Different WDR36 Mutation Pattern in Chinese Patients with Primary Open-angle Glaucoma

Purpose: To determine the distribution of WD repeat domain 36 (WDR36) sequence variants in Chinese patients with primary open-angle glaucoma (POAG). Methods: One hundred and thirty-five unrelated POAG patients (82 high tension glaucoma [HTG], 42 normal tension glaucoma [NTG], and 11 juvenile-onset POAG [JOAG] patients) and 77 unrelated controls were recruited. All 23 coding exons and splicing junctions of WDR36 were sequenced using BigDye® Terminator v3.1 cycle sequencing kit. Single nucleotide polymorphism (SNP) and haplotype associations were analyzed using PLINK (version 1.04). Results: Nineteen sequence alterations were identified, and eight of them were novel including two novel nonsynonymous SNPs (L240V and I713V). Except the common I264V polymorphism, no other previously reported disease-causing or disease-susceptibility mutations were found. The novel I713V mutation was observed in three (3.7%) patients with HTG. One intronic SNP, IVS5+30C>T (rs10038177), showed significantly higher frequency of minor allele T in HTG patients (16.5%) than in controls (1.3%; Odds ratio [OR]=15.0, p=7.9×10−7, Bonferroni corrected p=1.5×10−5). Haplotype GTA, which is composed of rs13153937, rs10038177, and rs11241095, was significantly associated with HTG (OR=22.5, p=0.002, Bonferroni corrected p=0.013). Neither the individual SNPs nor haplotypes of WDR36 were associated with NTG or JOAG (Bonferroni corrected p>0.05). Conclusions: Findings in this study suggest WDR36 to be associated with sporadic HTG but not with NTG or JOAG. Our results also suggest a different mutation pattern of WDR36 in the Chinese population from other ethnic populations

Hand grip strength as a nutritional assessment tool

Hand grip strength (HGS) is a new nutritional assessment parameter proposed by American Society for Parenteral and Enteral Nutrition (ASPEN) and the Academy of Nutrition and Dietetics (the Academy) for diagnosis of adult malnutrition related to acute illnesses, chronic diseases or starvation. Identification of ≥2 of the following conditions is considered to be malnourishment – weight loss, loss of muscle mass, loss of subcutaneous fat, fluid accumulation, diminished HGS and inadequate energy intake. HGS is also a marker of sarcopenia, a condition defined by low muscle mass and low muscle strength or performance, as identified by the European Working Group on Sarcopenia in Older People. It has also been shown that lower HGS is associated with deficits in activities of daily living (ADL) and mobility. HGS is emerging as an important screening tool especially in the malnourished and aging population. This research evaluates the applicability of HGS as a nutrition screening tool in long-term care older adults. Data from a total of 129 participants age ≥60 years involved in an ongoing walking program in long-term care facilities in Saskatoon available for analysis at the time this work was undertaken. Participants were randomly assigned for an intervention period of 16 weeks to one of three study groups: 1) Usual Care Group, 2) Interpersonal Interaction Group, and 3) Walking Program Group. Activity of daily living, cognition and depression scores and hand grip strength were recorded at baseline and every eight weeks. Information on vitamin D intake status prior to study commencement was also collected. This study provides values of low grip strength similar to those defined for the risk of sarcopenia in frail older adults. Stronger baseline HGS was correlated with greater ADL independence in females (B=0.079, P=0.044). Greater ability to eat at baseline was also associated with stronger grip in females when cognition status was taken into consideration. Baseline ADL (B=-0.024) and HGS (B=1.004) were significant predictors of subsequent ADL and HGS, respectively, in males (P<0.01). Baseline HGS was associated with subsequent ADL and HGS in females, but such association was modified by other covariates. In summary, if grip strength is to be used as a nutritional screening tool in long-term care facilities, dietitians shall be cautious of other factors such as the residents’ cognitive status and age and use in conjunction with other nutrition assessment methods

Early exclusion of major adverse cardiac events in emergency department chest pain patients: A prospective observational study

Background The current evaluation of patients with chest pain presenting to an emergency department (ED) with suspected acute coronary syndrome (ACS) is a lengthy process involving serial measurements of troponin. Objective We aimed to validate the diagnostic accuracy of a Thrombolysis in Myocardial Infarction (TIMI) score with single high-sensitive cardiac troponin T (hs-cTnT) for early rule out of 30-day major adverse cardiac events (MACE), and to compare the TIMI score with combinations of heart-type fatty acid binding protein (H-FABP) and a modified HEART (history, electrocardiogram, age, risk factors, troponin) score. Methods We recruited 602 consecutive adult patients with chest pain and suspected ACS in the ED. Each patient had TIMI and HEART scores, and a point-of-care H-FABP test. Results MACE occurred in 42 (7.0%) patients within 30 days. A low risk for 30-day MACE was identified by a modified TIMI score of 0 in 65 (11%) patients, and by a HEART score ≤ 2 in 96 (16%) patients. No MACE occurred in these groups, giving both scores a sensitivity of 100% (95% confidence interval [CI] 91.6–100%), and specificity of 11.6% (95% CI 9.2–14.5%) and 17.1% (95% CI 14.2–20.5%), respectively. Use of combined TIMI and HEART scores improved the specificity further to 22.0% (95% CI 18.7–25.6%) without lowering sensitivity. Early H-FABP measurement > 7 μg/L had a sensitivity of 41.5% (95% CI 27.8–56.6%) and a specificity of 91.1% (95% CI 88.4–93.2%) for predicting 30-day MACE. Conclusions A modified TIMI score of 0 or a HEART score of ≤ 2, incorporating a single hs-cTnT level, will identify patients with low risk of 30-day MACE for early discharge within 2 h of ED arrival

Physiological β-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma

BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/β-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological β-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of β-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells. RESULTS: Introduction of increased β-catenin signaling, haploid expression of β-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/β-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous β-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/β-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-β, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using β-catenin shRNA inhibitory assays, a dominant role for β-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres. CONCLUSIONS: Wnt/β-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/β-catenin signaling with stemness transition networks

CAN LABORATORY-BASED BIOMECHANICAL TEST RESULTS REFLECT THE PERCEIVED COMFORT DURING OVERGROUND RUNNING?

The purpose of this study was to measure the relationship between laboratory-based biomechanical test results and the perceived comfort of subjects obtained from overground running. Twelve male runners were recruited (age=20.3 ± 0.8 years, weight=61.1 ± 5.1 kg, height=171 ± 4 cm). They participated in three tests: Heel Cushioning Test, Rearfoot Movement Test, and Perceived Comfort Test. Human pendulum device with a controlled impact velocity at 1.15m/s was used in the first test to measure the heel cushioning properties. A digital camera was located posterior to the treadmill to record the rearfoot movement in the second test. And a questionnaire that consisted of three questions was used to measure the percevied comfort after overground running. The correlations between variables of Heel Cushioning Test and Perceived Comfort Test ranged from low (r = 0.118) to mediate (r = -0.564), and the correlations between variables of Rearfoot Movement Test and Perceived Comfort Test ranged from low (r = 0.160) to mediate (r = -0.563). Peak force plays an important role in determining the comfort rating. Loading rate was negatively related to perceived comfort in heel cushioning. Total rearfoot motion was found to contribute most in perceived comfort in medio-lateral control

Deep Convolutional Pooling Transformer for Deepfake Detection

Recently, Deepfake has drawn considerable public attention due to security and privacy concerns in social media digital forensics. As the wildly spreading Deepfake videos on the Internet become more realistic, traditional detection techniques have failed in distinguishing between real and fake. Most existing deep learning methods mainly focus on local features and relations within the face image using convolutional neural networks as a backbone. However, local features and relations are insufficient for model training to learn enough general information for Deepfake detection. Therefore, the existing Deepfake detection methods have reached a bottleneck to further improve the detection performance. To address this issue, we propose a deep convolutional Transformer to incorporate the decisive image features both locally and globally. Specifically, we apply convolutional pooling and re-attention to enrich the extracted features and enhance efficacy. Moreover, we employ the barely discussed image keyframes in model training for performance improvement and visualize the feature quantity gap between the key and normal image frames caused by video compression. We finally illustrate the transferability with extensive experiments on several Deepfake benchmark datasets. The proposed solution consistently outperforms several state-of-the-art baselines on both within- and cross-dataset experiments.Comment: Accepted to be published in ACM TOM

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

Background: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.published_or_final_versio

COMPARISON OF LANDING MANEUVERS BETWEEN SKILLFUL AND UNSKILLFUL FEMALE VOLLEYBALL PLAYERS

This study was to investigate the effect of training to the landing techniques of volleyball spike. Six female subjects were separated into two groups according to their experiences in playing volleyball. Kinematics parameters during landing phase were collected by using three-dimensional motion analysis technique. Pedar insole system with 50 Hz sampling frequency was employed to measure the insole peak force and pressure distribution. Significant differences were found in maximum impact force and peak pressure between the skillful and unskillful group. Skillful group also demonstrated a greater range of motion in the knee, hip and ankle joint respectively. The finding shows that the skillful group, who participated in regular volleyball, demonstrated a greater ability in reducing ground reaction force during landing, thus leading to a protective mechanism in preventing injury

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases

Prognostic significance of pleural fluid microbiological positivity in pleural infection: a bicentric 10-year retrospective observational study

Background: Despite its heterogeneity, there is currently limited data in pleural infection phenotyping. Using pleural fluid characteristics, pleural infection can be classified into microbiological-positive pleural infection (MPPI) and microbiological-negative pleural infection (MNPI). This study aimed to evaluate the prognostic significance of microbiological positivity in pleural infection, and to evaluate the performance of RAPID (renal, age, purulence, infection source, dietary factor) score in these subgroups. Methods: Consecutive patients hospitalized for pleural infection over a 10-year period in two acute-care hospitals in Hong Kong were evaluated. According to the pleural fluid characteristics, they were classified into MPPI and MNPI, respectively. Survival was evaluated using multivariate Cox regression analysis. Performance of RAPID score to predict mortality at 3-month and 1-year was evaluated using C-statistics. Results: In total, 381 patients with pleural infection were included. They were classified into MPPI (n = 169) and MNPI (n = 212), respectively. The MPPI group had more elderly home residence and use of large-bore chest tube, and higher Charlson comorbidity index and RAPID score, compared to the MNPI group. Length-of-stay, the need of surgery and intensive care were similar between the two groups. MPPI was associated with significantly increased risk of mortality (adjusted hazard ratio [aHR] 1.46, 95% CI 1.08–1.98). Three-month mortality was significantly higher in MPPI compared to MNPI (24.9% vs. 10.4%, p < 0.001; adjusted odd ratio 2.05, 95% CI 1.11–3.80). The trend continued at 1, 3, 5 and 7 years. RAPID score predicted 3-month and 1-year mortality in both groups (C-statistics, MPPI 0.71, 0.75; MNPI 0.84, 0.81). In the MPPI group, presence of Staphylococcus aureus (aHR 2.26, 95% CI 1.43–3.57) and Gram-negative organisms other than Enterobacteriaceae (aHR 2.00, 95% CI 1.10–3.61) were associated with worse survival, while presence of Streptococcus anginosus group was associated better survival (aHR 0.50, 95% CI 0.32–0.78), when compared to their absence. Conclusions: Pleural fluid microbiological positivity is independently associated with increased mortality in patients with pleural infections. This finding should complement the RAPID score in risk stratification and inform future research aimed at improving outcomes in this patient population