Publications by authors named "Amartya Sanyal"

16 Publications

  • Page 1 of 1

Identification and utilization of copy number information for correcting Hi-C contact map of cancer cell lines.

BMC Bioinformatics 2020 Nov 7;21(1):506. Epub 2020 Nov 7.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.

Background: Hi-C and its variant techniques have been developed to capture the spatial organization of chromatin. Normalization of Hi-C contact map is essential for accurate modeling and interpretation of high-throughput chromatin conformation capture (3C) experiments. Hi-C correction tools were originally developed to normalize systematic biases of karyotypically normal cell lines. However, a vast majority of available Hi-C datasets are derived from cancer cell lines that carry multi-level DNA copy number variations (CNVs). CNV regions display over- or under-representation of interaction frequencies compared to CN-neutral regions. Therefore, it is necessary to remove CNV-driven bias from chromatin interaction data of cancer cell lines to generate a euploid-equivalent contact map.

Results: We developed the HiCNAtra framework to compute high-resolution CNV profiles from Hi-C or 3C-seq data of cancer cell lines and to correct chromatin contact maps from systematic biases including CNV-associated bias. First, we introduce a novel 'entire-fragment' counting method for better estimation of the read depth (RD) signal from Hi-C reads that recapitulates the whole-genome sequencing (WGS)-derived coverage signal. Second, HiCNAtra employs a multimodal-based hierarchical CNV calling approach, which outperformed OneD and HiNT tools, to accurately identify CNVs of cancer cell lines. Third, incorporating CNV information with other systematic biases, HiCNAtra simultaneously estimates the contribution of each bias and explicitly corrects the interaction matrix using Poisson regression. HiCNAtra normalization abolishes CNV-induced artifacts from the contact map generating a heatmap with homogeneous signal. When benchmarked against OneD, CAIC, and ICE methods using MCF7 cancer cell line, HiCNAtra-corrected heatmap achieves the least 1D signal variation without deforming the inherent chromatin interaction signal. Additionally, HiCNAtra-corrected contact frequencies have minimum correlations with each of the systematic bias sources compared to OneD's explicit method. Visual inspection of CNV profiles and contact maps of cancer cell lines reveals that HiCNAtra is the most robust Hi-C correction tool for ameliorating CNV-induced bias.

Conclusions: HiCNAtra is a Hi-C-based computational tool that provides an analytical and visualization framework for DNA copy number profiling and chromatin contact map correction of karyotypically abnormal cell lines. HiCNAtra is an open-source software implemented in MATLAB and is available at https://github.com/AISKhalil/HiCNAtra .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-020-03832-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648276PMC
November 2020

Spatial inter-centromeric interactions facilitated the emergence of evolutionary new centromeres.

Elife 2020 05 29;9. Epub 2020 May 29.

Molecular Mycology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.

Centromeres of form on unique and different DNA sequences but a closely related species, , possesses homogenized inverted repeat (HIR)-associated centromeres. To investigate the mechanism of centromere type transition, we improved the fragmented genome assembly and constructed a chromosome-level genome assembly of by employing PacBio sequencing, chromosome conformation capture sequencing (3C-seq), chromoblot, and genetic analysis of engineered aneuploid strains. Further, we analyzed the 3D genome organization using 3C-seq data, which revealed spatial proximity among the centromeres as well as telomeres of seven chromosomes in . Intriguingly, we observed evidence of inter-centromeric translocations in the common ancestor of and . Identification of putative centromeres in closely related , and indicates loss of ancestral HIR-associated centromeres and establishment of evolutionary new centromeres (ENCs) in . We propose that spatial proximity of the homologous centromere DNA sequences facilitated karyotype rearrangements and centromere type transitions in human pathogenic yeasts of the CUG-Ser1 clade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.58556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292649PMC
May 2020

Hierarchical discovery of large-scale and focal copy number alterations in low-coverage cancer genomes.

BMC Bioinformatics 2020 Apr 16;21(1):147. Epub 2020 Apr 16.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.

Background: Detection of DNA copy number alterations (CNAs) is critical to understand genetic diversity, genome evolution and pathological conditions such as cancer. Cancer genomes are plagued with widespread multi-level structural aberrations of chromosomes that pose challenges to discover CNAs of different length scales, and distinct biological origins and functions. Although several computational tools are available to identify CNAs using read depth (RD) signal, they fail to distinguish between large-scale and focal alterations due to inaccurate modeling of the RD signal of cancer genomes. Additionally, RD signal is affected by overdispersion-driven biases at low coverage, which significantly inflate false detection of CNA regions.

Results: We have developed CNAtra framework to hierarchically discover and classify 'large-scale' and 'focal' copy number gain/loss from a single whole-genome sequencing (WGS) sample. CNAtra first utilizes a multimodal-based distribution to estimate the copy number (CN) reference from the complex RD profile of the cancer genome. We implemented Savitzky-Golay smoothing filter and Modified Varri segmentation to capture the change points of the RD signal. We then developed a CN state-driven merging algorithm to identify the large segments with distinct copy numbers. Next, we identified focal alterations in each large segment using coverage-based thresholding to mitigate the adverse effects of signal variations. Using cancer cell lines and patient datasets, we confirmed CNAtra's ability to detect and distinguish the segmental aneuploidies and focal alterations. We used realistic simulated data for benchmarking the performance of CNAtra against other single-sample detection tools, where we artificially introduced CNAs in the original cancer profiles. We found that CNAtra is superior in terms of precision, recall and f-measure. CNAtra shows the highest sensitivity of 93 and 97% for detecting large-scale and focal alterations respectively. Visual inspection of CNAs revealed that CNAtra is the most robust detection tool for low-coverage cancer data.

Conclusions: CNAtra is a single-sample CNA detection tool that provides an analytical and visualization framework for CNA profiling without relying on any reference control. It can detect chromosome-level segmental aneuploidies and high-confidence focal alterations, even from low-coverage data. CNAtra is an open-source software implemented in MATLAB. It is freely available at https://github.com/AISKhalil/CNAtra.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-020-3480-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160937PMC
April 2020

- and -chromosomal Interactions Define Pericentric Boundaries in the Absence of Conventional Heterochromatin.

Genetics 2019 08 29;212(4):1121-1132. Epub 2019 May 29.

Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India

The diploid budding yeast harbors unique CENPA-rich 3- to 5-kb regions that form the centromere (CEN) core on each of its eight chromosomes. The epigenetic nature of these CENs does not permit the stabilization of a functional kinetochore on an exogenously introduced CEN plasmid. The flexible nature of such centromeric chromatin is exemplified by the reversible silencing of a transgene upon its integration into the CENPA-bound region. The lack of a conventional heterochromatin machinery and the absence of defined boundaries of CENPA chromatin makes the process of CEN specification in this organism elusive. Additionally, upon native CEN deletion, can efficiently activate neocentromeres proximal to the native CEN locus, hinting at the importance of CEN-proximal regions. In this study, we examine this CEN-proximity effect and identify factors for CEN specification in We exploit a counterselection assay to isolate cells that can silence a transgene when integrated into the CEN-flanking regions. We show that the frequency of reversible silencing of the transgene decreases from the central core of to its peripheral regions. Using publicly available high-throughput chromosome conformation capture data, we identify a 25-kb region centering on the CENPA-bound core that acts as CEN-flanking compact chromatin (CFCC). - and -chromosomal interactions associated with the CFCC spatially segregates it from bulk chromatin. We further show that neocentromere activation on chromosome 7 occurs within this specified region. Hence, this study identifies a specialized CEN-proximal domain that specifies and restricts the centromeric activity to a unique region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1534/genetics.119.302179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707466PMC
August 2019

High-resolution RNA allelotyping along the inactive X chromosome: evidence of RNA polymerase III in regulating chromatin configuration.

Sci Rep 2017 04 3;7:45460. Epub 2017 Apr 3.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive 637551, Singapore.

We carried out padlock capture, a high-resolution RNA allelotyping method, to study X chromosome inactivation (XCI). We examined the gene reactivation pattern along the inactive X (Xi), after Xist (X-inactive specific transcript), a prototype long non-coding RNA essential for establishing X chromosome inactivation (XCI) in early embryos, is conditionally deleted from Xi in somatic cells (Xi). We also monitored the behaviors of X-linked non-coding transcripts before and after XCI. In each mutant cell line, gene reactivation occurs to ~6% genes along Xi in a recognizable pattern. Genes with upstream regions enriched for SINEs are prone to be reactivated. SINE is a class of retrotransposon transcribed by RNA polymerase III (Pol III). Intriguingly, a significant fraction of Pol III transcription from non-coding regions is not subjected to Xist-mediated transcriptional silencing. Pol III inhibition affects gene reactivation status along Xi, alters chromatin configuration and interferes with the establishment XCI during in vitro differentiation of ES cells. These results suggest that Pol III transcription is involved in chromatin structure re-organization during the onset of XCI and functions as a general mechanism regulating chromatin configuration in mammalian cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep45460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377358PMC
April 2017

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

Am J Respir Crit Care Med 2016 12;194(12):1465-1474

1 Channing Division of Network Medicine and.

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease.

Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.

Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.

Measurements And Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.

Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201602-0250OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215031PMC
December 2016

Architectural protein subclasses shape 3D organization of genomes during lineage commitment.

Cell 2013 Jun 23;153(6):1281-95. Epub 2013 May 23.

Department of Biology, Emory University, Atlanta, GA 30322, USA.

Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2013.04.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712340PMC
June 2013

From cells to chromatin: capturing snapshots of genome organization with 5C technology.

Methods 2012 Nov 5;58(3):255-67. Epub 2012 Nov 5.

Department of Biochemistry and Goodman Cancer Research Center, McGill University, 3655 Promenade Sir-William-Osler, Room 815A, Montréal, Québec, Canada H3G1Y6.

In eukaryotes, genome organization can be observed on many levels and at different scales. This organization is important not only to reduce chromosome length but also for the proper execution of various biological processes. High-resolution mapping of spatial chromatin structure was made possible by the development of the chromosome conformation capture (3C) technique. 3C uses chemical cross-linking followed by proximity-based ligation of fragmented DNA to capture frequently interacting chromatin segments in cell populations. Several 3C-related methods capable of higher chromosome conformation mapping throughput were reported afterwards. These techniques include the 3C-carbon copy (5C) approach, which offers the advantage of being highly quantitative and reproducible. We provide here an updated reference protocol for the production of 5C libraries analyzed by next-generation sequencing or onto microarrays. A procedure used to verify that 3C library templates bear the high quality required to produce superior 5C libraries is also described. We believe that this detailed protocol will help guide researchers in probing spatial genome organization and its role in various biological processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymeth.2012.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874844PMC
November 2012

The long-range interaction landscape of gene promoters.

Nature 2012 Sep;489(7414):109-13

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605-0103, USA.

The vast non-coding portion of the human genome is full of functional elements and disease-causing regulatory variants. The principles defining the relationships between these elements and distal target genes remain unknown. Promoters and distal elements can engage in looping interactions that have been implicated in gene regulation. Here we have applied chromosome conformation capture carbon copy (5C) to interrogate comprehensively interactions between transcription start sites (TSSs) and distal elements in 1% of the human genome representing the ENCODE pilot project regions. 5C maps were generated for GM12878, K562 and HeLa-S3 cells and results were integrated with data from the ENCODE consortium. In each cell line we discovered >1,000 long-range interactions between promoters and distal sites that include elements resembling enhancers, promoters and CTCF-bound sites. We observed significant correlations between gene expression, promoter-enhancer interactions and the presence of enhancer RNAs. Long-range interactions show marked asymmetry with a bias for interactions with elements located ∼120 kilobases upstream of the TSS. Long-range interactions are often not blocked by sites bound by CTCF and cohesin, indicating that many of these sites do not demarcate physically insulated gene domains. Furthermore, only ∼7% of looping interactions are with the nearest gene, indicating that genomic proximity is not a simple predictor for long-range interactions. Finally, promoters and distal elements are engaged in multiple long-range interactions to form complex networks. Our results start to place genes and regulatory elements in three-dimensional context, revealing their functional relationships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature11279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555147PMC
September 2012

The accessible chromatin landscape of the human genome.

Nature 2012 Sep;489(7414):75-82

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature11232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721348PMC
September 2012

An encyclopedia of mouse DNA elements (Mouse ENCODE).

Genome Biol 2012 Aug 13;13(8):418. Epub 2012 Aug 13.

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/gb-2012-13-8-418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491367PMC
August 2012

Chromatin globules: a common motif of higher order chromosome structure?

Curr Opin Cell Biol 2011 Jun 12;23(3):325-31. Epub 2011 Apr 12.

Program in Gene Function and Expression, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 01605-2324 Worcester, MA, USA.

Recent technological advances in the field of chromosome conformation capture are facilitating tremendous progress in the ability to map the three-dimensional (3D) organization of chromosomes at a resolution of several Kb and at the scale of complete genomes. Here we review progress in analyzing chromosome organization in human cells by building 3D models of chromatin based on comprehensive chromatin interaction datasets. We describe recent experiments that suggest that long-range interactions between active functional elements are sufficient to drive folding of local chromatin domains into compact globular states. We propose that chromatin globules are commonly formed along chromosomes, in a cell type specific pattern, as a result of frequent long-range interactions among active genes and nearby regulatory elements. Further, we speculate that increasingly longer range interactions can drive aggregation of groups of globular domains. This process would yield a compartmentalized chromosome conformation, consistent with recent observations obtained with genome-wide chromatin interaction mapping.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ceb.2011.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109114PMC
June 2011

A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression.

Nature 2011 Apr 20;472(7341):120-4. Epub 2011 Mar 20.

Howard Hughes Medical Institute, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature09819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670758PMC
April 2011

The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules.

Nat Struct Mol Biol 2011 Jan 5;18(1):107-14. Epub 2010 Dec 5.

Structural Genomics Unit, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nsmb.1936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056208PMC
January 2011

Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists.

Apoptosis 2007 Jun;12(6):1085-100

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka 560 012, India.

The role of pituitary gonadotropins in the regulation of spermatogenesis has been unequivocally demonstrated, although, the precise mechanism of this regulation is not clearly understood. Previous studies have shown that specific immunoneutralization of LH/testosterone caused apoptotic cell death of meiotic and post-meiotic germ cells while that of FSH resulted in similar death of meiotic cells. In the present study, the death process of germ cells has been characterized by depleting both FSH and testosterone by administering two different potent GnRH antagonists, Cetrorelix and Acyline to both rats and mice. Pro-survival factors like Bcl-2 and Bcl-x/l were unaltered in germ cells due to GnRH antagonist treatment, although a significant increase in several pro-apoptotic markers including Fas and Bax were evident at both protein and RNA levels. This culminated in cytochrome C release from mitochondria and eventually increase in the activity of caspase-8 and caspase-3. These data suggest that both extrinsic and intrinsic apoptotic death pathways are operative in the germ cells death following decrease in FSH and testosterone levels. Multiple injections of GnRH antagonist resulted in complete disappearance of germ cells except the spermatogonial cells and discontinuation of the treatment resulted in full recovery of spermatogenesis. In conclusion our present data suggest that the principal role of FSH and testosterone is to maintain spermatogenic homeostasis by inhibiting death signals for the germ cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10495-006-0039-3DOI Listing
June 2007
-->