67 research outputs found
Einstein Gravity and Beyond: Aspects of Higher-Curvature Gravity and Black Holes
No full textabstract: This thesis explores the different aspects of higher curvature gravity. The "membrane paradigm" of black holes in Einstein gravity is extended to black holes in f(R) gravity and it is shown that the higher curvature effects of f(R) gravity causes the membrane fluid to become non-Newtonian. Next a modification of the null energy condition in gravity is provided. The purpose of the null energy condition is to filter out ill-behaved theories containing ghosts. Conformal transformations, which are simple redefinitions of the spacetime, introduces serious violations of the null energy condition. This violation is shown to be spurious and a prescription for obtaining a modified null energy condition, based on the universality of the second law of thermodynamics, is provided. The thermodynamic properties of the black holes are further explored using merger of extremal black holes whose horizon entropy has topological contributions coming from the higher curvature Gauss-Bonnet term. The analysis refutes the prevalent belief in the literature that the second law of black hole thermodynamics is violated in the presence of the Gauss-Bonnet term in four dimensions. Subsequently a specific class of higher derivative scalar field theories called the galileons are obtained from a Kaluza-Klein reduction of Gauss-Bonnet gravity. Galileons are null energy condition violating theories which lead to violations of the second law of thermodynamics of black holes. These higher derivative scalar field theories which are non-minimally coupled to gravity required the development of a generalized method for obtaining the equations of motion. Utilizing this generalized method, it is shown that the inclusion of the Gauss-Bonnet term made the theory of gravity to become higher derivative, which makes it difficult to make any statements about the connection between the violation of the second law of thermodynamics and the galileon fields.Dissertation/ThesisDoctoral Dissertation Physics 201
Fast identification of biological pathways associated with a quantitative trait using group lasso with overlaps.
No full textWhere causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways.We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets.In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small
On coupling NEC-violating matter to gravity
No full textabstract: We show that effective theories of matter that classically violate the null energy condition cannot be minimally coupled to Einstein gravity without being inconsistent with both string theory and black hole thermodynamics. We argue however that they could still be either non-minimally coupled or coupled to higher-curvature theories of gravity.The final version of this article, as published in Physics Letters B, can be viewed online at: http://www.sciencedirect.com/science/article/pii/S0370269315001835?via%3Dihu
A Manual of Colloquial Hindustani and Bengali. By N. C. Chatterjee, Superintendent Board of Examiners, Calcutta. Published at Calcutta by the Author, 1914. Price, Rs. 2.8.
No full textA multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
No full textWe conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis
Author Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
No full textauthor correctio
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
No full textObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation
Molecular and developmental analysis of non-coding RNA metabolism in" C. elegans" : the exoribonuclease XRN2 and the RNA- binding proteins SART-3 and USIP-1
No full textAbout three quarters of a eukaryotic genome are transcribed into RNA. However, only <2% of these transcripts are translated into protein while the bulk of transcripts execute their biological function as RNA. Non-protein coding RNAs (ncRNAs) associate with proteins in ribonucleoprotein particles (RNPs) to regulate gene expression at various stages thereby greatly increasing the functional complexity of the genome. Nonetheless, the function and mode of action of the vast majority of ncRNAs is unknown and even in well studied examples little is known about the post-transcriptional regulation of ncRNAs themselves. In the thesis at hand, I explored the molecular and developmental functions of proteins implicated in the metabolism of ncRNAs, namely the miRNA-degrading enzyme XRN2 and the U6 snRNA-interacting proteins SART-3 and USIP-1. The XRN2 project was a collaboration with Takashi Miki and Hannes Richter.
XRN2 project
XRN2 is a conserved 5’-to-3’ exoribonuclease involved in various pathways including transcription termination and processing of precursor forms of rRNAs and snoRNAs. Our lab had established a function of XRN2 in the turnover of mature miRNAs, however, whether XRN2 targets all or specific miRNAs in vivo remained unclear. Although XRN2 substrates have extensively been characterized, the developmental function of XRN2 is essentially unexplored. Moreover, knowledge of co-factors regulating XRN2 function beyond transcription termination is scarce in multicellular organisms. In order to elucidate the developmental role of XRN2, we characterized an xrn-2 null and xrn-2 temperature-sensitive mutant. We found that XRN2 is essential during several stages of C. elegans development, including embryogenesis, and that only specific miRNAs are affected by XRN2 in vivo. Co-immunoprecipitations identified PAXT-1 (PArtner of XRN-Two 1) as a tight interaction partner of XRN2. paxt-1 depletion enhanced the xrn-2ts mutant phenotype and a paxt-1 null mutant slowed-down miRNA degradation in vivo, similar to XRN2 inactivation. These observations, as we showed, are due to a stabilizing effect of PAXT-1 on XRN2. Truncation mutants of PAXT-1 revealed a conserved N-terminal domain of unknown function, DUF3469, sufficient for XRN2 binding. We were excited to discover that human proteins containing DUF3469 were also able to bind to XRN2. Hence, we renamed DUF3469 to XRN2-binding domain (XTBD). Collectively, we identified PAXT-1 as an essential interaction partner of XRN2 in C. elegans and established a protein domain (XTBD) that serves as a binding platform for XRN2 beyond C. elegans.
Finally, the laboratory of Dr. Martin Simard found that the scavenger decapping enzyme DCS-1 interacts with the exonuclease XRN1, a paralogue of XRN2, to promote miRNA degradation in C. elegans. Collaborating on their project, I evaluated the subcellular localization of XRN1 and XRN2 in C. elegans and provided tools useful to their experiments such as an XRN1 antibody. This collaborative work has been published and can be found in section 7.
SART-3 project
The human protein SART3 and its yeast homolog Prp24 have previously been implicated in spliceosome assembly, namely the association of the U4 and U6 snRNP into the U4/U6 di-snRNP complex. Additionally, a physical interaction of SART3 with the Argonaute proteins AGO1 and AGO2 had been reported, suggesting an involvement of SART3 in the miRNA pathway. However, a putative function of SART3 in the miRNA pathway remained to be established. In order uncover such a function and to shed light on the so far largely neglected systemic role of SART3 in a multicellular context, I investigated its C. elegans homolog SART-3. Co-immunoprecipitations of SART-3 revealed an interaction with a previously uncharacterized putative terminal uridylyl transferase (TUTase), whereas I could not verify an interaction between SART-3 and AGO1/AGO2. It is known that SART3 binds specifically to the U6 snRNA which contains a post-transcriptionally elongated uridine (U)-tail essential for spliceosome assembly. Therefore it was appealing to assume that this U-tail is polymerized by the identified TUTase. Subsequent analyses unveiled an interaction between the TUTase and U6 snRNA, which hence was renamed to U Six snRNA Interacting Protein 1 (USIP-1). It appeared that USIP-1 binds to a U6 snRNA species that is devoid of Lsm proteins suggesting a role for USIP-1 early in spliceosome assembly. Moreover, knock-down of sart-3 in a usip-1 null mutant background led to a synthetic, embryonic lethal phenotype. This phenotype was rescued by transgenic expression of wild-type USIP-1. Although formal demonstration of TUTase-activity for USIP-1 is lacking, the synthetic lethality was not rescued by a supposedly catalytically inactive version of USIP-1. In sum, I established a physical and functional interaction between two previously uncharacterized proteins in C. elegans, SART-3 and USIP-1, and explored their developmental phenotypes
A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns
No full textIn cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here,as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA
- …
