NONO enhances mRNA processing of super-enhancer-associated GATA2 and HAND2 genes in neuroblastoma

High-risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA-binding protein, NONO, in neuroblastoma is associated with poor patient outcome; however, there is little understanding of the mechanism of NONO-dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biochemical and genome-wide molecular analysis to reveal complex NONO-dependent regulation of gene expression. NONO forms RNA- and DNA-tethered condensates throughout the nucleus and undergoes phase separation in vitro, modulated by nucleic acid binding. CLIP analyses show that NONO mainly binds to the 5′ end of pre-mRNAs and modulates pre-mRNA processing, dependent on its RNA-binding activity. NONO regulates super-enhancer-associated genes, including HAND2 and GATA2. Abrogating NONO RNA binding, or phase separation activity, results in decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA-binding activity of NONO may have therapeutic potential in this cancer context

3D thermal analysis of a permanent magnet motor with cooling fans

Overheating of permanent magnet (PM) machines has become a major technical challenge as it gives rise to magnet demagnetization, degradation of insulation materials, and loss of motor efficiency. This paper proposes a state-of-the-art cooling system for an axial flux permanent magnet (AFPM) machine with the focus on its structural optimization. A computational fluid dynamics (CFD) simulation with thermal consideration has been shown to be an efficient approach in the literature and is thus employed in this work. Meanwhile, a simplified numerical approach to the AFPM machine with complex configuration in 3D consisting of conduction, forced convection, and conjugate heat transfer is taken as a case study. Different simplification methods (including configuration and working conditions) and two optimized fans for forced convection cooling are designed and installed on the AFPM machine and compared to a natural convection cooling system. The results show that the proposed approach is effective for analyzing the thermal performance of a complex AFPM machine and strikes a balance between reasonable simplification, accuracy, and computational resource

"Forget" the Forget Gate: Estimating Anomalies in Videos using Self-contained Long Short-Term Memory Networks

Abnormal event detection is a challenging task that requires effectively handling intricate features of appearance and motion. In this paper, we present an approach of detecting anomalies in videos by learning a novel LSTM based self-contained network on normal dense optical flow. Due to their sigmoid implementations, standard LSTM's forget gate is susceptible to overlooking and dismissing relevant content in long sequence tasks like abnormality detection. The forget gate mitigates participation of previous hidden state for computation of cell state prioritizing current input. In addition, the hyperbolic tangent activation of standard LSTMs sacrifices performance when a network gets deeper. To tackle these two limitations, we introduce a bi-gated, light LSTM cell by discarding the forget gate and introducing sigmoid activation. Specifically, the LSTM architecture we come up with fully sustains content from previous hidden state thereby enabling the trained model to be robust and make context-independent decision during evaluation. Removing the forget gate results in a simplified and undemanding LSTM cell with improved performance effectiveness and computational efficiency. Empirical evaluations show that the proposed bi-gated LSTM based network outperforms various LSTM based models verifying its effectiveness for abnormality detection and generalization tasks on CUHK Avenue and UCSD datasets.Comment: 16 pages, 7 figures, Computer Graphics International (CGI) 202

Structural basis of dimerization and nucleic acid binding of human DBHS proteins NONO and PSPC1.

The Drosophila behaviour/human splicing (DBHS) proteins are a family of RNA/DNA binding cofactors liable for a range of cellular processes. DBHS proteins include the non-POU domain-containing octamer-binding protein (NONO) and paraspeckle protein component 1 (PSPC1), proteins capable of forming combinatorial dimers. Here, we describe the crystal structures of the human NONO and PSPC1 homodimers, representing uncharacterized DBHS dimerization states. The structures reveal a set of conserved contacts and structural plasticity within the dimerization interface that provide a rationale for dimer selectivity between DBHS paralogues. In addition, solution X-ray scattering and accompanying biochemical experiments describe a mechanism of cooperative RNA recognition by the NONO homodimer. Nucleic acid binding is reliant on RRM1, and appears to be affected by the orientation of RRM1, influenced by a newly identified 'β-clasp' structure. Our structures shed light on the molecular determinants for DBHS homo- and heterodimerization and provide a basis for understanding how DBHS proteins cooperatively recognize a broad spectrum of RNA targets

The positive mental health instrument: development and validation of a culturally relevant scale in a multi-ethnic asian population

<p>Abstract</p> <p>Background</p> <p>Instruments to measure mental health and well-being are largely developed and often used within Western populations and this compromises their validity in other cultures. A previous qualitative study in Singapore demonstrated the relevance of spiritual and religious practices to mental health, a dimension currently not included in exiting multi-dimensional measures. The objective of this study was to develop a self-administered measure that covers all key and culturally appropriate domains of mental health, which can be applied to compare levels of mental health across different age, gender and ethnic groups. We present the item reduction and validation of the Positive Mental Health (PMH) instrument in a community-based adult sample in Singapore.</p> <p>Methods</p> <p>Surveys were conducted among adult (21-65 years) residents belonging to Chinese, Malay and Indian ethnicities. Exploratory and confirmatory factor analysis (EFA, CFA) were conducted and items were reduced using item response theory tests (IRT). The final version of the PMH instrument was tested for internal consistency and criterion validity. Items were tested for differential item functioning (DIF) to check if items functioned in the same way across all subgroups. <b>Results: </b>EFA and CFA identified six first-order factor structure (General coping, Personal growth and autonomy, Spirituality, Interpersonal skills, Emotional support, and Global affect) under one higher-order dimension of Positive Mental Health (RMSEA = 0.05, CFI = 0.96, TLI = 0.96). A 47-item self-administered multi-dimensional instrument with a six-point Likert response scale was constructed. The slope estimates and strength of the relation to the theta for all items in each six PMH subscales were high (range:1.39 to 5.69), suggesting good discrimination properties. The threshold estimates for the instrument ranged from -3.45 to 1.61 indicating that the instrument covers entire spectrums for the six dimensions. The instrument demonstrated high internal consistency and had significant and expected correlations with other well-being measures. Results confirmed absence of DIF.</p> <p>Conclusions</p> <p>The PMH instrument is a reliable and valid instrument that can be used to measure and compare level of mental health across different age, gender and ethnic groups in Singapore.</p

Ethnic differences in the association of fat and lean mass with bone mineral density in the Singapore population

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Caesarean section without medical indications is associated with an increased risk of adverse short-term maternal outcomes: the 2004-2008 WHO Global Survey on Maternal and Perinatal Health

<p>Abstract</p> <p>Background</p> <p>There is worldwide debate about the appropriateness of caesarean sections performed without medical indications. In this analysis, we aim to further investigate the relationship between caesarean section without medical indication and severe maternal outcomes.</p> <p>Methods</p> <p>This is a multicountry, facility-based survey that used a stratified multistage cluster sampling design to obtain a sample of countries and health institutions worldwide. A total of 24 countries and 373 health facilities participated in this study. Data collection took place during 2004 and 2005 in Africa and the Americas and during 2007 and 2008 in Asia. All women giving birth at the facility during the study period were included and had their medical records reviewed before discharge from the hospital. Univariate and multilevel analysis were performed to study the association between each group's mode of delivery and the severe maternal and perinatal outcome.</p> <p>Results</p> <p>A total of 286,565 deliveries were analysed. The overall caesarean section rate was 25.7% and a total of 1.0 percent of all deliveries were caesarean sections without medical indications, either due to maternal request or in the absence of other recorded indications. Compared to spontaneous vaginal delivery, all other modes of delivery presented an association with the increased risk of death, admission to ICU, blood transfusion and hysterectomy, including antepartum caesarean section without medical indications (Adjusted Odds Ratio (Adj OR), 5.93, 95% Confidence Interval (95% CI), 3.88 to 9.05) and intrapartum caesarean section without medical indications (Adj OR, 14.29, 95% CI, 10.91 to 18.72). In addition, this association is stronger in Africa, compared to Asia and Latin America.</p> <p>Conclusions</p> <p>Caesarean sections were associated with an intrinsic risk of increased severe maternal outcomes. We conclude that caesarean sections should be performed when a clear benefit is anticipated, a benefit that might compensate for the higher costs and additional risks associated with this operation.</p

Gestational diabetes mellitus and retinal microvasculature.

BACKGROUND: Small-vessel dysfunction may be an important consequence of chronic hyperglycemia. We examined the association between gestational diabetes mellitus (GDM), a state of transient hyperglycemia during pregnancy, and retinal microvascular changes in pregnant women at 26-28 weeks of pregnancy. METHODS: A total of 1136 pregnant women with singleton pregnancies were recruited during their first trimester at two major Singapore maternity hospitals in an on-going birth cohort study. Participants underwent an oral glucose tolerance test and retinal imaging at 26-28 weeks gestation (n = 542). We used the 1999 World Health Organization (WHO) criteria to define GDM: ≥7.0 mmol/L for fasting glucose and/or ≥7.8 mmol/L for 2-h post-glucose. Retinal microvasculature was measured using computer software (Singapore I Vessel Analyzer, SIVA version 3.0, Singapore Eye Research Institute, Singapore) from the retinal photographs. RESULTS: In a multiple linear regression model adjusting for age, ethnicity and maternal education, mothers with GDM had narrower arteriolar caliber (-1.6 μm; 95% Confidence Interval [CI]: -3.1 μm, -0.2 μm), reduced arteriolar fractal dimension (-0.01 Df; 95% CI: -0.02 Df, -0.001 Df;), and larger arteriolar branching angle (1.8°; 95% CI: 0.3°, 3.3°) than mothers without GDM. After further adjusting for traditional risks of GDM, arteriolar branching angle remained significantly larger in mothers with GDM than those without GDM (2.0°; 95% CI: 0.5°, 3.6°). CONCLUSIONS: GDM was associated with a series of retinal arteriolar abnormalities, including narrower caliber, reduced fractal dimension and larger branching angle, suggesting that transient hyperglycemia during pregnancy may cause small-vessel dysfunction