To what extent has ASEAN succeeded in driving economic regionalism?

published_or_final_versionInternational and Public AffairsMasterMaster of International and Public Affair

Protocol of a systematic review and network meta-analysis for the prevention and treatment of perinatal depression

Introduction Perinatal depression is common and can often lead to adverse health outcomes for mother and child. Multiple pharmacological and non-pharmacological treatments have been evaluated against usual care or placebo controls in meta-analyses for preventing and treating perinatal depression compared. It is not yet established which of these candidate treatments might be the optimal approach for prevention or treatment. Methods and analysis A systematic review and Bayesian network meta-analyses will be conducted. Eight electronic databases shall be searched for randomised controlled trials that have evaluated the effectiveness of treatments for prevention and/or treatment of perinatal depression. Screening of articles shall be conducted by two reviewers independently. One network meta-analysis shall evaluate the effectiveness of interventions in preventing depression during the perinatal period. A second network meta-analysis shall compare the effectiveness of treatments for depression symptoms in women with perinatal depression. Bayesian 95% credible intervals shall be used to estimate the pooled mean effect size of each treatment, and surface under cumulative ranking area will be used to rank the treatments\u27 effectiveness. Ethics and dissemination We shall report our findings so that healthcare providers can make informed decisions on what might be the optimal approach for addressing perinatal depression to prevent cases and improve outcomes in those suffering from depression through knowledge exchange workshops, international conference presentations and journal article publications. PROSPERO registration number CRD42020200081

TSPYL2 Is Important for G1 Checkpoint Maintenance upon DNA Damage

Nucleosome assembly proteins play important roles in chromatin remodeling, which determines gene expression, cell proliferation and terminal differentiation. Testis specific protein, Y-encoded-like 2 (TSPYL2) is a nucleosome assembly protein expressed in neuronal precursors and mature neurons. Previous studies have shown that TSPYL2 binds cyclin B and inhibits cell proliferation in cultured cells suggesting a role in cell cycle regulation. To investigate the physiological significance of TSPYL2 in the control of cell cycle, we generated mice with targeted disruption of Tspyl2. These mutant mice appear grossly normal, have normal life span and do not exhibit increased tumor incidence. To define the role of TSPYL2 in DNA repair, checkpoint arrest and apoptosis, primary embryonic fibroblasts and thymocytes from Tspyl2 deficient mice were isolated and examined under unperturbed and stressed conditions. We show that mutant fibroblasts are impaired in G1 arrest under the situation of DNA damage induced by gamma irradiation. This is mainly attributed to the defective activation of p21 transcription despite proper p53 protein accumulation, suggesting that TSPYL2 is additionally required for p21 induction. TSPYL2 serves a biological role in maintaining the G1 checkpoint under stress condition

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

LARVA - An Integrative Framework for Large-scale Analysis of Recurrent Variants in Noncoding Annotations - And Other Tools for Cancer Genome Analysis

Initial approaches to cancer treatment have involved classifying cancer by the site in which it is first formed, and treating it with drugs and other therapies that have very broad targeting. These therapies are often prone to damaging healthy cells in the process, which may lead to additional health complications. With the advent of high-throughput sequencing, and the development of computational tools and software to process the subsequent deluge of sequencing data, much progress has been made on functionally annotating the human genome. Many genomes have been cost-effectively sequenced, providing insight into genetic variation between various human populations. The methods used to study population variation may also be used to study the basis of genetic disease, including cancer. It has now been demonstrated that there are many molecular subtypes of cancer, where each subtype is differentiated based on which important cellular molecule or DNA sequence has been disrupted. Hence, understanding the genetic basis of cancer is paramount to the development of new, personalized molecular therapies to treat cancer. Noncoding variants are known to be associated with disease, but they are not as commonly investigated as coding variants since assessing the functional impact of a mutation is difficult. For rare mutations, background mutation models have been set up for burden tests to discover highly mutated regions, which might be potential drivers of cancer. This has been developed for coding regions, leading to the successful use of burden tests to find highly mutated genes. However, this is challenging for noncoding regions because of mutation rate heterogeneity and potential correlations across regions, which give rise to huge overdispersion in the mutation count data. If not corrected, such overdispersions may suggest artefactual mutational hotspots. We address these issues with the development of a new computational framework called LARVA. LARVA intersects whole genome single nucleotide variant (SNV) calls with a comprehensive set of noncoding regulatory elements, and models these elements' mutation counts with a beta-binomial distribution to handle the overdispersion in a principled fashion. Furthermore, in estimating this distribution and determining the local mutation rate, LARVA incorporates regional genomic features like replication timing. The LARVA framework can be extended in certain ways to facilitate the analysis of its results. By storing information on highly mutated annotations in a relational database, it is possible to quickly extract the most interesting results for further analysis. Furthermore, results from multiple LARVA runs can be combined for a meta-analysis that could involve, for example, finding highly mutated pathways in cancer and other types of genetic disease. Since LARVA's computation consists of many independent units of work, it can benefit from various forms of parallel computation. These forms of computation include distributed computing with a large number of commodity processors, as well as more esoteric types of parallelization, such as general purpose graphics processing unit (GPU) computation. We make LARVA available as free software tool at larva.gersteinlab.org. We demonstrate the effectiveness of LARVA by showing how it identifies the well-known noncoding drivers, such as TERT promoter, on 760 cancer whole genomes. Furthermore, we show it is able to highlight several novel noncoding regulators that could be potential new noncoding drivers. We also make all of the highly mutated annotations available online. We also describe the Aggregation and Correlation Toolbox (ACT), a collection of software tools that facilitates the analysis of genomic signal tracks. The aggregation component takes a signal track and a series of genome regions, and creates an aggregate profile of the signal over the given regions. This enables the discovery of consistent signal patterns over related sets of annotations, implying potential connections between the signal and the regions. The correlation component of ACT takes two or more signal tracks and computes all pairwise track correlations. Correlation analyses are useful for finding similarities between various experiments, such as the binding sites of transcription factors as determined by ChIP-seq. The final component of ACT is a saturation tool designed to determine the number of experiments necessary to cover genomic features to saturation. This type of analysis can be illustrated with a ChIP-seq experiment where the inclusion of additional cell lines will reveal more binding sites for a transcription factor of interest: with each new cell line, a smaller fraction of the sites will be newly discovered, and a larger fraction will overlap discovered sites from previously used cell lines. The objective of ACT's saturation tool is to find the point of diminishing returns in the discovery of new sites, which may result in more efficiently planned experiments

Expression studies of NAP79: a new member of nucleosome assembly proteins

tocpublished_or_final_versionabstractPaediatrics and Adolescent MedicineMasterMaster of Philosoph

Hyperglycemia Altered DNA Methylation Status and Impaired Pancreatic Differentiation from Embryonic Stem Cells

The prevalence of type 2 diabetes (T2D) is rapidly increasing across the globe. Fetal exposure to maternal diabetes was correlated with higher prevalence of impaired glucose tolerance and T2D later in life. Previous studies showed aberrant DNA methylation patterns in pancreas of T2D patients. However, the underlying mechanisms remained largely unknown. We utilized human embryonic stem cells (hESC) as the in vitro model for studying the effects of hyperglycemia on DNA methylome and early pancreatic differentiation. Culture in hyperglycemic conditions disturbed the pancreatic lineage potential of hESC, leading to the downregulation of expression of pancreatic markers PDX1, NKX6−1 and NKX6−2 after in vitro differentiation. Genome-wide DNA methylome profiling revealed over 2000 differentially methylated CpG sites in hESC cultured in hyperglycemic condition when compared with those in control glucose condition. Gene ontology analysis also revealed that the hypermethylated genes were enriched in cell fate commitment. Among them, NKX6−2 was validated and its hypermethylation status was maintained upon differentiation into pancreatic progenitor cells. We also established mouse ESC lines at both physiological glucose level (PG-mESC) and conventional hyperglycemia glucose level (HG-mESC). Concordantly, DNA methylome analysis revealed the enrichment of hypermethylated genes related to cell differentiation in HG-mESC, including Nkx6−1. Our results suggested that hyperglycemia dysregulated the epigenome at early fetal development, possibly leading to impaired pancreatic development

Association of clinical factors with survival outcomes in laryngeal squamous cell carcinoma (LSCC).

10.1371/journal.pone.0224665PLoS One1411e0224665

Association of clinical factors with survival outcomes in laryngeal squamous cell carcinoma (LSCC).

AimTreatment strategies in laryngeal squamous cell cancer (LSCC) straddle the need for long term survival and tumor control as well as preservation of laryngeal function as far as possible. We sought to identify prognostic factors affecting LSCC outcomes in our population.MethodsClinical characteristics, treatments and survival outcomes of patients with LSCC were analysed. Baseline comorbidity data was collected and age-adjusted Charlson Comorbidity Index (aCCI) was calculated. Outcomes of overall survival (OS), progression-free survival (PFS) and laryngectomy-free survival (LFS) were evaluated.ResultsTwo hundred and fifteen patients were included, 170 (79%) underwent primary radiation/ chemoradiation and the remainder upfront surgery with adjuvant therapy where indicated. The majority of patients were male, Chinese and current/ex-smokers. Presence of comorbidity was common with median aCCI of 3. Median OS was 5.8 years. On multivariable analyses, high aCCI and advanced nodal status were associated with inferior OS (HR 1.24 per one point increase in aCCI, PConclusionIn our Asian population, the presence of comorbidities and high nodal status were associated with inferior OS, PFS and LFS whilst high T stage was associated with inferior LFS and OS