Linkage and association of myocilin (MYOC) polymorphisms with high myopia in a Chinese population

Author name used in this publication: Maurice K.H. Yap2006-2007 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Harnessing technology and molecular analysis to understand the development of cardiovascular diseases in Asia: a prospective cohort study (SingHEART)

BACKGROUND: Cardiovascular disease (CVD) imposes much mortality and morbidity worldwide. The use of "deep learning", advancements in genomics, metabolomics, proteomics and devices like wearables have the potential to unearth new insights in the field of cardiology. Currently, in Asia, there are no studies that combine the use of conventional clinical information with these advanced technologies. We aim to harness these new technologies to understand the development of cardiovascular disease in Asia. METHODS: Singapore is a multi-ethnic country in Asia with well-represented diverse ethnicities including Chinese, Malays and Indians. The SingHEART study is the first technology driven multi-ethnic prospective population-based study of healthy Asians. Healthy male and female subjects aged 21-69 years old without any prior cardiovascular disease or diabetes mellitus will be recruited from the general population. All subjects are consented to undergo a detailed on-line questionnaire, basic blood investigations, resting and continuous electrocardiogram and blood pressure monitoring, activity and sleep tracking, calcium score, cardiac magnetic resonance imaging, whole genome sequencing and lipidomic analysis. Outcomes studied will include mortality and cause of mortality, myocardial infarction, stroke, malignancy, heart failure, and the development of co-morbidities. DISCUSSION: An initial target of 2500 patients has been set. From October 2015 to May 2017, an initial 683 subjects have been recruited and have completed the initial work-up the SingHEART project is the first contemporary population-based study in Asia that will include whole genome sequencing and deep phenotyping: including advanced imaging and wearable data, to better understand the development of cardiovascular disease across different ethnic groups in Asia

In silico analyses of metagenomes from human atherosclerotic plaque samples

Background Through several observational and mechanistic studies, microbial infection is known to promote cardiovascular disease. Direct infection of the vessel wall, along with the cardiovascular risk factors, is hypothesized to play a key role in the atherogenesis by promoting an inflammatory response leading to endothelial dysfunction and generating a proatherogenic and prothrombotic environment ultimately leading to clinical manifestations of cardiovascular disease, e.g., acute myocardial infarction or stroke. There are many reports of microbial DNA isolation and even a few studies of viable microbes isolated from human atherosclerotic vessels. However, high-resolution investigation of microbial infectious agents from human vessels that may contribute to atherosclerosis is very limited. In spite of the progress in recent sequencing technologies, analyzing host-associated metagenomes remain a challenge. Results To investigate microbiome diversity within human atherosclerotic tissue samples, we employed high-throughput metagenomic analysis on: (1) atherosclerotic plaques obtained from a group of patients who underwent endarterectomy due to recent transient cerebral ischemia or stroke. (2) Presumed stabile atherosclerotic plaques obtained from autopsy from a control group of patients who all died from causes not related to cardiovascular disease. Our data provides evidence that suggest a wide range of microbial agents in atherosclerotic plaques, and an intriguing new observation that shows these microbiota displayed differences between symptomatic and asymptomatic plaques as judged from the taxonomic profiles in these two groups of patients. Additionally, functional annotations reveal significant differences in basic metabolic and disease pathway signatures between these groups. Conclusions We demonstrate the feasibility of novel high-resolution techniques aimed at identification and characterization of microbial genomes in human atherosclerotic tissue samples. Our analysis suggests that distinct groups of microbial agents might play different roles during the development of atherosclerotic plaques. These findings may serve as a reference point for future studies in this area of research

High-resolution digital phenotypes from consumer wearables and their applications in machine learning of cardiometabolic risk markers: cohort study

Background: Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized. Objective: We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk. Methods: We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events. Results: We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on high-resolution features had 17.9% and 7.36% improvement in Brier score over baselines based on age and gender and resting heart rate, respectively (P<.001 in each case). Furthermore, heart rate dynamics from different activity states contain distinct information (maximum absolute correlation coefficient of 0.15). Heart rate dynamics in sedentary states are most predictive of lipid abnormalities and obesity, whereas patterns in active states are most predictive of blood pressure abnormalities (P<.001). Moreover, in comparison with standard measures, higher resolution patterns in wearable heart rate recordings are better able to represent subtle physiological dynamics related to genomic risk for cardiometabolic disease (improvement of 11.9%-22.0% in Brier scores; P<.001). Finally, illustrative case studies reveal connections between these high-resolution phenotypes and actualized clinical events, even for borderline profiles lacking apparent cardiometabolic risk markers. Conclusions: High-resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance the prediction of cardiometabolic disease risk and could enable more proactive and personalized health management

Change of Positive Selection Pressure on HIV-1 Envelope Gene Inferred by Early and Recent Samples

HIV-1 infection has been on the rise in Japan recently, and the main transmission route has changed from blood transmission in the 1980s to homo- and/or hetero-sexual transmission in the 2000s. The lack of early viral samples with clinical information made it difficult to investigate the possible virological changes over time. In this study, we sequenced 142 full-length env genes collected from 16 Japanese subjects infected with HIV-1 in the 1980s and in the 2000s. We examined the diversity change in sequences and potential adaptive evolution of the virus to the host population. We used a codon-based likelihood method under the branch-site and clade models to detect positive selection operating on the virus. The clade model was extended to account for different positive selection pressures in different viral populations. The result showed that the selection pressure was weaker in the 2000s than in the 1980s, indicating that it might have become easier for the HIV to infect a new host and to develop into AIDS now than 20 years ago and that the HIV may be becoming more virulent in the Japanese population. The study provides useful information on the surveillance of HIV infection and highlights the utility of the extended clade models in analysis of virus populations which may be under different selection pressures

Novel roles for class II Phosphoinositide 3-Kinase C2 beta in signalling pathways involved in prostate cancer cell invasion

Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions such as proliferation, growth, survival and migration. The eight PI3K isoforms are grouped into three classes and the three enzymes belonging to the class II subfamily (PI3K-C2a, ß and ?) are the least investigated amongst all PI3Ks. Interest on these isoforms has been recently fuelled by the identification of specific physiological roles for class II PI3Ks and by accumulating evidence indicating their involvement in human diseases. While it is now established that these isoforms can regulate distinct cellular functions compared to other PI3Ks, there is still a limited understanding of the signalling pathways that can be specifically regulated by class II PI3Ks. Here we show that PI3K-C2ß regulates mitogen-activated protein kinase kinase (MEK1/2) and extracellular signal-regulated kinase (ERK1/2) activation in prostate cancer (PCa) cells. We further demonstrate that MEK/ERK and PI3K-C2ß are required for PCa cell invasion but not proliferation. In addition we show that PI3K-C2ß but not MEK/ERK regulates PCa cell migration as well as expression of the transcription factor Slug. These data identify novel signalling pathways specifically regulated by PI3K-C2ß and they further identify this enzyme as a key regulator of PCa cell migration and invasion

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Oncoproteomic Analysis Reveals Co-Upregulation of RELA and STAT5 in Carboplatin Resistant Ovarian Carcinoma

Ovarian cancer is one of the most lethal types of female malignancy. Although most patients are initially responsive to platinum-based chemotherapy, almost all develop recurrent chemoresistant tumors and succumb to their diseases. Elucidating the pathogenesis underlying drug resistance is fundamental to the development of new therapeutics, leading to improved clinical outcomes in these patients.We compared the proteomes of paired primary and recurrent post-chemotherapy ovarian high-grade serous carcinomas from nine ovarian cancer patients using CIEF/Nano-RPLC coupled with ESI-Tandem MS. As compared to their primary tumors, more than half of the recurrent tumors expressed higher levels of several proteins including CP, FN1, SYK, CD97, AIF1, WNK1, SERPINA3, APOD, URP2, STAT5B and RELA (NF-kappaB p65), which were also validated by quantitative RT-PCR. Based on shRNA screening for the upregulated genes in in vitro carboplatin-resistant cells, we found that simultaneous knockdown of RELA and STAT5B was most effective in sensitizing tumor cells for carboplatin treatment. Similarly, the NF-kappaB inhibitor, BMS-345541, and the STAT5 inhibitor, Dasatinib, significantly enhanced cell sensitivity to carboplatin. Moreover, both RELA and STAT5 are known to bind to the promoter region of Bcl-X, regulating its promoter activity. In this regard, augmented Bcl-xL expression was detected in carboplatin-resistant cells. Combined ectopic expression of RELA and STAT5B enhanced Bcl-xL promoter activity while treatment with BMS-345541 and Dasatinib decreased it. Chromatin immunoprecipitation of the Bcl-X promoter region using a STAT5 antibody showed induction of RELA and STAT5 DNA-binding segments both in naïve cells treated with a high concentration of carboplatin as well as in carboplatin-resistant cells.Proteomic analysis identified RELA and STAT5 as two major proteins associated with carboplatin resistance in ovarian tumors. Our results further showed that NF-kappaB and STAT5 inhibitor could sensitize carboplatin-resistant cells and suggest that such inhibitors can be used to benefit patients with carboplatin-resistant recurrent ovarian cancer

Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect ‘for better and worse'

Positive affect has been implicated in the phenomenological experience of various psychiatric disorders, vulnerability to develop psychopathology and overall socio-emotional functioning. However, developmental influences that may contribute to positive affect have been understudied. Here, we studied youths' 5-HTTLPR genotype and rearing environment (degree of positive and supportive parenting) to investigate the differential susceptibility hypothesis (DSH) that youth carrying short alleles of 5-HTTLPR would be more influenced and responsive to supportive and unsupportive parenting, and would exhibit higher and lower positive affect, respectively. Three independent studies tested this gene–environment interaction (GxE) in children and adolescents (age range 9–15 years; total N=1874). In study 1 (N=307; 54% girls), positive/supportive parenting was assessed via parent report, in study 2 (N=197; 58% girls) via coded observations of parent–child interactions in the laboratory and in study 3 (N=1370; 53% girls) via self report. Results from all the three studies showed that youth homozygous for the functional short allele of 5-HTTLPR were more responsive to parenting as environmental context in a ‘for better and worse' manner. Specifically, the genetically susceptible youth (that is, S'S' group) who experienced unsupportive, non-positive parenting exhibited low levels of positive affect, whereas higher levels of positive affect were reported by genetically susceptible youth under supportive and positive parenting conditions. These GxE findings are consistent with the DSH and may inform etiological models and interventions in developmental psychopathology focused on positive emotion, parenting and genetic susceptibility