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Background/aim: The aim of our study was to investigate the outcome of colon cancer with bladder invasion after surgical intervention., Patients and Methods: Between 2011 and 2022, a total of 41 patients diagnosed with colon cancer and bladder invasion underwent surgical procedures at Taichung Veterans General Hospital. The impact of various risk factors on overall survival (OS) was assessed using Kaplan-Meier analyses and Cox proportional hazards models., Results: Among the enrolled patients, 21 underwent radical cystectomy, while 20 underwent partial cystectomy. Twelve had tumors located in the rectum, 19 in the sigmoid colon, and 10 in both the rectum and sigmoid colon. The median OS was 71.8 months in stage 2, 50.8 months in stage 3, and 11.2 months in stage 4 (p=0.061). Median OS was 71.8 months in patients with negative surgical margins and 10.5 months in those with positive surgical margins (p=0.003). In multivariate regression analysis, positive surgical margins [hazard ratio (HR)=3.64, 95% confidence interval (CI)=1.28-10.34, p=0.015] and emergency operations (HR=4.57, 95%CI=1.34-15.55, p=0.015) significantly impacted OS., Conclusion: Complete resection of colon cancer with bladder invasion can yield excellent oncologic outcomes. The decision between partial and radical cystectomy should balance surgical margin clearance and the preservation of quality of life. Both surgical margin involvement and emergency operations are independent risk factors for OS., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Studies documenting and seeking to understand the mindset effect have yielded mixed and inconclusive findings. The present study sought to address the research question pertaining to the mindset effect on creative thinking and its underlying mechanism from the perspectives of social cognitive theory and mindset theory, which postulate a motivational mechanism underlying the mindset-creativity link. Specifically, this study aimed to examine the mediating role of creativity motivation in the effects of growth and fixed creative mindsets on creative thinking. A convenience sample of 948 college students from three universities in Hong Kong participated in the study. Creative mindset, creativity motivation, and creative thinking were assessed using the Chinese version of the Creative Mindset Scale, the Creativity Motivation Scale, and the Test for Creative Thinking-Drawing Production (TCT-DP), respectively. Lending support to the perspectives of social cognitive and mindset theories, the results of mediation analyses conducted using Preacher and Hayes's bootstrapping approach indicated that creativity motivation had partial mediating effects on the positive and negative roles of growth and fixed mindsets, respectively, in creative thinking. Enriching the research on the motivation mechanism underlying the impacts of creative mindsets on creative thinking, the results further illustrated that creativity motivation has a stronger mediating effect on the impact of growth creative mindset on creative thinking than on that of fixed creative mindset. The possible theoretical and educational implications of the findings of this research are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 He and Chiang.)

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments., (© 2024. The Author(s).)

Circular RNAs (circRNAs) are RNA molecules with a continuous loop structure characterized by back-splice junctions (BSJs). While analyses of short-read RNA sequencing have identified millions of BSJ events, it is inherently challenging to determine exact full-length sequences and alternatively spliced (AS) isoforms of circRNAs. Recent advances in nanopore long-read sequencing with circRNA enrichment bring an unprecedented opportunity for investigating the issues. Here, we developed FL-circAS (https://cosbi.ee.ncku.edu.tw/FL-circAS/), which collected such long-read sequencing data of 20 cell lines/tissues and thereby identified 884 636 BSJs with 1 853 692 full-length circRNA isoforms in human and 115 173 BSJs with 135 617 full-length circRNA isoforms in mouse. FL-circAS also provides multiple circRNA features. For circRNA expression, FL-circAS calculates expression levels for each circRNA isoform, cell line/tissue specificity at both the BSJ and isoform levels, and AS entropy for each BSJ across samples. For circRNA biogenesis, FL-circAS identifies reverse complementary sequences and RNA binding protein (RBP) binding sites residing in flanking sequences of BSJs. For functional patterns, FL-circAS identifies potential microRNA/RBP binding sites and several types of evidence for circRNA translation on each full-length circRNA isoform. FL-circAS provides user-friendly interfaces for browsing, searching, analyzing, and downloading data, serving as the first resource for discovering full-length circRNAs at the isoform level., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Extracorporeal membrane oxygenation (ECMO) is a vital emergency procedure providing respiratory and circulatory support to critically ill patients, especially those with compromised cardiopulmonary function. Its use has grown due to technological advances and clinical demand. Prolonged ECMO usage can lead to complications, necessitating the timely assessment of peripheral microcirculation for an accurate physiological evaluation. This study utilizes non-invasive near-infrared spectroscopy (NIRS) to monitor knee-level microcirculation in ECMO patients. After processing oxygenation data, machine learning distinguishes high and low disease severity in the veno-venous (VV-ECMO) and veno-arterial (VA-ECMO) groups, with two clinical parameters enhancing the model performance. Both ECMO modes show promise in the clinical severity diagnosis. The research further explores statistical correlations between the oxygenation data and disease severity in diverse physiological conditions, revealing moderate correlations with the acute physiologic and chronic health evaluation (APACHE II) scores in the VV-ECMO and VA-ECMO groups. NIRS holds the potential for assessing patient condition improvements.

Purpose: In patients with chemotherapy, there is no consensus on the timing of ileostomy closure. Ileostomy reversal could improve the quality of life and minimise the long-term adverse events of delayed closure. In this study, we evaluated the impact of chemotherapy on ileostomy closure and searched for the predictive factors for complications., Methods: We retrospectively analysed 212 patients with rectal cancer who underwent ileostomy closure surgery during and without chemotherapy and were consecutively enrolled between 2010 and 2016. As a result of the heterogeneity of the two groups, propensity score matching (PSM) was performed with a 1:1 PSM cohort., Results: A total of 162 patients were included in the analysis. The overall stoma closure-related complications (12.4% vs. 11.1%, p = 1.00) and major complications (2.5% vs. 6.2%, p = 0.44) were not significantly different between the two groups. Multivariate analysis demonstrated that chronic kidney disease and bevacizumab use are risk factors for major complications., Conclusion: Patients with oral or intravenous chemotherapy can safely have ileostomy closure with an adequate time delay from chemotherapy. When patients use bevacizumab, major complications related to ileostomy closure should still be cautioned., (© 2023. Springer Nature Switzerland AG.)

Trans-spliced RNAs (ts-RNAs) are a type of non-co-linear (NCL) transcripts that consist of exons in an order topologically inconsistent with the corresponding DNA template. Detecting ts-RNAs is often interfered by experimental artifacts, circular RNAs (circRNAs) and genetic rearrangements. Particularly, intragenic ts-RNAs, which are derived from separate precursor mRNA molecules of the same gene, are often mistaken for circRNAs through analyses of RNA-seq data. Here we developed a bioinformatics pipeline (NCLscan-hybrid), which integrated short and long RNA-seq reads to minimize false positives and proposed out-of-circle and rolling-circle long reads to distinguish between intragenic ts-RNAs and circRNAs. Combining NCLscan-hybrid screening and multiple experimental validation steps successfully confirmed that four NCL events, which were previously regarded as circRNAs in databases, originated from trans-splicing. CRISPR-based endogenous genome modification experiments further showed that flanking intronic complementary sequences can significantly contribute to ts-RNA formation, providing an efficient/specific method to deplete ts-RNAs. We also experimentally validated that one ts-RNA (ts-ARFGEF1) played an important role for p53-mediated apoptosis through affecting the PERK/eIF2a/ATF4/CHOP signaling pathway in breast cancer cells. This study thus described both bioinformatics procedures and experimental validation steps for rigorous characterization of ts-RNAs, expanding future studies for identification, biogenesis, and function of these important but understudied transcripts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Psoriasis imposes a substantial burden on patients' social, emotional, physical, and family life. Although psoriasis has no complete cure, various treatments are available to control its symptoms and improve a patients' quality of life., Objective: We aimed to compare the effectiveness of biologic versus non-biologic treatments on health-related quality of life among patients with psoriasis in Malaysia., Methods: This retrospective cross-sectional study evaluated data of adult patients diagnosed with psoriasis during 2007-18 from the Malaysian Psoriasis Registry. Baseline demographics, disease, and treatment characteristics were described. For a subset of patients treated with biologics and non-biologics who had baseline and 6-month follow-up data available, changes in the mean Dermatology Life Quality Index scores and the proportion of patients with a clinically relevant improvement (≥ 4 points) post-treatment were assessed., Results: Overall, 15,238 adult patients with psoriasis from the Malaysian Psoriasis Registry were included in the analysis. Patients receiving biologics showed a statistically significant reduction in the mean Dermatology Life Quality Index scores after 6 months compared with those receiving non-biologic treatment (- 5.7 vs - 0.8%; p < 0.001). The proportion of patients who achieved a ≥ 4-point improvement in Dermatology Life Quality Index scores was approximately two times greater in the biologic-treated group versus the non-biologic-treated group (56.4 vs 27.7%)., Conclusions: Biologic treatment showed a greater reduction in the Dermatology Life Quality Index scores of patients with psoriasis versus non-biologic treatment. These results highlight the importance of early treatment with more efficacious treatment options, such as biologic therapies, to improve the overall health-related quality of life of patients with psoriasis., (© 2023. The Author(s).)

Background: Robotic surgery and ERAS protocol care are both prominent developments and have each become global trends. However, the effects and learning curves of combining robotic surgery and ERAS care in colorectal resection have not yet been well validated. This study aimed to present our real-world experience and establish the learning curves necessary for the implementation of an ERAS program in minimally-invasive surgery for colorectal resection, while also evaluating the impact that the development of the robotic technique has on ERAS outcomes., Methods: A total of 155 patients who received elective, minimally-invasive surgery, including laparoscopic and robotic surgery for colorectal resection, with ERAS care during the period June 2019 to September 2021 were included in this retrospective analysis. Patients were divided chronologically into five groups (31 cases per quintile). Patient demographics, tumor characteristics, perioperative data, ERAS compliance, and surgical outcomes were all compared among the quintiles. Learning curves were evaluated based on ERAS compliance and optimal recovery, which are composed of an absence of major complications, postoperative length of stay (LOS) of no more than five days, and no readmission within 30 days. A multivariable logistic regression model was used to assess factors associated with postoperative LOS., Results: There were no statistically significant differences seen overall or between the quintile groups in regards to demographic and tumor characteristic parameters. A total of 79 patients (51%) received robotic surgery, with the ratio of robotic groups rising chronologically from zero in the first quintile to 90.3% in the fifth quintile ( p < 0.001). The median compliance rate of total ERAS protocol was 83.3% overall, 72.2% in the first quintile and 83.3% in the 2nd-5th quintiles ( p < 0.001). A total of 85 patients underwent optimal recovery after surgery, four patients in the first quintile, 11 patients in the second quintile, and 21, 24, 25 patients in the 3rd-5th quintiles respectively ( p < 0.001). There were significant improvements from early to later groups upon postoperative LOS ( p < 0.001). In addition, the surgical outcomes including first oral intake within 24 hours after surgery, time to first stool and early termination of intravenous fluid administration showed significant improvement among the quintiles. A multivariable logistic regression model demonstrated that robotic surgery was superior to laparoscopic surgery upon postoperative LOS (odds ratio = 5.029, 95% confidence interval [CI] = 1.321 to 19.142; p = 0.018)., Conclusions: Our experience demonstrated that an effective implementation of the ERAS program in minimally-invasive colorectal surgery requires 31 patients to accomplish the higher compliance and requires more cases to reach the maturation phase for optimal recovery. We believe that developing a robotic platform would have no impact on the learning curve of ERAS implementation. Moreover, there is a beneficial effect on the postoperative length of surgery provided through the combination of ERAS care and robotic surgery for patients undergoing colorectal resection.

Circular RNAs (circRNAs) are non-polyadenylated RNAs with a continuous loop structure characterized by a non-colinear back-splice junction (BSJ). Although millions of circRNA candidates have been identified, it remains a major challenge for determining circRNA reliability because of various types of false positives. Here, we systematically assess the impacts of numerous factors related to circRNA identification, conservation, biogenesis, and function on circRNA reliability by comparisons of circRNA expression from mock and the corresponding colinear/polyadenylated RNA-depleted datasets based on three different RNA treatment approaches. Eight important indicators of circRNA reliability are determined. The relative contribution to variability explained analyses reveal that the relative importance of these factors in affecting circRNA reliability in descending order is the conservation level of circRNA, full-length circular sequences, supporting BSJ read count, both BSJ donor and acceptor splice sites at the same colinear transcript isoforms, both BSJ donor and acceptor splice sites at the annotated exon boundaries, BSJs detected by multiple tools, supporting functional features, and both BSJ donor and acceptor splice sites undergoing alternative splicing. This study thus provides a useful guideline and an important resource for selecting high-confidence circRNAs for further investigations., (© 2023 Chuang et al.)

Genetic risk variants and transcriptional expression changes in autism spectrum disorder (ASD) were widely investigated, but their causal relationship remains largely unknown. Circular RNAs (circRNAs) are abundant in brain and often serve as upstream regulators of mRNAs. By integrating RNA-sequencing with genotype data from autistic brains, we assessed expression quantitative trait loci of circRNAs (circQTLs) that cis-regulated expression of nearby circRNAs and trans-regulated expression of distant genes (trans-eGenes) simultaneously. We thus identified 3619 circQTLs that were also trans-eQTLs and constructed 19,804 circQTL-circRNA-trans-eGene regulatory axes. We conducted two different types of approaches, mediation and partial correlation tests (MPT), to determine the axes with mediation effects of circQTLs on trans-eGene expression through circRNA expression. We showed that the mediation effects of the circQTLs (trans-eQTLs) on circRNA expression were positively correlated with the magnitude of circRNA-trans-eGene correlation of expression profile. The positive correlation became more significant after adjustment for the circQTLs. Of the 19,804 axes, 8103 passed MPT. Meanwhile, we performed causal inference test (CIT) and identified 2070 circQTL-trans-eGene-ASD diagnosis propagation paths. We showed that the CIT-passing genes were significantly enriched for ASD risk genes, genes encoding postsynaptic density proteins, and other ASD-relevant genes, supporting the relevance of the CIT-passing genes to ASD pathophysiology. Integration of MPT- and CIT-passing axes further constructed 352 circQTL-circRNA-trans-eGene-ASD diagnosis propagation paths, wherein the circRNA-trans-eGene axes may act as causal mediators for the circQTL-ASD diagnosis associations. These analyses were also successfully applied to an independent dataset from schizophrenia brains. Collectively, this study provided the first framework for systematically investigating trans-genetic effects of circQTLs and inferring the corresponding causal relations in diseases. The identified circQTL-circRNA-trans-eGene regulatory interactions, particularly the internal modules that were previously implicated in the examined disorders, also provided a helpful dataset for further investigating causative biology and cryptic regulatory mechanisms underlying the neuropsychiatric diseases., (© 2022. The Author(s).)

Photonic crystals possess metastructures with a unique dispersion relation. An integrated optical circuit plays a crucial role in quantum computing, for which miniaturized optical components can be designed according to the characteristics of photonic crystals. Because the stable light transmission mode for a square waveguide is transverse electric or transverse magnetic polarization, we designed a half-waveplate element with a photonic crystal that can rotate the polarization direction of the light incident on a waveguide by 90°. Using the dispersion relation of photonic crystals, the polarization rotation length and the optical axis's angle of deviation from the electric field in the eigenmode can be effectively calculated. Polarization rotators designed on the basis of photonic crystal structures can effectively reduce the insertion loss of components and exhibit favorable polarization rotation performance.

The authority of user personal health records (PHRs) is usually determined by the owner of a cloud computing system. When a PHR file is accessed, a dynamic access control algorithm must be used to authenticate the users. The proposed dynamic access control algorithm is based on a novel Lagrange interpolation polynomial with timestamps, mainly functioning to authenticate the users with key information. Moreover, the inclusion of timestamps allows user access within an approved time slot to enhance the security of the healthcare cloud system. According to the security analysis results, this healthcare cloud system can effectively resist common attacks, including external attacks, internal attacks, collaborative attacks and equation-based attacks. Furthermore, the overall computational complexity of establishing and updating the polynomials is O( n * m * (log m ) 2 ), which is a promising result, where m denotes the degree of $ polynomial~G\left(x, y\right) $ and n denotes the number of secure users in the hierarchy.

Background: Circular RNAs (circRNAs) are a class of non-coding RNAs formed by pre-mRNA back-splicing, which are widely expressed in animal/plant cells and often play an important role in regulating microRNA (miRNA) activities. While numerous databases have collected a large amount of predicted circRNA candidates and provided the corresponding circRNA-regulated interactions, a stand-alone package for constructing circRNA-miRNA-mRNA interactions based on user-identified circRNAs across species is lacking., Results: We present CircMiMi (circRNA-miRNA-mRNA interactions), a modular, Python-based software to identify circRNA-miRNA-mRNA interactions across 18 species (including 16 animals and 2 plants) with the given coordinates of circRNA junctions. The CircMiMi-constructed circRNA-miRNA-mRNA interactions are derived from circRNA-miRNA and miRNA-mRNA axes with the support of computational predictions and/or experimental data. CircMiMi also allows users to examine alignment ambiguity of back-splice junctions for checking circRNA reliability and examine reverse complementary sequences residing in the sequences flanking the circularized exons for investigating circRNA formation. We further employ CircMiMi to identify circRNA-miRNA-mRNA interactions based on the circRNAs collected in NeuroCirc, a large-scale database of circRNAs in the human brain. We construct circRNA-miRNA-mRNA interactions comprising differentially expressed circRNAs, and miRNAs in autism spectrum disorder (ASD) and cross-species analyze the relevance of the targets to ASD. We thus provide a rich set of ASD-associated circRNA-miRNA-mRNA axes and a useful starting point for investigation of regulatory mechanisms in ASD pathophysiology., Conclusions: CircMiMi allows users to identify circRNA-mediated interactions in multiple species, shedding light on regulatory roles of circRNAs. The software package and web interface are freely available at https://github.com/TreesLab/CircMiMi and http://circmimi.genomics.sinica.edu.tw/ , respectively., (© 2022. The Author(s).)

Background: Genital psoriasis is often under-recognized and the exact burden is unknown in Malaysia., Objectives: To identify the prevalence of genital psoriasis, its clinical features, risk factors, and impact on quality of life and sexual health., Methods: This prospective, observational study was conducted in the dermatology clinic of our hospital from 1 st September 2020 until 31 st March 2021, involving all adult patients with psoriasis. The genital examination was performed and the subjects were interviewed using questionnaires., Results: A total of 262 patients were recruited, with a male to female ratio of 1.5:1 (mean age of 51 years old). They comprised 42.0% Chinese, followed by 36.6% of Malay, 21.4% of Indians and others. Up to 46.1% of patients had a current or history of genital psoriasis. The most common area involved for males was the scrotum (44.1%) and labia majora (62.5%) for female patients. Itching (79.2%) was the most frequent symptom encountered. Chinese patients had 2.67 times odd (CI 1.55-4.61) of having genital psoriasis compared to non-Chinese patients. Other independent risk factors included flexural involvement, male gender, and Type 1 psoriasis. Genital psoriasis was associated with greater impairment on quality of life and sexual health (mean total Dermatology Life Quality Index: 8.8 vs 6.5, P = 0.006), International Index of Erectile Function (mean: 48.5 vs 57.0, P = 0.011) and revised version of Female Sexual Distress Scales (mean: 20.7 vs 11.4, P = 0.022)., Conclusions: Genital psoriasis is common and it has a profound impact on patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Dermatology.)

Introduction and Importance: The most common symptoms of primary gastrointestinal (GI) lymphoma are non-specific, such as nausea, vomiting, diarrhea, weight loss, and abdominal pain. The rare acute symptoms include bowel obstruction, intussusception, and perforation. Primary small bowel lymphoma accounts for the smallest proportion of all GI malignancies. We report a case of intestinal lymphoma presenting with bloody stools and anemia., Case Presentation: The patient initially underwent both duodenoscopy and colonoscopy with negative findings. Isotopic red blood cell (RBC) scan was then performed due to persistent bleeding along with computed tomography angiography (CTA) because of suspected bleeding in the left abdomen. Successful embolization over the arcade of the sigmoid and left colic arteries was performed. However, the bleeding did not stop, and ischemic colitis was diagnosed by repeat colonoscopy. A coloenteric fistula was finally discovered during emergent laparotomy., Clinical Discussion: GI lymphomas are a rare disease entity among the all GI malignancies. Despite acute abdominal symptoms including obstruction, perforation, bleeding and intussusception, enteral fistula is also one of the complications. It was seen to be a long-term complication after treatment or disease process in most of cases, however it could occur as the initial manifestation. GI bleeding is a life-threatening condition and commonly needs prompt decision making. There were no standard managements for these patients, it depends on clinical judgements from physician individually., Conclusion: This is a rare condition that has not been previously described in Taiwan. Early diagnosis and timely management will decrease morbidity and mortality in the GI lymphoma population., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The factors that predict the progression of Mycoplasma pneumoniae infection remain inconclusive. Therefore, we investigated macrolide resistance prevalence, M pneumoniae genotype, and clinical characteristics of childhood M pneumoniae respiratory tract infections in Taiwan., Methods: A total of 295 children hospitalized with respiratory tract infections with positive serological M pneumoniae immunoglobulin M test results were enrolled in this 3-year prospective study. Oropharyngeal swabs were obtained for M pneumoniae cultures and polymerase chain reaction tests. All M pneumoniae specimens were further characterized by P1 typing, multilocus variable-number tandem-repeat analysis (MLVA), and macrolide resistance genotyping. The clinical characteristics and blood cytokine profiles were analyzed accordingly., Results: Of 138 M pneumoniae specimens, type I P1 was the predominant (136 of 138, 98.6%). The MLVA type P (4-4-5-7-2) was the leading strain (42 of 138, 30.4%), followed by type J, U, A, and X. The overall macrolide-resistant rate was 38.4% (53 of 138); the resistance rate increased dramatically yearly: 10.6% in 2017, 47.5% in 2018, and 62.5% in 2019 ( P  < .001). All macrolide-resistant M pneumoniae (MRMP) harbored the A2063G mutation and were MLVA type 4-5-7-2 (49 of 53, 92.5%), especially type U and X. No significant differences in clinical symptoms, duration of hospital stay, and radiographic findings were identified among patients between MRMP and macrolide-sensitive M pneumoniae (MSMP) groups. Patients with MRMP infection had more febrile days before and during hospitalization and higher interleukin (IL)-13 and IL-33 levels than patients with MSMP infection ( P  < .05)., Conclusions: Macrolide-resistant M pneumoniae surged in Taiwan throughout the study period, but macrolide resistance was not a determinant factor of clinical severity., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Real-time global mental health surveillance is urgently needed for tracking the long-term impact of the COVID-19 pandemic., Objective: This study aimed to use Google Trends data to investigate the impact of the pandemic on global mental health by analyzing three keywords indicative of mental distress: "insomnia," "depression," and "suicide.", Methods: We examined increases in search queries for 19 countries. Significant increases were defined as the actual daily search value (from March 20 to April 19, 2020) being higher than the 95% CIs of the forecast from the 3-month baseline via ARIMA (autoregressive integrated moving average) modeling. We examined the correlation between increases in COVID-19-related deaths and the number of days with significant increases in search volumes for insomnia, depression, and suicide across multiple nations., Results: The countries with the greatest increases in searches for insomnia were Iran, Spain, the United States, and Italy; these countries exhibited a significant increase in insomnia searches on more than 10 of the 31 days observed. The number of COVID-19-related deaths was positively correlated to the number of days with an increase in searches for insomnia in the 19 countries (ρ=0.64, P=.003). By contrast, there was no significant correlation between the number of deaths and increases in searches for depression (ρ=-0.12, P=.63) or suicide (ρ=-0.07, P=.79)., Conclusions: Our analysis suggests that insomnia could be a part of routine mental health screening during the COVID-19 pandemic., (©Yu-Hsuan Lin, Ting-Wei Chiang, Yu-Lun Lin. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.09.2020.)

Background: There are numerous mobile apps for tracking work hours, but only a few of them record work hours automatically instead of relying on manual logging. No apps have been customized for medical staff, whose work schedules are highly complicated as they have both regular hours and on-call duties., Objective: The specific aims of this study were to (1) identify the Staff Hours app users' GPS-defined work hours, (2) examine the overtime work hours from the app-recorded total work hours and the participants' self-reported scheduled work hours, and (3) compare these app-recorded total work hours among different occupations., Methods: We developed an app, Staff Hours, to automatically calculate a user's work hours via GPS background data. Users can enter their scheduled hours, including regular hours and on-call duties. The app automatically generates overtime reports by comparing the app-recorded total work hours with the user-defined scheduled hours. A total of 183 volunteers (60 females and 123 males; mean age 32.98 years, SD 6.74) were included in this study. Most of the participants (162/183, 88.5%) were medical staff, and their positions were resident physicians (n=89), visiting staff (n=38), medical students (n=10), registered nurses (n=25), and non-health care professionals (non-HCPs; n=21)., Results: The total work hours (mean 55.69 hours, SD 21.34) of the 183 participants were significantly higher than their scheduled work hours (mean 50.67 hours, SD 21.44; P=.01). Medical staff had significantly longer total work hours (mean 57.01 hours, SD 21.20) than non-HCPs (mean 45.48 hours, SD 20.08; P=.02). Residents (mean 60.38 hours, SD 18.67) had significantly longer work hours than visiting staff (mean 51.42 hours, SD 20.33; P=.03) and non-HCPs (mean 45.48 hours, SD 20.08; P=.004)., Conclusions: Staff Hours is the first automatic GPS location-based app designed for medical staff to track work hours and calculate overtime. For medical staff, this app could keep complete and accurate records of work hours in real time, reduce bias, and allow for better complying with labor regulations., (©Ting-Wei Chiang, Si-Yu Chen, Yuan-Chien Pan, Yu-Hsuan Lin. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 25.02.2020.)

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.

Transcriptionally non-co-linear (NCL) transcripts can originate from trans-splicing (trans-spliced RNA; 'tsRNA') or cis-backsplicing (circular RNA; 'circRNA'). While numerous circRNAs have been detected in various species, tsRNAs remain largely uninvestigated. Here, we utilize integrative transcriptome sequencing of poly(A)- and non-poly(A)-selected RNA-seq data from diverse human cell lines to distinguish between tsRNAs and circRNAs. We identified 24,498 NCL events and found that a considerable proportion (20-35%) of them arise from both tsRNAs and circRNAs, representing extensive alternative trans-splicing and cis-backsplicing in human cells. We show that sequence generalities of exon circularization are also observed in tsRNAs. Recapitulation of NCL RNAs further shows that inverted Alu repeats can simultaneously promote the formation of tsRNAs and circRNAs. However, tsRNAs and circRNAs exhibit quite different, or even opposite, expression patterns, in terms of correlation with the expression of their co-linear counterparts, expression breadth/abundance, transcript stability, and subcellular localization preference. These results indicate that tsRNAs and circRNAs may play different regulatory roles and analysis of NCL events should take the joint effects of different NCL-splicing types and joint effects of multiple NCL events into consideration. This study describes the first transcriptome-wide analysis of trans-splicing and cis-backsplicing, expanding our understanding of the complexity of the human transcriptome.

Adenosine-to-inosine (A-to-I) editing is widespread across the kingdom Metazoa. However, for the lack of comprehensive analysis in nonmodel animals, the evolutionary history of A-to-I editing remains largely unexplored. Here, we detect high-confidence editing sites using clustering and conservation strategies based on RNA sequencing data alone, without using single-nucleotide polymorphism information or genome sequencing data from the same sample. We thereby unveil the first evolutionary landscape of A-to-I editing maps across 20 metazoan species (from worm to human), providing unprecedented evidence on how the editing mechanism gradually expands its territory and increases its influence along the history of evolution. Our result revealed that highly clustered and conserved editing sites tended to have a higher editing level and a higher magnitude of the ADAR motif. The ratio of the frequencies of nonsynonymous editing to that of synonymous editing remarkably increased with increasing the conservation level of A-to-I editing. These results thus suggest potentially functional benefit of highly clustered and conserved editing sites. In addition, spatiotemporal dynamics analyses reveal a conserved enrichment of editing and ADAR expression in the central nervous system throughout more than 300 Myr of divergent evolution in complex animals and the comparability of editing patterns between invertebrates and between vertebrates during development. This study provides evolutionary and dynamic aspects of A-to-I editome across metazoan species, expanding this important but understudied class of nongenomically encoded events for comprehensive characterization., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The RNA-guided Cas9 nuclease is being widely employed to engineer the genomes of various cells and organisms. Despite the efficient mutagenesis induced by Cas9, off-target effects have raised concerns over the system's specificity. Recently a "double-nicking" strategy using catalytic mutant Cas9(D10A) nickase has been developed to minimise off-target effects. Here, we describe a Cas9(D10A)-based screening approach that combines an All-in-One Cas9(D10A) nickase vector with fluorescence-activated cell sorting enrichment followed by high-throughput genotypic and phenotypic clonal screening strategies to generate isogenic knockouts and knock-ins highly efficiently, with minimal off-target effects. We validated this approach by targeting genes for the DNA-damage response (DDR) proteins MDC1, 53BP1, RIF1 and P53, plus the nuclear architecture proteins Lamin A/C, in three different human cell lines. We also efficiently obtained biallelic knock-in clones, using single-stranded oligodeoxynucleotides as homologous templates, for insertion of an EcoRI recognition site at the RIF1 locus and introduction of a point mutation at the histone H2AFX locus to abolish assembly of DDR factors at sites of DNA double-strand breaks. This versatile screening approach should facilitate research aimed at defining gene functions, modelling of cancers and other diseases underpinned by genetic factors, and exploring new therapeutic opportunities.

Analysis of RNA-seq data often detects numerous 'non-co-linear' (NCL) transcripts, which comprised sequence segments that are topologically inconsistent with their corresponding DNA sequences in the reference genome. However, detection of NCL transcripts involves two major challenges: removal of false positives arising from alignment artifacts and discrimination between different types of NCL transcripts (trans-spliced, circular or fusion transcripts). Here, we developed a new NCL-transcript-detecting method ('NCLscan'), which utilized a stepwise alignment strategy to almost completely eliminate false calls (>98% precision) without sacrificing true positives, enabling NCLscan outperform 18 other publicly-available tools (including fusion- and circular-RNA-detecting tools) in terms of sensitivity and precision, regardless of the generation strategy of simulated dataset, type of intragenic or intergenic NCL event, read depth of coverage, read length or expression level of NCL transcript. With the high accuracy, NCLscan was applied to distinguishing between trans-spliced, circular and fusion transcripts on the basis of poly(A)- and nonpoly(A)-selected RNA-seq data. We showed that circular RNAs were expressed more ubiquitously, more abundantly and less cell type-specifically than trans-spliced and fusion transcripts. Our study thus describes a robust pipeline for the discovery of NCL transcripts, and sheds light on the fundamental biology of these non-canonical RNA events in human transcriptome., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Gene expression is largely regulated by DNA methylation, transcription factor (TF), and microRNA (miRNA) before, during, and after transcription, respectively. Although the evolutionary effects of TF/miRNA regulations have been widely studied, evolutionary analysis of simultaneously accounting for DNA methylation, TF, and miRNA regulations and whether promoter methylation and gene body (coding regions) methylation have different effects on the rate of gene evolution remain uninvestigated. Here, we compared human-macaque and human-mouse protein evolutionary rates against experimentally determined single base-resolution DNA methylation data, revealing that promoter methylation level is positively correlated with protein evolutionary rates but negatively correlated with TF/miRNA regulations, whereas the opposite was observed for gene body methylation level. Our results showed that the relative importance of these regulatory factors in determining the rate of mammalian protein evolution is as follows: Promoter methylation ≈ miRNA regulation > gene body methylation > TF regulation, and further indicated that promoter methylation and miRNA regulation have a significant dependent effect on protein evolutionary rates. Although the mechanisms underlying cooperation between DNA methylation and TFs/miRNAs in gene regulation remain unclear, our study helps to not only illuminate the impact of these regulatory factors on mammalian protein evolution but also their intricate interaction within gene regulatory networks., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Yju2 is an essential splicing factor required for the first catalytic step after the action of Prp2. We dissected the structure of Yju2 and found that the amino (Yju2-N) and carboxyl (Yju2-C) halves of the protein can be separated and reconstituted for Yju2 function both in vivo and in vitro. Yju2-N has a weak affinity for the spliceosome but functions in promoting the first reaction, with the second reaction being severely impeded. The association of Yju2-N with the spliceosome is stabilized by the presence of Yju2-C at both the precatalytic and postcatalytic stages. Strikingly, Yju2-N supported a low level of the second reaction even in the absence of Prp16. Prp16 is known to mediate destabilization of Yju2 and Cwc25 after the first reaction to allow progression of the second reaction. We propose that in the absence of the C domain, Yju2-N is not stably associated with the spliceosome after lariat formation, and thus bypasses the need for Prp16. We also showed, by UV cross-linking, that Yju2 directly contacts U2 snRNA primarily in the helix II region both pre- and postcatalytically and in the branch-binding region only at the precatalytic stage, suggesting a possible role for Yju2 in positioning the branch point during the first reaction.

Different patient-related information in medical organizations is the primary reference for medical personnel diagnosing, treating, and caring patients. With the rapid development of information technology, paper-based medical records have gradually been changed to electronic forms. However, different medical organizations present individual system specifications and data-saving formats so that the medical information of the same patient cannot be exchanged, shared, and securely accessed. In order not to largely change the present medical information systems as well as not to increase abundant costs, Virtual Integrated Medical-information Systems (VIMS) is proposed to assist various hospitals in information exchange. Furthermore, with Mobile Agent, the dispersed medical information can be securely integrated. It presents confidentiality, non-repudiation, source authentication, and integrity in network transmission. Virtual Integrated Medical-information Systems (VIMS) is a virtual electronic integration system combined with Mobile Agent technology. With the features of independence, adaptability, mobility, objectives, and autonomy, Mobile Agent is applied to overcome the problems from heterogeneous systems. With the features, the over-dispersed medical records can be integrated. Moreover, Mobile Agent can ensure the instantaneity and usability of medical records from which doctors can make the most appropriate evaluation and diagnoses. It will avoid the waste of medical resources, such as repetition medication, as well as become the reference of further consultation or health check. Not only can it improve the medical care quality, but it can be provided for medical research.

The regulatory domain (PA3346RS), comprising the receiver and stalk domains, of the response regulator PA3346 requires phosphorylation for activation with magnesium ions as cofactors in order to modulate the downstream protein phosphatase activity for the regulation of swarming motility in Pseudomonas aeruginosa PAO1. Fusion-tagged recombinant PA3346RS of total molecular mass 25.3 kDa has been overexpressed in Escherichia coli, purified using Ni(2+)-NTA and Q-Sepharose ion-exchange columns and crystallized using the hanging-drop vapour-diffusion method. X-ray diffraction data were collected from PA3346RS crystals to 2.0 Å resolution. The crystal belonged to space group P4(1) or P4(3), with unit-cell parameters a = 82.38, c = 73.34 Å. Preliminary analysis indicated the presence of a dimer of PA3346RS in the asymmetric unit, with a solvent content of 48.6%.

Aminoacylhistidine dipeptidases (PepD, EC 3.4.13.3) belong to the family of M20 metallopeptidases from the metallopeptidase H clan that catalyze a broad range of dipeptide and tripeptide substrates, including L-carnosine and L-homocarnosine. Homocarnosine has been suggested as a precursor for the neurotransmitter γ-aminobutyric acid (GABA) and may mediate the antiseizure effects of GABAergic therapies. Here, we report the crystal structure of PepD from Vibrio alginolyticus and the results of mutational analysis of substrate-binding residues in the C-terminal as well as substrate specificity of the PepD catalytic domain-alone truncated protein PepD(CAT). The structure of PepD was found to exist as a homodimer, in which each monomer comprises a catalytic domain containing two zinc ions at the active site center for its hydrolytic function and a lid domain utilizing hydrogen bonds between helices to form the dimer interface. Although the PepD is structurally similar to PepV, which exists as a monomer, putative substrate-binding residues reside in different topological regions of the polypeptide chain. In addition, the lid domain of the PepD contains an "extra" domain not observed in related M20 family metallopeptidases with a dimeric structure. Mutational assays confirmed both the putative di-zinc allocations and the architecture of substrate recognition. In addition, the catalytic domain-alone truncated PepD(CAT) exhibited substrate specificity to l-homocarnosine compared with that of the wild-type PepD, indicating a potential value in applications of PepD(CAT) for GABAergic therapies or neuroprotection.

Cwc25 has previously been identified to associate with pre-mRNA splicing factor Cef1/Ntc85, a component of the Prp19-associated complex (nineteen complex, or NTC) involved in spliceosome activation. We show here that Cwc25 is neither tightly associated with NTC nor required for spliceosome activation but is required for the first catalytic reaction. The affinity-purified spliceosome formed in Cwc25-depleted extracts contained only pre-mRNA and could be chased into splicing intermediates upon the addition of recombinant Cwc25 in an ATP-independent manner, suggesting that Cwc25 functions in the final step of the first catalytic reaction after the action of Prp2. Yju2 and a heat-resistant factor of unknown identity, HP, have previously been shown to be required for the same step of the splicing pathway. Cwc25, although resistant to heat treatment, is not sufficient to replace the function of HP, indicating that another heat-resistant factor, which we named HP-X, is involved. The requirement of Cwc25 and HP-X for the first catalytic reaction could be partially compensated for when the affinity-purified spliceosome was incubated in the presence of low concentrations of Mn(2+). These results have implications for the possible roles of Cwc25 and HP-X in facilitating juxtaposition of the 5' splice site and the branch point during the first catalytic reaction.