Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Tender evaluation and selection system for design & build (D&B) project

This research aims to establish a tender evaluation model for D&B projects that combines both qualitative and quantitative criteria with a fairing assessment recommendation.Master of Science (International Construction Management

NTUC Income : managing social mission and business goals in a market-driven economy

(formerly titled "NTUC Income Moves Into Uncharted Waters -- A Union-based Insurance Cooperative Faces The Liberalization Of The Financial Industry In Singapore") This case traces the corporate history and development of NTUC Income (INCOME), the only insurance cooperative in Singapore. Established in 1970 as the "poor man's insurer" with the social goal of providing coverage for the low and middle income groups, INCOME today ranks among the top life and general insurers in Singapore. While INCOME has been very profitable since its inception, it has never lost sight of its social and community role of serving its policyholders and the citizens of Singapore. This fact was not missed by the Prime Minister of Singapore who urged the cooperative "not to forget those in the lower income bracket" when he graced the cooperative's 30th anniversary celebration as Guest-of-Honour. Since 2001, the local insurance industry had undergone major changes in the form of new regulations following the Monetary Authority of Singapore's liberalization of the financial services industry. One regulation, in particular, required all insurance agents in Singapore to undergo at least 30 hours of professional training annually. This ruling would have an adverse impact on INCOME's part-time agents who made up more than 80 percent of the cooperative's sales force. Many were likely to quit and INCOME could soon see its part-time sales force halved. The liberalization was also expected to attract new players to the insurance market. With new challenges posed by the liberalization, what would the future hold for INCOME? INCOME had enjoyed years of tremendous growth and had emerged from the Asian Crisis relatively unscathed. Could its previous success help pave the way for continued prosperity? In the face of greater competition, how should INCOME continue to meet its social objectives without neglecting or giving up some of its business goals

An empirical study on the efficiency of the Singapore equity market.

This paper aims to determine the efficiency of the Singapore stock market empirically, using conventional least-squared regression as well as more sophisticated testing techniques such as Vector Autoregression (VAR) andvariance bounds tests. The results will provide much insight into the development of the equity market in light of Singapore’s efforts to become a global financial hub

Maritime Interdiction Operations in Logistically Barren Environments

Includes supplementary materialThis report contains analysis that shows that existing technology exists to improve Maritime Interdiction Operations (MIO) by approximately 30%. Furthermore, analysis contained herein will aid MIO planning for future operations. Since MIOs are an inherently dangerous, but necessary activity with far reaching implications to theater political and economic dynamics, this improvement is of great interest. MIO is a Naval solution to the problems of smuggling weapons, explosives, people and narcotics. MIO, when employed correctly has the potential to save lives and limit economic/political damage.N

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM

Topography of transcriptionally active chromatin in glioblastoma

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer–driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Ministry of Health (MOH)National Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThe discovery of ETC-168 (also known as AUM168 in AUM Biosciences) was financially supported by the Biomedical Sciences Institutes and Joint Council Office (JCO Project 11 03 FG 07 05), Agency for Science, Technology and Research, Singapore. This work is funded by the NIH (R01-CA200992-04 to H.P.K., and R35CA197628 and R01CA213138 to M.M.), the Howard Hughes Medical Institute (HHMI-55108547 to M.M.), the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research Investigator Award (NMRC/STaR/0021/2014 to H.P.K.), the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2017-T2-1-033 to H.P.K.), the NMRC Centre Grant Programme awarded to the National University Cancer Institute of Singapore (NMRC/CG/012/2013 and CGAug16M005), the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives, the RNA Biology Center at the Cancer Science Institute of Singapore (MOE2014-T3-1-006), the NMRC Open Fund Young Individual Research Grants (MOH-OFYIRG18May-0001 to L.X. and MOH-OFYIRG19Nov-0016 to Y.C.), and the NMRC Translational and Clinical Research Flagship Programme grant (NMRC/TCR/016-NNI/2016 to B.T.A. and C.T.). In addition, this work is supported by the NUS Center for Cancer Research, Cancer Programme under Translational Research Programmes, Yong Loo Lin School of Medicine, NUS (NUHSRO/2020/122/MSC/07/Cancer), a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research grant through donations from the Yong Loo Lin Trust, and philanthropic donations from the Melamed family, and Valerie Baker Fairbank who also gave us encouragement. J.C. is supported by the Start-up Grant of HZNU (4125C5021820470), National Natural Science Foundation of China (81802338 and 82072646), and Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (LR21H160001). Y.H. is supported by Jiangsu Province Commission of Health and Family Planning Research funding (H2017064) and Suzhou Science and Technology Development Plan (SS201864). M.M. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar