Publications by authors named "Vivek Rai"

43 Publications

Genetic effects on liver chromatin accessibility identify disease regulatory variants.

Am J Hum Genet 2021 Jul 25;108(7):1169-1189. Epub 2021 May 25.

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.001DOI Listing
July 2021

Atx regulates skeletal muscle regeneration via LPAR1 and promotes hypertrophy.

Cell Rep 2021 Mar;34(9):108809

Institute of Life Sciences (An Autonomous Institute of Department of Biotechnology), Bhubaneswar 751023, India. Electronic address:

Muscle differentiation is a multifaceted and tightly controlled process required for the formation of skeletal muscle fibers. Satellite cells are the direct cellular contributors to muscle repair in injuries or disorders. Here, we show that autotaxin (Atx) expression and activity is required for satellite cell differentiation. Conditional ablation of Atx or its pharmacological inhibition impairs muscle repair. Mechanistically, we identify LPAR1 as the key receptor in Atx-LPA signaling. Myogenic gene array and pathway analysis identified that Atx-LPA signaling activates ribosomal protein S6 kinase (S6K), an mTOR-dependent master regulator of muscle cell growth via LPAR1. Furthermore, Atx transgenic mice show muscle hypertrophic effects and accelerated regeneration. Intramuscular injections of Atx/LPA show muscle hypertrophy. In addition, the regulatory effects of Atx on differentiation are conserved in human myoblasts. This study identifies Atx as a critical master regulator in murine and human muscles, identifying a promising extracellular ligand in muscle formation, regeneration, and hypertrophy.
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http://dx.doi.org/10.1016/j.celrep.2021.108809DOI Listing
March 2021

Endovascular thrombectomy time metrics in the era of COVID-19: observations from the Society of Vascular and Interventional Neurology Multicenter Collaboration.

J Neurointerv Surg 2021 Feb 8. Epub 2021 Feb 8.

Cooper Neurological Institute, Cooper University Health Care, Camden, New Jersey, USA

Background: Unprecedented workflow shifts during the coronavirus disease 2019 (COVID-19) pandemic have contributed to delays in acute care delivery, but whether it adversely affected endovascular thrombectomy metrics in acute large vessel occlusion (LVO) is unknown.

Methods: We performed a retrospective review of observational data from 14 comprehensive stroke centers in nine US states with acute LVO. EVT metrics were compared between March to July 2019 against March to July 2020 (primary analysis), and between state-specific pre-peak and peak COVID-19 months (secondary analysis), with multivariable adjustment.

Results: Of the 1364 patients included in the primary analysis (51% female, median NIHSS 14 [IQR 7-21], and 74% of whom underwent EVT), there was no difference in the primary outcome of door-to-puncture (DTP) time between the 2019 control period and the COVID-19 period (median 71 vs 67 min, P=0.10). After adjustment for variables associated with faster DTP, and clustering by site, there remained a trend toward shorter DTP during the pandemic (β=-73.2, 95% CI -153.8-7.4, Pp=0.07). There was no difference in DTP times according to local COVID-19 peaks vs pre-peak months in unadjusted or adjusted multivariable regression (β=-3.85, 95% CI -36.9-29.2, P=0.80). In this final multivariable model (secondary analysis), faster DTP times were significantly associated with transfer from an outside institution (β=-46.44, 95% CI -62.8 to - -30.0, P<0.01) and higher NIHSS (β=-2.15, 95% CI -4.2to - -0.1, P=0.05).

Conclusions: In this multi-center study, there was no delay in EVT among patients treated for intracranial occlusion during the COVID-19 era compared with the pre-COVID era.
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http://dx.doi.org/10.1136/neurintsurg-2020-017205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871225PMC
February 2021

Decline in mild stroke presentations and intravenous thrombolysis during the COVID-19 pandemic: The Society of Vascular and Interventional Neurology Multicenter Collaboration.

Clin Neurol Neurosurg 2021 02 15;201:106436. Epub 2020 Dec 15.

Cooper Neurological Institute, Cooper University Hospital, Camden, NJ, 08103, USA.

Background: To evaluate overall ischemic stroke volumes and rates, specific subtypes, and clinical presentation during the COVID-19 pandemic in a multicenter observational study from eight states across US.

Methods: We compared all ischemic strokes admitted between January 2019 and May 2020, grouped as; March-May 2020 (COVID-19 period) and March-May 2019 (seasonal pre-COVID-19 period). Primary outcome was stroke severity at admission measured by NIHSS stratified as mild (0-7), moderate [8-14], and severe (>14). Secondary outcomes were volume of large vessel occlusions (LVOs), stroke etiology, IV-tPA rates, and discharge disposition.

Results: Of the 7969 patients diagnosed with acute ischemic stroke during the study period, 933 (12 %) presented in the COVID-19 period while 1319 (17 %) presented in the seasonal pre-COVID-19 period. Significant decline was observed in the mean weekly volumes of newly diagnosed ischemic strokes (98 ± 3 vs 50 ± 20,p = 0.003), LVOs (16.5 ± 3.8 vs 8.3 ± 5.9,p = 0.008), and IV-tPA (10.9 ± 3.4 vs 5.3 ± 2.9,p = 0.0047), whereas the mean weekly proportion of LVOs (18 % ±5 vs 16 % ±7,p = 0.24) and IV-tPA (10.4 % ±4.5 vs. 9.9 % ±2.4,p = 0.66) remained the same, when compared to the seasonal pre-COVID-19 period. Additionally, an increased proportion of patients presented with a severe disease (NIHSS > 14) during the COVID-19 period (29.7 % vs 24.5 %,p < 0.025). The odds of being discharged to home were 26 % greater in the COVID-19 period when compared to seasonal pre-COVID-19 period (OR:1.26, 95 % CI:1.07-1.49,p = 0.016).

Conclusions: During COVID-19 period there was a decrease in volume of newly diagnosed ischemic stroke cases and IV-tPA administration. Patients admitted to the hospital had severe neurological clinical presentation and were more likely to discharge home.
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http://dx.doi.org/10.1016/j.clineuro.2020.106436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836428PMC
February 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Influence of the COVID-19 Pandemic on Treatment Times for Acute Ischemic Stroke: The Society of Vascular and Interventional Neurology Multicenter Collaboration.

Stroke 2021 01 30;52(1):40-47. Epub 2020 Nov 30.

Department of Neurology, University of Pittsburgh Medical Center Mercy Hospital, PA (S.M.D., A.P.J.).

Background And Purpose: The pandemic caused by the novel coronavirus disease 2019 (COVID-19) has led to an unprecedented paradigm shift in medical care. We sought to evaluate whether the COVID-19 pandemic may have contributed to delays in acute stroke management at comprehensive stroke centers.

Methods: Pooled clinical data of consecutive adult stroke patients from 14 US comprehensive stroke centers (January 1, 2019, to July 31, 2020) were queried. The rate of thrombolysis for nontransferred patients within the Target: Stroke goal of 60 minutes was compared between patients admitted from March 1, 2019, and July 31, 2019 (pre-COVID-19), and March 1, 2020, to July 31, 2020 (COVID-19). The time from arrival to imaging and treatment with thrombolysis or thrombectomy, as continuous variables, were also assessed.

Results: Of the 2955 patients who met inclusion criteria, 1491 were admitted during the pre-COVID-19 period and 1464 were admitted during COVID-19, 15% of whom underwent intravenous thrombolysis. Patients treated during COVID-19 were at lower odds of receiving thrombolysis within 60 minutes of arrival (odds ratio, 0.61 [95% CI, 0.38-0.98]; =0.04), with a median delay in door-to-needle time of 4 minutes (=0.03). The lower odds of achieving treatment in the Target: Stroke goal persisted after adjustment for all variables associated with earlier treatment (adjusted odds ratio, 0.55 [95% CI, 0.35-0.85]; <0.01). The delay in thrombolysis appeared driven by the longer delay from imaging to bolus (median, 29 [interquartile range, 18-41] versus 22 [interquartile range, 13-37] minutes; =0.02). There was no significant delay in door-to-groin puncture for patients who underwent thrombectomy (median, 83 [interquartile range, 63-133] versus 90 [interquartile range, 73-129] minutes; =0.30). Delays in thrombolysis were observed in the months of June and July.

Conclusions: Evaluation for acute ischemic stroke during the COVID-19 period was associated with a small but significant delay in intravenous thrombolysis but no significant delay in thrombectomy time metrics. Taking steps to reduce delays from imaging to bolus time has the potential to attenuate this collateral effect of the pandemic.
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http://dx.doi.org/10.1161/STROKEAHA.120.032789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934334PMC
January 2021

Lysophosphatidic acid-RAGE axis promotes lung and mammary oncogenesis via protein kinase B and regulating tumor microenvironment.

Cell Commun Signal 2020 10 27;18(1):170. Epub 2020 Oct 27.

Laboratory of Vascular Immunology, Institute of Life Sciences, (An Autonomous Institute of Department of Biotechnology (DBT) New Delhi), Bhubaneswar, 751023, India.

Background: Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor of the immunoglobulin superfamily. Lysophosphatidic acid (LPA) is a ligand for RAGE and is involved in physiological and pathophysiological conditions including cancer. However, RAGE-LPA axis is unexplored in lung and mammary cancer.

Methods: RAGE was silenced in A549, MDA MB-231 and MCF7 using RAGE shRNA. For in vitro tumorigenesis, we performed wound healing, colony formation, cell proliferation and invasion assays. Evaluation of expression of oncogenes, EMT markers and downstream signaling molecules was done by using western blot and immunohistochemistry. For subcellular expression of RAGE, immunofluorescence was done. In vivo tumorigenesis was assessed by intraperitoneal injection of cancer cells in nude mice.

Results: Here we show RAGE mediated profound increase in proliferation, migration and invasion of lung and mammary cancer cells via LPA in Protein kinase B (PKB) dependent manner. LPA mediated EMT transition is regulated by RAGE. In vivo xenograft results show significance of RAGE in LPA mediated lung and mammary tumor progression, angiogenesis and immune cell infiltration to tumor microenvironment.

Conclusion: Our results establish the significance and involvement of RAGE in LPA mediated lung and mammary tumor progression and EMT transition via RAGE. RAGE-LPA axis may be a therapeutic target in lung and mammary cancer treatment strategies. Video Abstract.
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http://dx.doi.org/10.1186/s12964-020-00666-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592382PMC
October 2020

RAGE and its ligands: from pathogenesis to therapeutics.

Crit Rev Biochem Mol Biol 2020 12 16;55(6):555-575. Epub 2020 Sep 16.

Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India.

Receptor for advanced glycation end products (RAGE) is an immunoglobulin-like receptor present on cell surface. RAGE binds to an array of structurally diverse ligands, acts as a pattern recognition receptor (PRR) and is expressed on cells of different origin performing different functions. RAGE ligation leads to the initiation of a cascade of signaling events and is implicated in diseases, such as inflammation, cancer, diabetes, vascular dysfunctions, retinopathy, and neurodegenerative diseases. Because of the significant involvement of RAGE in the progression of numerous diseases, RAGE signaling has been targeted through use of inhibitors and anti-RAGE antibodies as a treatment strategy and therapy. Here in this review, we have summarized the physical and physiological aspects of RAGE biology in mammalian system and the importance of targeting this molecule in the treatment of various RAGE mediated pathologies. Highlights Receptor for advanced glycation end products (RAGE) is a member of immunoglobulin superfamily of receptors and involved in many pathophysiological conditions. RAGE ligation with its ligands leads to initiation of distinct signaling cascades and activation of numerous transcription factors. Targeting RAGE signaling through inhibitors and anti-RAGE antibodies can be promising treatment strategy.
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http://dx.doi.org/10.1080/10409238.2020.1819194DOI Listing
December 2020

MYH9 suppresses melanoma tumorigenesis, metastasis and regulates tumor microenvironment.

Med Oncol 2020 Sep 9;37(10):88. Epub 2020 Sep 9.

Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, 751023, India.

Non-muscle myosin IIA heavy chain (MYH9) has been implicated in many physiological and pathological functions including cell adhesion, polarity, motility to cancer. However, its role in melanoma remains unexplored. The aim of our study was to evaluate the role of MYH9 in melanoma tumor development and metastasis and further to find out the potential underlying mechanisms. In this study, we evaluated the in vitro migratory and invasive properties and in vivo tumor development and metastasis in C57BL/6 mice by silencing MYH9 in B16F10 melanoma cells. Knocking down MYH9 enhanced migration and invasiveness of B16F10 cells in vitro. Furthermore, MYH9 silencing accelerated tumor growth and metastasis in melanoma subcutaneous and intravenous mouse models. Next, oncogenes analysis revealed epithelial-mesenchymal transition and Erk signaling pathway are being regulated with MYH9 expression. Finally, MYH9 silencing in B16F10 cells modulates the tumor microenvironment by manipulating the leukocytes and macrophages infiltration in tumors. These findings established the opposing role of MYH9 as a tumor suppressor in melanoma suggesting specific MYH9 based approaches in therapeutics.
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http://dx.doi.org/10.1007/s12032-020-01413-6DOI Listing
September 2020

Single-cell ATAC-Seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures.

Mol Metab 2020 02 20;32:109-121. Epub 2019 Dec 20.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:

Objective: Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome-wide association studies (GWAS) have identified > 400 independent signals that encode genetic predisposition. More than 90% of associated single-nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express distinct hormonal programs, so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity.

Methods: We present genome-wide single-cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on U-Net architecture to accurately predict open chromatin peak calls in rare cell populations.

Results: We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, T2D GWAS SNPs are significantly enriched in beta cell-specific and across cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep learning models can improve signal recovery and feature reconstruction of rarer cell populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals.

Conclusions: Collectively, we identify the islet cell type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways.
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http://dx.doi.org/10.1016/j.molmet.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961712PMC
February 2020

Sequenceserver: A Modern Graphical User Interface for Custom BLAST Databases.

Mol Biol Evol 2019 12;36(12):2922-2924

School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.

Comparing newly obtained and previously known nucleotide and amino-acid sequences underpins modern biological research. BLAST is a well-established tool for such comparisons but is challenging to use on new data sets. We combined a user-centric design philosophy with sustainable software development approaches to create Sequenceserver, a tool for running BLAST and visually inspecting BLAST results for biological interpretation. Sequenceserver uses simple algorithms to prevent potential analysis errors and provides flexible text-based and visual outputs to support researcher productivity. Our software can be rapidly installed for use by individuals or on shared servers.
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http://dx.doi.org/10.1093/molbev/msz185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878946PMC
December 2019

Hypoplastic left heart syndrome [HLHS]: treatment options in present era.

Indian J Thorac Cardiovasc Surg 2019 Apr 31;35(2):196-202. Epub 2018 Oct 31.

Department of Pediatric Cardiac Surgery, Jagiellonian University Children's Hospital, Ul. Wielicka 265, 30-663 Krakow, Poland.

Hypoplastic left heart syndrome (HLHS) is the most severe form of congenital heart defect (CHD). The first successful intervention for it was undertaken by Norwood in 1983. Since then, there have been much development in the pre, intra, and postoperative treatment option in staged palliative surgical procedures. Early diagnostic management, prenatal interventions, innovative diagnostic methods, constantly modified surgical techniques, and hybridization contribute to a significant progress in treatment options. This will allow for defining an optimal strategy of improving survival and quality of life in HLHS patients. The development of intervention cardiology makes possible the stepwise treatment of the defect with one operation only. The first and third stage may be done by hybrid or interventional methods, then only the second stage of treatment needs to be done surgically. The world experience and all the available literature says that the 1st-stage procedure could be done now safely either directly or with a bridge to Norwood followed by the stage 2 with a Glen or Hemi-Fontan and followed by a Fontan down the lane surgically.
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http://dx.doi.org/10.1007/s12055-018-0742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525540PMC
April 2019

Risk factors for recoarctation of aorta after Norwood procedure in patients with hypoplastic left heart syndrome.

Folia Med Cracov 2018;58(3):11-21

Department of Pediatric Cardiac Surgery, University Children's Hospital, Jagiellonian University Medical College, Wielicka 265, Kraków, Poland.

Background: Recoarctation (reCoA) of the aorta is a common complication afer the Norwood procedure. Untreated, it can lead to failure of the systemic ventricle and death. The main goal of the study is to define risk factors of reCoA after the Norwood procedure in hypoplastic left heart syndrome (HLHS).

Methods: We retrospectively analyzed the pre-, intra- and postoperative data of 96 successive patients who underwent the Norwood procedure between 2007 and 2011. In case of reCoA balloon angioplasty was performed. We analyzed and compared the data of the patients with reCoA and without reCoA using the StatSo STATISTICA TM 10 software.

Results: ReCoA was noted in 23 patients (33.3%). This complication was diagnosed 95.1 days (49-156 days) on the average a er the Norwood procedure. Balloon angioplasty successfully allowed for decreasing the mean gradient across the site of the narrowing from the average 27.5 mmHg to the average 9.7 mmHg (p = 0.008) and enlarged the neo-isthmus by the average of 2 mm (p <0.05). The risks factors seemed to be the diameter of the ascending aorta OR = 7.82 (p = 0.001), atresia of the mitral valve OR = 7.00 (p = 0.003) and atresia of the aortic valve - OR = 6.22 (p = 0.002).

Conclusion: Balloon angioplasty seems to be an effective intervention in case of reCoA. A low diameter of the native ascending aorta (<=3mm) and the presence of atresia of the mitral and/or aortic valve should intensify the vigilance of a cardiologist in the search for signs of reCoA of the aorta.
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http://dx.doi.org/10.24425/fmc.2018.125070DOI Listing
October 2019

Initial experience with intracorporeal continuous ow LVAD in pediatric patients in Poland.

Folia Med Cracov 2018;58(2):57-66

Department of Pediatric Cardiac Surgery, Jagiellonian University Children's Hospital, Wielicka 265, Kraków,

The Aim: The aim of the study is to present the initial experience with continuous flow left ventricle assist device (CF-LVAD) in pediatric patients with BSA below 1.5 m2.

Material And Methods: Between 2016 and 2017, CF-LVAD (the Heartware System) have been implanted in three pediatric patients in the Department of Pediatric Cardiac Surgery, Jagiellonian University, Krakow, Poland. The indications for initiating CF-LVAD were end-stage congestive heart failure due to dilated cardiomyopathy in all children.

Results: Implanted patients have had BSA of 1.09, 1.42, 1.2 m2, and 37, 34, 34 kg of body weight and the age 12, 11, 12 years, respectively. The time of support was 550 days in two patients and 127 in another one, and is ongoing. The main complication has been driveline infection.

Conclusion: The outcomes from our single-center experience using the HeartWare CF-LVAD have been excellent with a low incidence of complication and no necessity to reoperation in our patients. Children could be successfully and safely discharged home.
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http://dx.doi.org/10.24425/fmc.2018.124658DOI Listing
September 2019

Cysteine mediated disulfide bond formation in RAGE V domain facilitates its functionally relevant dimerization.

Biochimie 2018 Nov 1;154:55-61. Epub 2018 Aug 1.

Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, 751023, India. Electronic address:

Receptor for Advanced Glycation End product (RAGE) is a multiligand receptor implicated in diverse pathological conditions such as diabetes, atherosclerosis, cancer and neural diseases. Extracellular, RAGE consists of V, C1 and C2 domains. Here, we show RAGE exists as a monomer in equilibrium with a fraction of a covalently linked dimer of monomers via its V domain through cysteine. In order to understand the functional implication of this dimer, we examined the binding capacity and functional potential of RAGE dimer via advanced glycation end products (AGEs) which shows enhanced binding capacity towards V domain, ERK phosphorylation, cytokine release and actin polymerization ability of the dimeric form for AGEs compared with the reduced monomeric form. Our data, suggests that the dimeric state of RAGE controls its function and ligand mediated signaling which may play important role in RAGE mediated various diseases.
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http://dx.doi.org/10.1016/j.biochi.2018.07.024DOI Listing
November 2018

Outcome of Norwood operation for hypoplastic left heart syndrome.

Indian J Thorac Cardiovasc Surg 2018 Jul 22;34(3):337-344. Epub 2017 Nov 22.

Department of Pediatric Cardiac Surgery, Jagiellonian University Children's Hospital, Krakow, Poland.

Purpose: The Norwood procedure, the first surgical step of staged palliation for hypoplastic left heart syndrome (HLHS), is also applied for other complex single ventricle lesions. This study aimed to evaluate the outcome of the Norwood operation in a single center over 4 years and to identify clinical and anatomic risk factors for overall mortality.

Methods: A retrospective review of the pediatric cardiovascular surgery database was performed to identify infants with HLHS who underwent NP (Norwood procedure) at our institution between January 2007 and December 2011. Our study population consisted of 85 patients with HLHS.

Results: Early mortality (30 days postoperative period) between January 2007 and December 2011 for Norwood operation was 7 (8.2%) out of 85 patient, and overall mortality was 24 (28.2%).

Conclusion: Our single-center experience shows that the Norwood operation can be performed for complex single ventricle lesions with similarly good early outcomes regardless of the underlying anatomy.
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http://dx.doi.org/10.1007/s12055-017-0603-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525726PMC
July 2018

Lysophosphatidic acid converts monocytes into macrophages in both mice and humans.

Blood 2017 03 9;129(9):1177-1183. Epub 2017 Jan 9.

Department of Infectious Disease Biology, Institute of Life Sciences (An Autonomous Institute of Department of Biotechnology New Delhi), Bhubaneswar, India; and.

Monocytes and macrophages represent critical arms of the innate immune system and are considered regulators and effectors of inflammation and the innate immune response. Monocytes can mobilize from bone marrow, traffic to their required destination, and differentiate into effector cells, depending on the local tissue environment, to perform multiple roles during infection or inflammation, making them important components of body's immune defense. Macrophages have diverse roles in tissue homeostasis, development, and tissue repair following injury. Adult bone marrow monocytes can give rise to tissue-resident macrophages during infection or inflammatory reactions, besides self-replication of tissue resident macrophages. Lysophosphatidic acid (LPA), a lipid by-product of autotaxin activity, is involved in cancer, vascular defects, and neural tissue, but is largely unexplored in immune system. Here, we reveal an unexpected function of LPA that transfigures CD11b murine monocytes into F4/80 macrophages. LPA-stimulated Akt/mTOR signaling is critical for LPA-mediated macrophage development in mice. Additionally, transcriptome analysis reveals that PPARγ is the key transcriptional regulator in the development of LPA-induced macrophages. In humans, LPA mediates macrophage formation following similar pathways. These findings identify a critical role for LPA in regulating innate immune system.
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http://dx.doi.org/10.1182/blood-2016-10-743757DOI Listing
March 2017

Evaluation of HDPE and LDPE degradation by fungus, implemented by statistical optimization.

Sci Rep 2017 01 4;7:39515. Epub 2017 Jan 4.

Earth and Environmental Science Research Laboratory, Department of Earth Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, Nadia, West Bengal, India.

Plastic in any form is a nuisance to the well-being of the environment. The 'pestilence' caused by it is mainly due to its non-degradable nature. With the industrial boom and the population explosion, the usage of plastic products has increased. A steady increase has been observed in the use of plastic products, and this has accelerated the pollution. Several attempts have been made to curb the problem at large by resorting to both chemical and biological methods. Chemical methods have only resulted in furthering the pollution by releasing toxic gases into the atmosphere; whereas; biological methods have been found to be eco-friendly however they are not cost effective. This paves the way for the current study where fungal isolates have been used to degrade polyethylene sheets (HDPE, LDPE). Two potential fungal strains, namely, Penicillium oxalicum NS4 (KU559906) and Penicillium chrysogenum NS10 (KU559907) had been isolated and identified to have plastic degrading abilities. Further, the growth medium for the strains was optimized with the help of RSM. The plastic sheets were subjected to treatment with microbial culture for 90 days. The extent of degradation was analyzed by, FE-SEM, AFM and FTIR. Morphological changes in the plastic sheet were determined.
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http://dx.doi.org/10.1038/srep39515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209683PMC
January 2017

Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling.

Structure 2016 09 11;24(9):1509-22. Epub 2016 Aug 11.

Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA. Electronic address:

The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to characterize structurally due to the large sizes of and transient interactions between monomers. The receptor for advanced glycation end products (RAGE), a signaling molecule central to the induction and perpetuation of inflammatory responses, is a weak constitutive oligomer. The RAGE domain interaction surfaces that mediate homo-dimerization were identified by combining segmental isotopic labeling of extracellular soluble RAGE (sRAGE) and nuclear magnetic resonance spectroscopy with chemical cross-linking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head to head forming an asymmetric dimer with the C termini directed toward the cell membrane. Ligand-induced association of RAGE homo-dimers on the cell surface increases the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and activating signaling pathways.
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http://dx.doi.org/10.1016/j.str.2016.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014727PMC
September 2016

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction.

Sci Rep 2016 Mar 3;6:22450. Epub 2016 Mar 3.

Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.

The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).
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http://dx.doi.org/10.1038/srep22450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776135PMC
March 2016

RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis.

Neurosci Biobehav Rev 2016 Mar 25;62:48-55. Epub 2015 Dec 25.

Institute of Life Sciences, Bhubaneswar 751023, India. Electronic address:

RAGE, the receptor of advanced glycation end-products, is thought to be one of the potential contributors to the neurodegeneration. It has been shown that RAGE activation triggers an increase in proinflammatory molecules, oxidative stressors and cytokines. RAGE involvement has been documented in the pathogenesis of a number of neurodegenerative diseases such amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's, Creutzfeld-Jakob' diseases and various neurodegenerative conditions such as diabetic neuropathy, familial amyloid polyneuropathy, Charcot neuroarthropathy and vasculitic neuropathy. Although the detailed mechanisms of RAGE contribution to the neurodegeneration remains unclear, studies indicate that RAGE detrimental actions are exerted via its binding to the pro-inflammatory ligands such as advanced glycation end-products, S100/calgranulin and amphoterin and subsequent activation of downstream regulatory pathways such as NF-κB, STAT and JKN pathways. Here, in this review we attempt to shed light onto molecular events and pathological pathways involved in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis (ALS)--a progressive and fatal neurodegenerative disorder, summarizing current knowledge and the prospect of RAGE in the pathogenesis of this disastrous disease.
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http://dx.doi.org/10.1016/j.neubiorev.2015.12.006DOI Listing
March 2016

Facets of Nanotechnology as Seen in Food Processing, Packaging, and Preservation Industry.

Biomed Res Int 2015 3;2015:365672. Epub 2015 Nov 3.

Earth and Environmental Science Research Laboratory, Department of Earth Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741 246, India.

Nanotechnology has proven its competence in almost all possible fields we are aware of. However, today nanotechnology has evolved in true sense by contributing to a very large extent to the food industry. With the growing number of mouths to feed, production of food is not adequate. It has to be preserved in order to reach to the masses on a global scale. Nanotechnology made the idea a reality by increasing the shelf life of different kinds of food materials. It is not an entirely full-proof measure; however it has brought down the extent of wastage of food due to microbial infestation. Not only fresh food but also healthier food is being designed with the help of nano-delivery systems which act as a carrier for the food supplements. There are regulations to follow however as several of them pose serious threats to the wellbeing of the population. In coming days, newer modes of safeguarding food are going to be developed with the help of nanotechnology. In this paper, an overview has been given of the different methods of food processing, packaging, and preservation techniques and the role nanotechnology plays in the food processing, packaging, and preservation industry.
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http://dx.doi.org/10.1155/2015/365672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646997PMC
September 2016

Receptor for advanced glycation end-products in neurodegenerative diseases.

Rev Neurosci 2015 ;26(6):691-8

This review, for the first time, aims to summarize the current knowledge in the emerging field of RAGE (receptor for advanced glycation end-products) studies in neurodegeneration and neurodegenerative diseases. RAGE, a member of the multiligand cell surface immunoglobulin family, has been implicated in numerous pathological conditions - from diabetes and cardiovascular diseases to tumors and neurodegenerative disorders, such as Alzheimer's disease, familial amyloid polyneuropathy, diabetic neuropathy, Parkinson's disease, and Huntington's disease. Until now, the detailed mechanisms of the contribution of RAGE to neurodegeneration remain elusive; however, mounting evidence suggests that its detrimental actions are triggered by its ligand interactions and contribute to increased neuroinflammation, neuronal degeneration, and apoptosis. Deciphering the role of RAGE in neurodegenerative disorders will be a milestone in our basic understanding of the mechanisms involved in the pathogenesis of neurodegeneration, helping to delineate molecular links between complex RAGE signaling pathways and neuronal dysfunction and neurodegeneration.
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http://dx.doi.org/10.1515/revneuro-2015-0003DOI Listing
September 2016

An in vitro Comparison of Endodontic Medicaments Propolis and Calcium Hydroxide alone and in Combination with Ciprofloxacin and Moxifloxacin against Enterococcus Faecalis.

J Contemp Dent Pract 2015 05 1;16(5):394-9. Epub 2015 May 1.

Postgraduate Student, Department of Conservative Dentistry and Endodontics Saraswati Dental College, Lucknow, Uttar Pradesh, India Phone:01452425650, e-mail:

Aim: To evaluate and compare the antimicrobial properties of propolis and calcium hydroxide alone and in combination with ciprofloxacin and moxifloxacin against Enterococcus faecalis (E. Faecalis).

Materials And Methods: The laboratory study was carried out to test the effectiveness of propolis and calcium hydroxidealone as well as in combination with the established endodontic medicaments (moxifloxacin and ciprofloxacin). The various combinations were-group 1: propolis, group 2: calcium hydroxide, group 3: moxifloxacin, group 4: ciprofoxacin, group 5: propolis + moxifloxacin, group 6: propolis + Ciprofloxacin, group 7: calcium hydroxide + ciprofloxacin, group 8: calcium hydroxide + moxifloxacin. The efficacy of these medicaments was tested by checking for the zone of inhibition for the specific strain (ATCC 29212) of E. faecalis at different time intervals, i.e. 24, 48 and 72 hours.

Results: Mean zone of inhibition was maximum in group V (21.94 ± 4.26) followed by group VI (18.80 ± 1.93), group I (18.71 ± 4.26), group VIII (15.88 ± 2.59), group III (14.91 ± 1.00), group VII (14.57 ± 2.17), group IV (13.91 ± 1.00) and minimum in group II (12.89 ± 2.14). Mean zone of inhibition was found to be maximum at 72 hours and minimum at 24 hours. At all time intervals, the combination of Propalis with Moxifocacin showed the maximum antimicrobial efficacy.

Conclusion: On the basis of the results of the present study, it can be concluded that propolis and calcium hydroxide show synergistic effect with moxifloxacin and ciprofloxacin against E. Faecalis. Propolis in combination with antibiotics and alone is more effective than calcium hydroxide.

Clinical Significance: Since propolis alone and in combination with antibiotics was observed to be more effective than calcium hydroxide, propolis can be considered as an intracanal medicament when compared to traditional calcium hydroxide.
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http://dx.doi.org/10.5005/jp-journals-10024-1696DOI Listing
May 2015

Treatment effect with anti-RAGE F(ab')2 antibody improves hind limb angiogenesis and blood flow in Type 1 diabetic mice with left femoral artery ligation.

Vasc Med 2015 Jun 25;20(3):212-8. Epub 2015 Mar 25.

Department of Medicine, Columbia University Medical Center, New York, NY, USA

We investigated treatment with a receptor for advanced glycation endproduct (RAGE) blocking antibody on angiogenic response to hind limb ischemia in diabetic mice. Streptozotocin treated C57BL/6 mice received either murine monoclonal anti-RAGE F(ab')2 intraperitoneally (n=10) or saline (n=9) for 9 weeks. Diabetic plus 10 non-diabetic C57BL/6 mice underwent left femoral artery ligation and 5 days later angiogenesis imaging with (99m)Tc-Arg-Gly-Asp (RGD) nanoSPECT/CT. Twenty-four days later, hind limb blood flow was measured with ultrasound, the mice were euthanized, and tissue was taken for immunohistochemistry. The angiogenic imaging signal in ischemic limbs was higher in RAGE-ab treated versus saline treated mice at day 5 (3.1±1.4 vs 1.68±0.35, p=0.02) and blood flow was higher at day 24 (1.49±0.5 vs 0.61±0.39, p=0.04). Immunohistochemistry of ischemic muscles showed greater capillary density in the RAGE-ab treated group versus the vehicle-treated group (p<0.001) (NS from non-diabetic mice). In conclusion, treatment with anti-RAGE F(ab')2 in diabetic mice improves neovascularization in the ischemic leg.
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http://dx.doi.org/10.1177/1358863X14568337DOI Listing
June 2015

Dental and skeletal maturity- a biological indicator of chronologic age.

J Clin Diagn Res 2014 Sep 20;8(9):ZC60-4. Epub 2014 Sep 20.

Senior Lecturer, Department of Pedodontics and Preventive Dentistry, Sardar Patel Post Graduate Institute of Dental and Medical Sciences , Lucknow, India .

Introduction: Precise evaluation of the developmental stage of a child is not only an integral part of both diagnosis and treatment of paediatric patients; it is also essential in Forensic Medicine and Dentistry. Physiologic age can be estimated by somatic, sexual, skeletal and dental maturity.

Aim: Investigate the relationship between the dental age (DA) and skeletal age (SA) of children and comparing it with the chronological age (CA).

Materials And Methods: The dental age estimation methods of Schour and Massler (S&M), and Demirjian and Goldstien (D&G) and skeletal assessment methods of Greulich and Pyle (G&P), and Tanner et al., (TW2) were used to analyze the orthopantomograms and hand-wrist radiographs respectively of 150 healthy subjects within the age range of 5-15 y and compared with the Chronological Age.

Statistical Analysis: Data collected was statistically analysed using the SPSS version 15.0 STATISTICAL ANALYSIS Software. For all tests p-value of <0.05 were considered statistically significance.

Results: Dental age estimation techniques were found comparable and equally reliable as the skeletal age estimation methods. Strong correlations between dental and skeletal maturation were demonstrated.
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http://dx.doi.org/10.7860/JCDR/2014/10079.4862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225977PMC
September 2014

The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs.

Biochemistry 2014 May 13;53(20):3327-35. Epub 2014 May 13.

Department of Chemistry, State University of New York at Albany , Albany, New York 12222, United States.

Diabetes-induced hyperglycemia increases the extracellular concentration of methylglyoxal. Methylglyoxal-derived hydroimidazolones (MG-H) form advanced glycation end products (AGEs) that accumulate in the serum of diabetic patients. The binding of hydroimidozolones to the receptor for AGEs (RAGE) results in long-term complications of diabetes typified by vascular and neuronal injury. Here we show that binding of methylglyoxal-modified albumin to RAGE results in signal transduction. Chemically synthesized peptides containing hydroimidozolones bind specifically to the V domain of RAGE with nanomolar affinity. The solution structure of an MG-H1-V domain complex revealed that the hydroimidazolone moiety forms multiple contacts with a positively charged surface on the V domain. The high affinity and specificity of hydroimidozolones binding to the V domain of RAGE suggest that they are the primary AGE structures that give rise to AGEs-RAGE pathologies.
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http://dx.doi.org/10.1021/bi500046tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038343PMC
May 2014

A broader view: microbial enzymes and their relevance in industries, medicine, and beyond.

Biomed Res Int 2013 11;2013:329121. Epub 2013 Sep 11.

Department of Earth Sciences, Indian Institute of Science Education and Research-Kolkata Nadia, Mohanpur, West Bengal 741252, India.

Enzymes are the large biomolecules that are required for the numerous chemical interconversions that sustain life. They accelerate all the metabolic processes in the body and carry out a specific task. Enzymes are highly efficient, which can increase reaction rates by 100 million to 10 billion times faster than any normal chemical reaction. Due to development in recombinant technology and protein engineering, enzymes have evolved as an important molecule that has been widely used in different industrial and therapeutical purposes. Microbial enzymes are currently acquiring much attention with rapid development of enzyme technology. Microbial enzymes are preferred due to their economic feasibility, high yields, consistency, ease of product modification and optimization, regular supply due to absence of seasonal fluctuations, rapid growth of microbes on inexpensive media, stability, and greater catalytic activity. Microbial enzymes play a major role in the diagnosis, treatment, biochemical investigation, and monitoring of various dreaded diseases. Amylase and lipase are two very important enzymes that have been vastly studied and have great importance in different industries and therapeutic industry. In this review, an approach has been made to highlight the importance of different enzymes with special emphasis on amylase and lipase in the different industrial and medical fields.
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http://dx.doi.org/10.1155/2013/329121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784079PMC
June 2014

Combinatorial library of improved peptide aptamers, CLIPs to inhibit RAGE signal transduction in mammalian cells.

PLoS One 2013 13;8(6):e65180. Epub 2013 Jun 13.

Department of Chemistry, State University of New York at Albany, Albany, New York, United States of America.

Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin. We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clones, to be used as a molecular tool in the study of biological pathways. The Thioredoxin scaffold was modified to increase solubility and eliminate aggregation of the peptide aptamers. The CLIPs was used in a yeast two-hybrid screen to identify peptide aptamers that bind to various domains of the Receptor for Advanced Glycation End products (RAGE). NMR spectroscopy was used to identify interaction surfaces between the peptide aptamers and RAGE domains. Cellular functional assays revealed that in addition to directly interfering with known binding sites, peptide aptamer binding distal to ligand sites also inhibits RAGE ligand-induced signal transduction. This finding underscores the potential of using CLIPs to select allosteric inhibitors of biological targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065180PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681763PMC
January 2014