A quantum McKay correspondence for fractional 2p-branes on LG orbifolds

We study fractional 2p-branes and their intersection numbers in non-compact orbifolds as well the continuation of these objects in Kahler moduli space to coherent sheaves in the corresponding smooth non-compact Calabi-Yau manifolds. We show that the restriction of these objects to compact Calabi-Yau hypersurfaces gives the new fractional branes in LG orbifolds constructed by Ashok et. al. in hep-th/0401135. We thus demonstrate the equivalence of the B-type branes corresponding to linear boundary conditions in LG orbifolds, originally constructed in hep-th/9907131, to a subset of those constructed in LG orbifolds using boundary fermions and matrix factorization of the world-sheet superpotential. The relationship between the coherent sheaves corresponding to the fractional two-branes leads to a generalization of the McKay correspondence that we call the quantum McKay correspondence due to a close parallel with the construction of branes on non-supersymmetric orbifolds. We also provide evidence that the boundary states associated to these branes in a conformal field theory description corresponds to a sub-class of the boundary states associated to the permutation branes in the Gepner model associated with the LG orbifold.Comment: LaTeX2e, 1+39 pages, 3 figures (v2) refs added, typos and report no. correcte

A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.Singapore. Ministry of Education (Grant T208B3109)Singapore. Agency for Science, Technology and Research (BMRC 08/1/21/19/574)Singapore-MIT Alliance (Computational and Systems Biology Flagship Project)Swedish Research Counci

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Outsourcing Portfolio Configuration and Firm Performance

Research examining the impact of outsourcing on firm performance is largely focused on discrete client-vendor dyads. As firms increasingly engage with multiple vendors simultaneously, the benefits of such outsourcing could be amplified or attenuated based on the firm’s ability to effectively coordinate across the vendors in its outsourcing portfolio. This study examines the impact of the outsourcing portfolio configuration on firm performance. Using a sample of 178 client outsourcing portfolios across 59 clients, spanning the years 2000-2013, the study finds that the portfolio configuration, based on the attributes of its size, diversity and functional heterogeneity, to have a curvilinear relationship on the firm’s performance

Outsourcing Portfolio Configuration and Firm Performance

Research examining the impact of outsourcing on firm performance is largely focused on discrete client-vendor dyads. As firms increasingly engage with multiple vendors simultaneously, the benefits of such outsourcing could be amplified or attenuated based on the firm’s ability to effectively coordinate across the vendors in its outsourcing portfolio. This study examines the impact of the outsourcing portfolio configuration on firm performance. Using a sample of 178 client outsourcing portfolios across 59 clients, spanning the years 2000-2013, the study finds that the portfolio configuration, based on the attributes of its size, diversity and functional heterogeneity, to have a curvilinear relationship on the firm’s performance

Whole-Genome comparative analysis reveals genetic mechanisms of disease resistance and heat tolerance of tropical Bos indicus cattle breeds

The Bos indicus cattle breeds have been naturally selected over thousands of years for disease resistance and thermo-tolerance. However, a genetic mechanism of these specific inherited characteristics needs to be discovered. Hence, in this study, the whole-genome comparative analysis of Bos indicus cattle breeds of Kangayam, Tharparkar, Sahiwal, Red Sindhi, and Hariana of the Indian subcontinent was conducted. The genetic variants identification analysis revealed a total of 15,58,51,012 SNPs and 1,00,62,805 InDels in the mapped reads across all Bos indicus cattle breeds. The functional annotation of 17,252 genes that comprised both, SNPs and InDels, of high functional impact on proteins, has been carried out. The functional annotation results revealed the pathways that were involved in the innate immune response including toll-like receptors, a retinoic acid-inducible gene I like receptors, NOD-like receptors, Jak-STAT signaling pathways, and the non-synonymous variants in the candidate immune genes. Further, we also identified several pathways involved in heat shock response, hair and skin properties, oxidative stress response, osmotic stress response, thermal sweating, feed intake, metabolism, and the non-synonymous variants in the candidate thermo-tolerant genes. These pathways and genes were directly or indirectly contributing to the disease resistance and thermo-tolerance adaptations of Bos indicus cattle breeds.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Retinal Cell Type DNA Methylation and Histone Modifications Predict Reprogramming Efficiency and Retinogenesis in 3D Organoid Cultures

Summary: Diverse cell types can be reprogrammed into pluripotent stem cells by ectopic expression of Oct4 (Pou5f1), Klf4, Sox3, and Myc. Many of these induced pluripotent stem cells (iPSCs) retain memory, in terms of DNA methylation and histone modifications (epigenetic memory), of their cellular origins, and this may bias subsequent differentiation. Neurons are difficult to reprogram, and there has not been a systematic side-by-side characterization of reprogramming efficiency or epigenetic memory across different neuronal subtypes. Here, we compare reprogramming efficiency of five different retinal cell types at two different stages of development. Retinal differentiation from each iPSC line was measured using a quantitative standardized scoring system called STEM-RET and compared to the epigenetic memory. Neurons with the lowest reprogramming efficiency produced iPSC lines with the best retinal differentiation and were more likely to retain epigenetic memory of their cellular origins. In addition, we identified biomarkers of iPSCs that are predictive of retinal differentiation. : Wang et al. reprogram retinal cell types into iPSCs and test their ability to make retinal organoids. They discover an inverse correlation between reprogramming efficiency and retinal differentiation linked to DNA/chromatin modifications and nuclear organization. These data identify molecular markers of iPSC lines that are efficient at producing retina. Keywords: iPSCs, epigenetics, reprogramming, retina, epigenetic memory, retinal organoid, chromHMM, Meis