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Dissecting microregulation of a master regulatory network

Amit U Sinha, Vivek Kaimal, Jing Chen, Anil G Jegga
2008 BMC Genomics  
We termed these 143 miRNAs as p53-miRs (Kaimal and Sinha et al., unpublished).  ...  In an earlier study (Kaimal and Sinha et al., unpublished) , scanning the 474 human miR-NAs for putative p53 sites, we identified 143 miRNAs that have at least one p53 site (using p53MH algorithm [22  ... 
doi:10.1186/1471-2164-9-88 pmid:18294391 pmcid:PMC2289817 fatcat:nxuqeztdkvawxpls5rgzodvduy

SENSITIVITY ANALYSIS FOR REVERSAL DISTANCE AND BREAKPOINT REUSE IN GENOME REARRANGEMENTS

AMIT U SINHA, JAROSLAW MELLER
2007 Biocomputing 2008  
Identifying syntenic regions and quantifying evolutionary relatedness between genomes by interrogating genome rearrangement events is one of the central goals of comparative genomics. However, identification of synteny blocks and the resulting assessment of genome rearrangements are dependent on the choice of conserved markers, the definition of conserved segments, and the choice of various parameters that are used to construct such segments for two genomes. In this work, we performed an
more » ... d sensitivity analysis of synteny block generation using alternative sets of markers in multiple genomes. A simple approach to synteny block aggregation is used, which depends on two principle parameters: the maximum gap (max_gap) between adjacent blocks to be merged, and the minimum length (min_len) of synteny blocks. In particular, the dependence on the choice of conserved markers and max_gap/min_len aggregation parameters is assessed for two important quantities that can be used to characterize evolutionary relationships between genomes, namely the reversal distance and breakpoint reuse. We observe that the number of synteny blocks depends on both parameters, while the reversal distance depends mostly on min_len. On the other hand, we observe that relative reversal distances between mammalian genomes, which are defined as ratios of distances between different pairs of genomes, are nearly constant for both parameters. Similarly, the breakpoint reuse rate was found to be almost constant for different data sets and a wide range of parameters. Breakpoint reuse is also strongly correlated with evolutionary distances, increasing for pairs of more divergent genomes. Finally, we demonstrate that the role of parameters may be further reduced by using a multi-way analysis that involves markers conserved in multiple genomes, which opens a way to guide the choice of a correct parameterization. Supplementary Materials (SM) at http://cinteny.cchmc.org/doc/sensitivity.php
doi:10.1142/9789812776136_0005 fatcat:buhvqef77fa2fm5djpf6suhae4

Cinteny: flexible analysis and visualization of synteny and genome rearrangements in multiple organisms

Amit U Sinha, Jaroslaw Meller
2007 BMC Bioinformatics  
Identifying syntenic regions, i.e., blocks of genes or other markers with evolutionary conserved order, and quantifying evolutionary relatedness between genomes in terms of chromosomal rearrangements is one of the central goals in comparative genomics. However, the analysis of synteny and the resulting assessment of genome rearrangements are sensitive to the choice of a number of arbitrary parameters that affect the detection of synteny blocks. In particular, the choice of a set of markers and
more » ... he effect of different aggregation strategies, which enable coarse graining of synteny blocks and exclusion of micro-rearrangements, need to be assessed. Therefore, existing tools and resources that facilitate identification, visualization and analysis of synteny need to be further improved to provide a flexible platform for such analysis, especially in the context of multiple genomes. Results: We present a new tool, Cinteny, for fast identification and analysis of synteny with different sets of markers and various levels of coarse graining of syntenic blocks. Using Hannenhalli-Pevzner approach and its extensions, Cinteny also enables interactive determination of evolutionary relationships between genomes in terms of the number of rearrangements (the reversal distance). In particular, Cinteny provides: i) integration of synteny browsing with assessment of evolutionary distances for multiple genomes; ii) flexibility to adjust the parameters and re-compute the results on-the-fly; iii) ability to work with user provided data, such as orthologous genes, sequence tags or other conserved markers. In addition, Cinteny provides many annotated mammalian, invertebrate and fungal genomes that are pre-loaded and available for analysis at http://cinteny.cchmc.org. Conclusion: Cinteny allows one to automatically compare multiple genomes and perform sensitivity analysis for synteny block detection and for the subsequent computation of reversal distances. Cinteny can also be used to interactively browse syntenic blocks conserved in multiple genomes, to facilitate genome annotation and validation of assemblies for newly sequenced genomes, and to construct and assess phylogenomic trees.
doi:10.1186/1471-2105-8-82 pmid:17343765 pmcid:PMC1821339 fatcat:dddodla73bb6vplkvurs234sna

iCanPlot: Visual Exploration of High-Throughput Omics Data Using Interactive Canvas Plotting

Amit U. Sinha, Scott A. Armstrong, Nicholas James Provart
2012 PLoS ONE  
Increasing use of high throughput genomic scale assays requires effective visualization and analysis techniques to facilitate data interpretation. Moreover, existing tools often require programming skills, which discourages bench scientists from examining their own data. We have created iCanPlot, a compelling platform for visual data exploration based on the latest technologies. Using the recently adopted HTML5 Canvas element, we have developed a highly interactive tool to visualize tabular
more » ... and identify interesting patterns in an intuitive fashion without the need of any specialized computing skills. A module for geneset overlap analysis has been implemented on the Google App Engine platform: when the user selects a region of interest in the plot, the genes in the region are analyzed on the fly. The visualization and analysis are amalgamated for a seamless experience. Further, users can easily upload their data for analysis-which also makes it simple to share the analysis with collaborators. We illustrate the power of iCanPlot by showing an example of how it can be used to interpret histone modifications in the context of gene expression.
doi:10.1371/journal.pone.0031690 pmid:22393367 pmcid:PMC3290527 fatcat:gsyxssxdsvaddifmmwlv3vmieu

An antioxidant nanozyme that uncovers the cytoprotective potential of vanadia nanowires

Amit A. Vernekar, Devanjan Sinha, Shubhi Srivastava, Prasath U. Paramasivam, Patrick D'Silva, Govindasamy Mugesh
2014 Nature Communications  
B S O N A C V n N A C C u S O 4 B S O 4 3 ** +CuSO 4 +3-AT +GSH 2 1 Fold amplex red MFI 0 U T 3 -A T A A V n V n V n + A A V n + B S O V n + A A V n + B S O N A C V n N A C C u S O 4 B S O O 2 A A B S  ...  This is presumably due to scavenging of H 2 O 2 by Vn that may prevent the stimulation of Nrf2 response. 0.0 E V E V E V G P x ↑ G P x 1 G P x ↑ U T U T U T H 2 O 2 AA BSO Vn Vn Vn+AA Vn+BSO Vn+AA Vn+BSO  ... 
doi:10.1038/ncomms6301 pmid:25412933 fatcat:6bdmafm5e5dnvkxhl7ubnoppxu

eXframe: reusable framework for storage, analysis and visualization of genomics experiments

Amit U Sinha, Emily Merrill, Scott A Armstrong, Tim W Clark, Sudeshna Das
2011 BMC Bioinformatics  
Sinha et al. BMC Bioinformatics 2011, 12:452 http://www.biomedcentral.com/1471-2105/12/452 Page 11 of 13  ... 
doi:10.1186/1471-2105-12-452 pmid:22103807 pmcid:PMC3235155 fatcat:w4xj72om4rcttnhrnxzbxkwyze

Genomes of Wolbachia endosymbionts from the human filarial parasites Mansonella perstans and Mansonella ozzardi [article]

Amit Sinha, Zhiru Li, Catherine B Poole, Laurence Ettwiller, Nathália F Lima, Marcelo U Ferreira, Fanny F Fombad, Samuel Wanji, Clotilde Carlow
2021 bioRxiv   pre-print
U.  ...  U. F., F.F. F., S.W. collected the clinical samples. A.S., Z. L, C.B. P., L. E. 538 performed the sequencing experiments and bioinformatics analysis. A.S., Z. L, C.B.  ... 
doi:10.1101/2021.03.23.436630 fatcat:j2oq4pkuerfg7i5wd4kvwzeiam

Chromatin-modifying enzymes as modulators of reprogramming

Tamer T. Onder, Nergis Kara, Anne Cherry, Amit U. Sinha, Nan Zhu, Kathrin M. Bernt, Patrick Cahan, B. Ogan Mancarci, Juli Unternaehrer, Piyush B. Gupta, Eric S. Lander, Scott A. Armstrong (+1 others)
2012 Nature  
et al. 2012. Chromatin modifying enzymes as modulators of reprogramming. Nature 483(7391): 598-602. Published Version Abstract Generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming involves global epigenetic remodeling 1 . While several proteins are known to regulate chromatin marks associated with the distinct epigenetic states of cells before and after reprogramming 2,3 , the role of specific chromatin modifying enzymes in reprogramming remains to be determined. To address
doi:10.1038/nature10953 pmid:22388813 pmcid:PMC3501145 fatcat:2eu2bbwgh5clrgrjzcvgdewe7m

Olbrzymi tętniak obejmujący kilka tętnic wieńcowych, w tym pień tętnicy wieńcowej lewej, powodujący objawy ostrego zespołu wieńcowego u 23-letniego chorego: nietypowe powikłanie choroby Kawasaki

Santosh Kumar Sinha, Prakash Kumar, Amit Goel, Karandeep Singh, Mahmadula Razi, Ramesh Thakur
2018 Folia Cardiologica  
U dorosłych przyczyną rozwoju CAA w przeważającej większości przypadków pozostaje miażdżyca, natomiast u dzieci najczęściej są one następstwem choroby Kawasaki.  ...  onset diabetes of the young), u którego występowały objawy ostrego zespołu wieńcowego.  ...  intervention in lieu of non ST elevation myocardial infarction after proper consent. 6F JR3.5 and JL3.5 Proflo TM diagnostic catheters (Medtronic, USA) were used for catheterisation after administering 2,500 U  ... 
doi:10.5603/fc.2018.0045 fatcat:u2wns3nmhfhqbltdhht4ie5jja

The King's Brief Interstitial Lung Disease (KBILD) questionnaire: an updated minimal clinically important difference

Aish Sinha, Amit Suresh Patel, Richard J Siegert, Sabrina Bajwah, Toby M Maher, Elizabeth A Renzoni, Athol U Wells, Irene J Higginson, Surinder S Birring
2019 BMJ Open Respiratory Research  
IntroductionThe King's Brief Interstitial Lung Disease (KBILD) is a 15-item validated health-related quality of life (HRQOL) questionnaire. The method of scoring the KBILD has recently changed to incorporate a logit-scale transformation from one that used raw item responses, as this is potentially a more linear scale. The aim of this study was to re-evaluate the KBILD minimal clinically important difference (MCID) using the new logit -transformed scoring.Methods57 patients with interstitial
more » ... disease (17 idiopathic pulmonary fibrosis, IPF) were asked to complete the KBILD questionnaire on two occasions in outpatient clinics. At the second visit, patients also completed a 15-item global rating of change of health status questionnaire (GRCQ). The MCID was calculated as the mean of four different methods: the change in KBILD for patients indicating a small change in GRCQ, patients with a 7%–12% change in FVC, 1 SE of measurement of baseline KBILD and effect size (ES) of 0.3.ResultsThe mean (SD) KBILD total score for all patients was 55.3 (15.6). 16 patients underwent a therapeutic intervention. 36 patients reported a change in their condition on the GRCQ; 22 deteriorated, 14 improved and 21 were unchanged. There was a significant change in KBILD total score in patients reporting a change in GRCQ; mean (SD) 57.0 (13.6) versus 50.0 (9.7); mean difference 7.0; 95% CI of difference 3.0 to 11.0; p<0.01. The change in KBILD total score correlated with the GRCQ scale; r=−0.49, p<0.01. The mean KBILD total score MCID was 5. The MCID of KBILD domains were 6 for Psychological, 7 for Breathlessness and Activities, and 11 for Chest Symptoms.ConclusionThe KBILD is a responsive tool for longitudinal assessment of HRQOL in patients with ILD. The MCID of the KBILD total score is a 5-unit change.
doi:10.1136/bmjresp-2018-000363 pmid:30956799 pmcid:PMC6424243 fatcat:me7npxp4rjhebj5bpc2ozm6ydy

MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L

Kathrin M. Bernt, Nan Zhu, Amit U. Sinha, Sridhar Vempati, Joerg Faber, Andrei V. Krivtsov, Zhaohui Feng, Natalie Punt, Amanda Daigle, Lars Bullinger, Roy M. Pollock, Victoria M. Richon (+2 others)
2011 Cancer Cell  
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to
more » ... gulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
doi:10.1016/j.ccr.2011.06.010 pmid:21741597 pmcid:PMC3329803 fatcat:7acdsn4oova3pfxmdxwxtvooyq

Npm1 Haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice

Andrew Muranyi, Tobias Ammer, Anna Kechter, Vijay P. S. Rawat, Amit U Sinha, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Anca Azoitei, Cagatay Günes, Annalisa Mupo, George S. Vassiliou, Shiva Bamezai (+1 others)
2022 Blood Advances  
NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle-associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wildtype in the nucleus and nucleolus, caused by loss of one wild-type
more » ... llele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice which transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1 binding occupancies such that it binds the promoter of the stem cell and cell cycle-associated oncogene, structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild type harboring Hoxa9/Meis1 transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c positive AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared to AML cells with non-mutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.
doi:10.1182/bloodadvances.2022007015 pmid:35468619 fatcat:d3iuufbka5brtfuq3rq6iq5y4e

H3K79 Methylation Profiles Define Murine and Human MLL-AF4 Leukemias

Andrei V. Krivtsov, Zhaohui Feng, Madeleine E. Lemieux, Joerg Faber, Sridhar Vempati, Amit U. Sinha, Xiaobo Xia, Jonathan Jesneck, Adrian P. Bracken, Lewis B. Silverman, Jeffery L. Kutok, Andrew L. Kung (+1 others)
2008 Cancer Cell  
We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human
more » ... d ALLs could be distinguished from other ALLs by their H3K79 profiles, and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We thus demonstrate that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4driven gene expression.
doi:10.1016/j.ccr.2008.10.001 pmid:18977325 pmcid:PMC2591932 fatcat:x3ltqr6l4fad7owrzihm3vf22m

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

Simone S. Riedel, Jessica N. Haladyna, Matthew Bezzant, Brett Stevens, Daniel A. Pollyea, Amit U. Sinha, Scott A. Armstrong, Qi Wei, Roy M. Pollock, Scott R. Daigle, Craig T. Jordan, Patricia Ernst (+2 others)
2016 Journal of Clinical Investigation  
Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1
more » ... nd DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1 hi leukemia, and human MN1 hi /HOXA9 hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1 hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML.
doi:10.1172/jci80825 pmid:26927674 pmcid:PMC4811120 fatcat:v6cgfdelmfejdddpki6gdyllui

Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia

Brenton G. Mar, Lars B. Bullinger, Kathleen M. McLean, Peter V. Grauman, Marian H. Harris, Kristen Stevenson, Donna S. Neuberg, Amit U. Sinha, Stephen E. Sallan, Lewis B. Silverman, Andrew L. Kung, Luca Lo Nigro (+2 others)
2014 Nature Communications  
Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in
more » ... D2, including frameshift and nonsense mutations, are present Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to S.A.A. (armstros@mskcc.org). Contributions B.G.M., L.B.B, and S.A.A. conceived and designed the project. K.M.M. and B.G.M. performed the sequencing library preparation and preparing of samples for Sanger sequencing. B.G.M. and P at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.
doi:10.1038/ncomms4469 pmid:24662245 pmcid:PMC4016990 fatcat:bnln5phfqjdj3kacrtni45olve
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