-1 gene expression in T lymphocytes and cells of the monocyte-macrophage lineage. Among these, proteins of the CCAAT/enhancer binding protein (C/EBP) family are of particular importance in regulating HIV-1 gene expression within cells of the monocytic lineage during the course of hematologic development and cellular activation. Few studies have examined the role of C/EBPs in long terminal repeat (LTR)-directed viral gene expression of HIV-1 subtypes other than subtype B. Within subtype B viruses, two functional C/EBP sites located upstream of the TATA box are required for efficient viral replication in cells of the monocyte-macrophage lineage. We report the identification of three putative subtype C C/EBP sites, upstream site 1 and 2 (C-US1 and C-US2) and downstream site 1 (C-DS1). C-US1 and C-DS1 were shown to form specific DNA-protein complexes with members of the C/EBP family (C/EBPα, β, and δ). Functionally, within the U-937 monocytic cell line, subtype B and C LTRs were shown to be equally responsive to C/EBPβ-2, although the basal activity of subtype C LTRs appeared to be higher. Furthermore, the synergistic interaction between C/EBPβ-2 and Tat with the subtype C LTR was also observed in U-937 cells as previously demonstrated with the subtype B LTR.
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http://dx.doi.org/10.1016/j.biopha.2010.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998390PMC
December 2010

Uptake studies of environmentally hazardous (51)Cr in Mung beans.

Environ Pollut 2008 Jan 27;151(2):423-7. Epub 2007 Jul 27.

Department of Botany, University of Calcutta, Kolkata, India.

Attempt has been made to study the accumulation behaviour of a common plant, Mung bean (Vigna radiata) towards Cr(III) and Cr(VI) to have an insight on the migration and bio-magnification of Cr. For this purpose healthy germinated Mung bean seeds were sown in the sand in the presence of Hoagland's nutrient solution containing measured amount of K(2)(51)Cr(2)O(7) and (51)Cr(NO(3))(3).9H(2)O. Growth rate was also studied in the presence and absence of phosphate salts in the medium. It has been found that the transfer of chromium from soil to plant is significantly low (maximum 5% for both Cr(III) and Cr(VI)). Maximum accumulation of Cr occurs in the root with respect to the total chromium accumulation by the plant. Other parts of the Mung bean plant, e.g. cotyledons, shoot and leaves, show negligible accumulation. Therefore, the chance of direct intake of Cr through food as well as through the grazing animals to human body is less.
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http://dx.doi.org/10.1016/j.envpol.2007.06.028DOI Listing
January 2008

Separation of no-carrier-added 66,67Ga produced in heavy ion-induced cobalt target using alginate biopolymers.

Appl Radiat Isot 2007 Aug 14;65(8):891-6. Epub 2007 Apr 14.

Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata-700064, India.

Heavy ion activation of natural cobalt foil with 84MeV (12)C results in the formation of no-carrier-added (nca) (66,67)As radionuclides, along with their corresponding decay products, (66,67)Ge and (66,67)Ga, in the matrix. Because arsenic and germanium radionuclides are short-lived, after a cooling period of 10h only nca gallium radionuclides remain in the matrix. We attempted to separate the nca gallium radionuclides from the target matrix cobalt by biopolymeric calcium alginate (CA) and Fe-doped calcium alginate (Fe-CA) beads. A complete separation has been achieved by adsorbing (66,67)Ga and a lesser amount of bulk cobalt at pH 3 on Fe-CA beads, followed by desorbing cobalt from the beads with 0.4M NaNO(2).
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http://dx.doi.org/10.1016/j.apradiso.2007.03.019DOI Listing
August 2007

Speciation-dependent studies on removal of arsenic by iron-doped calcium alginate beads.

Appl Radiat Isot 2007 Jul 12;65(7):769-75. Epub 2007 Mar 12.

Department of Botany, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.

This work aims to study the differential attitude of Fe-doped calcium alginate (Fe-CA) beads towards As(III) and As(V) compounds so that speciation-dependent environmentally sustainable methodologies can be developed for removal of arsenic from contaminated water. Throughout the experiment, (76)As has been used as precursor of stable arsenic. The affinity of As(V) towards the Fe-CA beads is greater than that of As(III). Removal efficiency of Fe-CA beads for As(V) increases with increasing number of beads and longer shaking times. At pH 3, 30 Fe-CA beads remove As(V) completely from a solution containing 20mgkg(-1) As(V). The technique has been successfully applied to the ground water collected from an arsenic-contaminated area.
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http://dx.doi.org/10.1016/j.apradiso.2007.02.007DOI Listing
July 2007