Structural and functional insight into human O-GlcNAcase

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Moriah.

Moriah is a narrative short film written, shot and produced by Chan Yi Hern (Bobby), Charlene Chan Shu Min, Wong Oi Shan, and Yew Si Yang, Marcus, as part of the group members’ Final Year Project (FYP) at the Wee Kim Wee School of Communication and Information, Nanyang Technological University. Known collectively as Fourbidden Productions, the team is supervised by Mr. Kym Campbell. Moriah is a discussion of universal problems of sacrifice and surrender to a higher power. It unravels the secret behind the death of a young woman and compels two Catholic priests to confront their personal struggles with God. This final report documents the nine months that Fourbidden Productions took to complete the film – from inspiration to concept, concept to print, and finally from print to screen. More importantly, this report discusses the philosophy that informed our decisions, how major obstacles were overcome, and the lessons we learnt through the making of Moriah.Bachelor of Communication & Informatio

Association between employer’s knowledge and attitude towards smoking cessation and voluntary promotion in workplace: a survey study

Background Workplace smoking cessation (SC) intervention is effective in increasing quit rate but little was known about the factors associated with voluntary SC promotion. Comprehensive smoke-free legislation, including banning smoking in all indoor area of workplaces, has been enforced in Hong Kong. This survey investigated the prevalence of company’s compliance with smoke-free legislation and examined the relation between voluntary SC promotion in workplace and employer’s knowledge of and attitude towards smoking and SC. Material and Methods Half (50.3%, n = 292) of a convenience sample of companies completed a self-administered questionnaire on company’s voluntary SC promotion in the workplace. Factors investigated included company’s characteristics (size, type, and number of smoking employees); employers’ knowledge of smoking, second-hand smoke and SC effects on health; perceived responsibility in assisting employees to quit smoking and smoking prohibition in workplace (smoke free policy). Logistic regression yielded adjusted odds ratio (aOR) for voluntary SC promotion. Results A notable proportion of companies (14.7%) showed non-compliance with the smoke free workplace ordinance and only 10% voluntarily promoted SC. Perceived greater negative impact of smoking on the company (adjusted odds ratio[aOR] 1.94, 95% confidence interval [CI] 1.18-3.20) and better knowledge of smoking (aOR 1.40, 95%CI 1.00-1.94) were associated with voluntary SC promotion. Positive but non-significant associations were observed between perceived responsibility of assisting employees to quit, workplace smoke free policy and voluntary SC promotion. Company characteristics were generally not associated with voluntary SC promotion except white collar companies were less likely to promote SC (aOR 0.26, 95% CI 0.08-0.85). Conclusions This is the first survey on company’s SC promotion in the Chinese population. A notable proportion of companies was not compliant with the smoke-free workplace ordinance. Employers with a higher level of knowledge and perceived impact of smoking on companies and from blue-collar companies were more likely to promote SC in workplace. The findings inform future workplace intervention design and policy

Evaluating a pilot community-based FITMIND exercise programme for psychosis in Hong Kong

Abstract Background Exercise interventions can improve clinical symptoms and cognition in patients with psychosis in addition to their physical health. However, their benefits may not be maximally generalised to those who cannot access gymnasium facilities, which were commonly required previously. This study evaluated a 12-week community exercise programme named FITMIND, which aims to help patients with psychosis establish exercise habits through easy-to-learn aerobic exercise and yoga, with the support of trained volunteers. Method This study analysed the profiles of 49 patients with psychosis who were referred by the case manager of the early psychosis programme in the public hospital in Hong Kong or enrolled in the programme through the project website. The outcome measures were working memory, physical activity (PA) participation, quality of life, and mood symptoms. Results At baseline, seven participants (14.3%) met the recommendation of the PA for severe mental illnesses. After the 12-week programme, participants demonstrated significant improvement in vigorous-intensity PA, moderate-to-vigorous PA, compliance with international guidelines for PA, and mood symptoms. Conclusion The FITMIND exercise programme is a feasible community-based intervention that can improve PA participation and mood in patients with psychosis. Further systematic studies are needed to examine the long-term beneficial effects of the programme

Pro-angiogenic activity of astragaloside IV in HUVECs in vitro and zebrafish in vivo

Astragaloside IV (AS-IV) is a natural product isolated from the Chinese medical herb, Radix Astragali, which has been reported to be a potential candidate for treating diseases associated with abnormal angiogenesis; however, the effect of AS-IV on angiogenesis and its underlying mechanisms are yet to be fully elucidated. In the present study, we investigated the angiogenic effect of AS-IV in vitro using human umbilical vein endothelial cells (HUVECs), and in vivo using zebrafish. AS-IV was found to stimulate the proliferation and migration of HUVECs in an XTT assay and a wound healing migration assay, respectively. Moreover, AS-IV stimulated the invasive ability of HUVECs and significantly increased the mean tube length of HUVECs in Matrigel. AS-IV induced an angiogenic response in HUVECs and enhanced mRNA expression of vascular endothelial growth factor (VEGF) and a VEGF receptor known as kinase‑domain region/fetal liver kinase-1/VEGF receptor 2 (KDR/Flk-1/VEGFR2), as well as activation of Akt as demonstrated by quantitative real-time PCR and Western blot analysis, respectively. The AS-IV-induced proliferation of HUVECs was capable of being suppressed by a KDR inhibitor (SU5416) and an Akt inhibitor (SH-6). AS-IV also rescued blood vessel loss in Tg (fli-1:EGFP) zebrafish. Altogether, our results suggest that AS-IV exerts potential pro-angiogenic effects in vitro and in vivo, and that its pro-angiogenic activity probably involves both VEGF- and Akt-dependent signaling pathways

The Frequency of Clinical Seizures in Paroxysmal Events in a Neonatal Intensive Care Unit

Background: In general clinical practice, neonatal seizures are identified visually by direct clinical observation. The study aimed to examine the frequency of clinical seizures in paroxysmal events in a neonatal intensive care unit. Methods: We conducted a prospective study of continuous video-EEG monitoring in a neonatal intensive care unit between January 2017 and December 2020. The demographic data were also reviewed. Results: Sixty-four neonates were enrolled. The median total video-EEG monitoring duration was 24.1 h (IQR 17.5–44.8 h). There were 309 clinically suspected seizure episodes, of which 181 (58.6%) were the motor type and 128 (41.4%) were the non-motor type. Only 63 (20.4%) of these events were confirmed to be clinical seizures on a simultaneous video-EEG recording. In terms of the impact of continuous video-EEG monitoring on clinical management, the anti-epileptic drugs were changed in 42 (65.6%) of the 64 neonates. Conclusion: In the identification of neonatal seizures, a clinical diagnosis by direct observation alone is not enough. The use of continuous video-EEG monitoring plays an important role in the diagnosis of neonatal seizures and in guiding clinical management decisions

Electrographic Seizures in Neonates with a High Risk of Encephalopathy

Background: Neonatal encephalopathy is caused by a wide variety of acute brain insults in newborns and presents with a spectrum of neurologic dysfunction, such as consciousness disturbance, seizures, and coma. The increased excitability in the neonatal brain appears to be highly susceptible to seizures after a variety of insults, and seizures may be the first clinical sign of a serious neurologic disorder. Subtle seizures are common in the neonatal period, and abnormal clinical paroxysmal events may raise the suspicion of neonatal seizures. Continuous video electroencephalographic (EEG) monitoring is the gold standard for the diagnosis of neonatal seizures. The aim of this study was to identify the prevalence of electrographic seizures and the impact of monitoring in neonates with a high risk of encephalopathy. Methods: We conducted this prospective cohort study in a tertiary neonatal intensive care unit over a 4-year period. Neonates with a high risk of encephalopathy who were receiving continuous video EEG monitoring were eligible. The patients were divided into 2 groups: (1) acute neonatal encephalopathy (ANE) and (2) other high-risk encephalopathy conditions (OHRs). The neonates’ demographic characteristics, etiologies, EEG background feature, presence of electrographic seizures and the impact of monitoring were analyzed. Results: A total of 71 neonates with a high risk of encephalopathy who received continuous video EEG monitoring were enrolled. In this consecutive cohort, 42 (59.2%) were monitored for ANE and 29 (40.8%) were monitored for OHRs. At the time of starting EEG monitoring, 54 (76.1%) of the neonates were term infants. The median gestational age at monitoring was 39 weeks (interquartile range, 37–41 weeks). The median total EEG monitoring duration was 64.7 h (interquartile range, 22.2–72.4 h). Electrographic seizures were captured in 25 of the 71 (35.2%) neonates, of whom 20 (80%) had electrographic-only seizures without clinical correlation. Furthermore, of these 20 neonates, 13 (65%) developed electrographic status epilepticus. Electrographic seizures were most commonly found in the ANE group (17, 40.5%) than in the OHRs group (8, 27.6%) (p = 0.013). Besides, normal/mild abnormality and inactive EEG background were less electrographic seizure than moderate and major abnormality EEG background (2 of 30, 6.7% vs. 23 of 41, 56.1%, p < 0.001). Finally, continuous video EEG monitoring excluded the diagnosis of electrographic seizures in two-thirds of the monitored neonates who had paroxysmal events mimicking seizures and led to a change in clinical management in 39.4% of the neonates. Conclusions: Our findings showed that monitoring could accurately detect seizures, and that it could be used to guide seizure medication management. Therefore, continuous video EEG monitoring has important clinical management implications in neonates with a high risk of encephalopathy

New loci and coding variants confer risk for age-related macular degeneration in East Asians

加齢黄斑変性の発症に関わるアジア人特有の遺伝子変異を発見. 京都大学プレスリリース. 2015-02-05.Updated 30 March 2015. [Corrigendum] doi:10.1038/ncomms7817Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2, 119 patients with exudative AMD and 5, 691 controls, with independent replication in 4, 226 patients and 10, 289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10[-22]). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17mmoll-1 (P=5.82 × 10[-21]) in East Asians (n=7, 102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10[-18]), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10[-11]) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10[-8]). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature