Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries.

Most membrane proteins are modified by covalent addition of complex sugars through N- and O-glycosylation. Unlike proteins, glycans do not typically adopt specific secondary structures and remain very mobile, shielding potentially large fractions of protein surface. High glycan conformational freedom hinders complete structural elucidation of glycoproteins. Computer simulations may be used to model glycosylated proteins but require hundreds of thousands of computing hours on supercomputers, thus limiting routine use. Here, we describe GlycoSHIELD, a reductionist method that can be implemented on personal computers to graft realistic ensembles of glycan conformers onto static protein structures in minutes. Using molecular dynamics simulation, small-angle X-ray scattering, cryoelectron microscopy, and mass spectrometry, we show that this open-access toolkit provides enhanced models of glycoprotein structures. Focusing on N-cadherin, human coronavirus spike proteins, and gamma-aminobutyric acid receptors, we show that GlycoSHIELD can shed light on the impact of glycans on the conformation and activity of complex glycoproteins.

Assessment of foetal dose and occupational exposure for pregnant workers in nuclear medicine using the Taiwanese pregnancy phantom.

For pregnant workers in nuclear medicine, radiation doses can pose a risk to their foetus. However, foetal radiation doses cannot be measured directly. In this study, a method of estimating foetal radiation doses was developed through simulations and measurements of phantoms of pregnant women in the three trimesters. The uterus and abdominal surface doses for monoenergetic photons (137Cs) and medical diagnostic X-rays were measured, and uterine dose conversion coefficients (UDCCs) were calculated. The accuracy of the UDCC estimates were validated for measurements from thermoluminescent dosemeter (TLD) chips and TLD badges on the abdomen or chest. The foetal effective dose could be estimated using TLD chips and TLD badges on the abdomen or chest, or through literature estimation method. The proposed method can be used to easily and accurately estimate foetal effective doses from chest-worn TLD badges, ensuring accurate estimation in the early stage of pregnancy when a worker may not yet be wearing an abdominal badge. A flowchart for applying the UDCC method to approximate a foetal dose is also provided to ensure that total doses remain below the maximum of 1 mSv recommended in the International Commission on Radiological Protection 103 guidelines.

Altered Protein Dynamics and a More Reactive Catalytic Cysteine in a Neurodegeneration-associated UCHL1 Mutant.

A mutant of ubiquitin C-terminal hydrolase L1 (UCHL1) detected in early-onset neurodegenerative patients, UCHL1R178Q, showed higher catalytic activity than wild-type UCHL1 (UCHL1WT). Lying within the active-site pocket, the arginine is part of an interaction network that holds the catalytic histidine in an inactive arrangement. However, the structural basis and mechanism of enzymatic activation upon glutamine substitution was not understood. We combined X-ray crystallography, protein nuclear magnetic resonance (NMR) analysis, enzyme kinetics, covalent inhibition analysis, and biophysical measurements to delineate activating factors in the mutant. While the crystal structure of UCHL1R178Q showed nearly the same arrangement of the catalytic residues and active-site pocket, the mutation caused extensive alteration in the chemical environment and dynamics of more than 30 residues, some as far as 15 Å away from the site of mutation. Significant broadening of backbone amide resonances in the HSQC spectra indicates considerable backbone dynamics changes in several residues, in agreement with solution small-angle X-ray scattering (SAXS) analyses which indicate an overall increase in protein flexibility. Enzyme kinetics show the activation is due to a kcat effect despite a slightly weakened substrate affinity. In line with this, the mutant shows a higher second-order rate constant (kinact/Ki) in a reaction with a substrate-derived irreversible inhibitor, Ub-VME, compared to the wild-type enzyme, an observation indicative of a more reactive catalytic cysteine in the mutant. Together, the observations underscore structural plasticity as a factor contributing to enzyme kinetic behavior which can be modulated through mutational effects.

CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

UTERINE DOSE CONVERSION COEFFICIENTS FOR EXTERNAL PHOTONS FOR THE TAIWANESE PREGNANT WOMEN.

The Oak Ridge National Laboratory (ORNL) phantoms based on data of Caucasians have been widely used for fetal dosimetry. However, there are differences in body size during pregnancy among Taiwanese and Caucasians. In this study, the uterine dose conversion coefficients (DCCs) of Taiwanese pregnant women were evaluated to facilitate the use of it to estimate the possible uterine dose (usually regarded as fetal dose) of pregnant Taiwanese women during radiation practice or medical exposures. The uterine DCCs in this study were calculated based on the established Taiwanese pregnancy voxel phantoms, and were compared with the uterine DCCs of the International Commission on Radiological Protection. The applicability of evaluating uterine DCCs with different phantoms was also discussed. Results showed that if the ORNL phantoms are used to evaluate the uterine dose of Taiwanese pregnant women, the uterine dose may be underestimated. This study provides the uterine DCCs assessed with the Taiwanese pregnancy phantoms for future dose assessment of Taiwanese.

Greenspace related to bipolar disorder in Taiwan: Quantitative benefits of saving DALY loss and increasing income.

Scientific evidence reported that surrounding greenspace could promote better mental health. Considering bipolar disorder as the health outcome, this study aimed to investigate the association between greenspace and bipolar disorder in Taiwan and quantified the benefits of greenspace on bipolar disorder adjusted for the international greenspace availability standard. By examining datasets across 348 townships, two quantitative measures (i.e., disability-adjusted life year loss and income) were used to represent the benefits. The incidence rate of bipolar disorder was obtained from Taiwan's National Health Insurance Research Database. Normalized different vegetation index (NDVI) was measured as a proxy for the greenspace availability. A generalized additive mixed model coupled with a sensitivity test were applied to evaluate the statistical association. The prevented fraction for the population (PFP) was then applied to develop a scenario for quantifying benefit. The result showed a significant negative association between greenspace and bipolar disorder in Taiwan. Compared to low greenspace, areas with medium and high greenspace may reduce the bipolar risk by 21% (RR = 0.79; 95% CI = 0.76-0.83) and 51% (RR = 0.49; 95% CI = 0.45-0.53). Calculating benefits, we found that the development of a scenario by increasing greenspace adjusted for availability indicator in township categorized as low greenspace could save in DALY loss due to bipolar disorder up to10.97% and increase in income up to 11.04% from the current situation. Lastly, this was the first study in Asia-Pacific to apply a customized greenspace increment scenario to quantify the benefits to a particular health burden such as bipolar disorder.

Association between residential greenspace structures and frailty in a cohort of older Chinese adults.

Background: Frailty is a late-life clinical syndrome resulting from the accumulation of aging-induced decline. Greenspaces measured with normalized difference vegetation index (NDVI) are protective of frailty. However, NDVI is not as informative as structure indices in describing greenspaces' constitution, shape, and connectivity measured by the largest patch index (LPI), shape index, and cohesion index representing larger, more complex, and more dense greenspaces through higher values. We aim to study the association between greenness structures and frailty in a cohort of Chinese older adults. Methods: We included older adults from 2008-2014 China Longitudinal Healthy Longevity Survey (CLHLS). We used greenspace indices from satellite to quantify structures (area-edge, shape, proximity) at county-level, and calculated frailty index (FI) as an outcome. We did cross-sectional analyses using linear and logistical regression, and longitudinal analyses using the generalized estimating equations (GEE). Results: Among 8776 baseline participants, mean LPI, shape, cohesion, and FI are 7.93, 8.11, 97.6, and 0.17. In cross-sectional analyses, we find negative dose-response relationships for greenspace structures and frailty, especially in females, centenarians, illiterate people, city residents, unmarried people, and individuals with increased frailty. Participants living in the highest quartile of LPI, shape, and cohesion have 32% (95%CI: 21-42%), 35% (95%CI: 24-44%), and 37% (95%CI: 26%-46%) lower odds of frailty than the lowest quartile. However, we do not find a significant association in longitudinal analyses. Conclusions: Higher levels of greenness structures (area-edge, shape, and proximity) might be related to lower frailty, while a clear longitudinal benefit cannot be identified in this analysis.

Areas dominated by vegetation (greenspaces) are associated with reduced frailty, an aging-related decline in physical function. Here, we aimed to look at the association between specific greenspace structures and frailty in a cohort of older Chinese adults. We use demographic and health data from a 6-year survey and greenspace structure data from satellites to conduct our statistical analysis. We find that a larger area, more complex shape, more concentrated greenspaces, and greater proximity might lower levels of frailty, especially in females, people aged 100 and above, illiterate people, city residents, unmarried people, and individuals with increased frailty. These findings help us to understand how the environment impacts our health and how we might mitigate frailty in older aged adults.

Clinical assessment of SARS-CoV-2 antigen rapid detection compared with RT-PCR assay for emerging variants at a high-throughput community testing site in Taiwan.

OBJECTIVES: With the emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) B.1.1.7 lineage in the ongoing coronavirus disease 2019 (COVID-19) pandemic, Taiwan confronted a COVID-19 flare up in May 2021. Large-scale, accurate, affordable and rapid diagnostic tests such as the lateral flow assay can help to prevent community transmission, but their performance characteristics in real-world conditions and relevant subpopulations remain unclear. METHODS: The COVID-19 Antigen Rapid Test Kit (Eternal Materials, New Taipei City, Taiwan) was used in a high-throughput community testing site; the paired reverse transcription polymerase chain reaction (RT-PCR) results served as a reference for sensitivity and specificity calculations. RESULTS: Of 2096 specimens tested using the rapid antigen test, 70 (3.33%) were positive and 2026 (96.7%) were negative. This clinical performance was compared with the RT-PCR results. The sensitivity and specificity of the rapid antigen test were 76.39% [95% confidence interval (CI) 64.91-85.60%] and 99.26% (95% CI 98.78-99.58%), respectively, with high sensitivity in subjects with cycle threshold values ≤24. Further, the rapid antigen test detected the SARS-CoV-2 B.1.1.7 lineage effectively. CONCLUSIONS: Considering the short turnaround times and lower costs, this simple SARS-CoV-2 antigen detection test for rapid screening combined with RT-PCR as a double confirmatory screening tool can facilitate the prevention of community transmission during COVID-19 emergencies.

Residential green space structures are associated with a lower risk of bipolar disorder: A nationwide population-based study in Taiwan.

Although many researchers have identified the potential psychological benefits offered by greenness, the association between green space structures and mental disorders is not well understood. The purpose of this study was to identify associations between green space structures and the incidence of bipolar disorder. To this end, we investigated 1,907,776 individuals collected from Taiwan's National Health Insurance Research Database. After a follow-up investigation from 2005 to 2016, among those with no history of bipolar disorder, 20,548 individuals were further found to be diagnosed with bipolar disorder. A geographic information system and landscape index were used to quantify three indices of green space structures: mean patch area (area and edge), mean fractal dimension index (shape), and mean proximity index (proximity). Additionally, greenness indices, the normalized difference vegetation index, and the enhanced vegetation index were used to confirm the association between greenness and incidence of bipolar disorder. These five indices were used to represent the individual's exposure according to the township of the hospital that they most frequently visited with symptoms of the common cold. Spearman's correlation analysis was performed to select variables by considering their collinearity. Subsequently, the frailty model for each index was used to examine the specific associations between those respective indices and the incidence of bipolar disorder by adjusting for related risk factors, such as socioeconomic status, metabolic syndrome, and air pollution. A negative association was identified between the mean patch area and the mean proximity index, and the incidence of bipolar disorder. In contrast, a positive association was found between the mean fractal dimension index and the incidence of bipolar disorder. We observed similar results in sensitivity testing and subgroup analysis. Exposure to green spaces with a larger area, greater proximity, lower complexity, and greener area may reduce the risk of bipolar disorder.

Development of Hourly Indoor PM2.5 Concentration Prediction Model: The Role of Outdoor Air, Ventilation, Building Characteristic, and Human Activity.

Exposure to indoor particulate matter less than 2.5 µm in diameter (PM2.5) is a critical health risk factor. Therefore, measuring indoor PM2.5 concentrations is important for assessing their health risks and further investigating the sources and influential factors. However, installing monitoring instruments to collect indoor PM2.5 data is difficult and expensive. Therefore, several indoor PM2.5 concentration prediction models have been developed. However, these prediction models only assess the daily average PM2.5 concentrations in cold or temperate regions. The factors that influence PM2.5 concentration differ according to climatic conditions. In this study, we developed a prediction model for hourly indoor PM2.5 concentrations in Taiwan (tropical and subtropical region) by using a multiple linear regression model and investigated the impact factor. The sample comprised 93 study cases (1979 measurements) and 25 potential predictor variables. Cross-validation was performed to assess performance. The prediction model explained 74% of the variation, and outdoor PM2.5 concentrations, the difference between indoor and outdoor CO2 levels, building type, building floor level, bed sheet cleaning, bed sheet replacement, and mosquito coil burning were included in the prediction model. Cross-validation explained 75% of variation on average. The results also confirm that the prediction model can be used to estimate indoor PM2.5 concentrations across seasons and areas. In summary, we developed a prediction model of hourly indoor PM2.5 concentrations and suggested that outdoor PM2.5 concentrations, ventilation, building characteristics, and human activities should be considered. Moreover, it is important to consider outdoor air quality while occupants open or close windows or doors for regulating ventilation rate and human activities changing also can reduce indoor PM2.5 concentrations.

Effect of Chemotherapy, Laparoscopy, and Cytology on Stage IC Ovarian Clear Cell Carcinoma: A Long-Term, Single-Center Study.

Ovarian clear cell carcinoma (OCCC) is the second common histology of epithelial ovarian cancer in Taiwan. Stage IC is common, especially during minimally invasive surgery. Adjuvant chemotherapy in stage IC OCCC is unavoidable, and paclitaxel-based chemotherapy in Taiwan is self-paid. However, surgical spillage from minimally invasive surgery as a cause of unfavorable prognosis is still uncertain. The information of patients with stage IC OCCC, corresponding to a period of January 1995 to December 2016, was retrospectively collected following a chart and pathology review. Data regarding surgical methods, cytology status, regimens of adjuvant chemotherapy, survivorship, progression-free survival (PFS), and overall survival (OS) period were analyzed. In total, 88 patients were analyzed, and 64 and 24 patients were treated with paclitaxel- and nonpaclitaxel-based chemotherapy, respectively. Recurrence was identical between the two groups: PFS (47.5 ± 41.36 versus 54.0 ± 53.9 months, p = 0.157) and OS (53.5 ± 38.14 versus 79.0 ± 49.42 months, p = 0.070). Of the 88 patients, 12 had undergone laparoscopy for histological confirmation before complete open staging surgery; however, their PFS (49.5 ± 46.84 versus 49.0 ± 35.55 months, p = 0.719) and OS (56.5 ± 43.4 versus 51.0 ± 32.77 months, p = 0.600) were still comparable. Cytology results were only available for 51 patients, and positive washing cytology results seemed to worsen PFS (p = 0.026) but not OS (p = 0.446). In conclusion, adjuvant nonpaclitaxel chemotherapy and laparoscopic tumor spillage before the staging operation did not worsen the outcome in stage IC OCCC. Positive washing cytology has a negative effect on PFS but not on OS.

Association Between Surrounding Greenness and Schizophrenia: A Taiwanese Cohort Study.

This study aims to investigate the association between surrounding greenness and schizophrenia incidence in Taiwan. Data of 869,484 individuals without a history of schizophrenia were included from the Longitudinal Health Insurance Database from 2000 through 2010 for analysis. The diagnoses of schizophrenia were based on ICD-9 codes. Greenness exposure was assessed using the satellite-based normalized difference vegetation index, assuming individuals lived near the hospital they most often visited for common cold during the study period. Cox proportional hazards models were applied to assess the association between greenness exposure and schizophrenia incidence after adjustments were made for the potential confounders. A total of 5,069 schizophrenia cases were newly diagnosed during the study period. A negative significant (P < 0.05) association found using 2,000-m buffer distances (distance of a moderately paced 20-min walk) in the whole Taiwan island, cities, and metropolitan areas. The results of the stratified analysis based on sex and health insurance rate suggested surrounding greenness has approximately equal effects of reducing the risk of schizophrenia, regardless of sex or financial status. In conclusion, our findings suggest that more surrounding greenness may reduce the risk of schizophrenia.

A hybrid feature-based segmentation and classification system for the computer aided self-diagnosis of otitis media.

We propose a novel hybrid otitis media (OM) computer aided detection (CAD) system, designed to aid in the self-diagnosis of various forms of OM. OM is a prevalent disease in both children and adults. Our system is able to differentiate normal ear from acute otitis media (AOM), otitis media with effusion (OME) and the multi-categories of chronic otitis media including perforation, retraction, cholesteatoma, etc. We propose a modified double active contour segmentation method designed for use with otoscope images, and enabled to handle user acquired data. To describe the visual symptoms (e.g., red, bulging, effusion, perforation, retraction, etc.) of otitis media accurately, we extract color, geometric and texture features by grid color moment, Gabor filter, local binary pattern and histogram of oriented gradients. A powerful classification structure based on Adaboost is used to select the most useful features and build a strong classifier. Our system achieves classification accuracy as high as 88.06% and is suitable for real use. In addition, some interesting observations about OM otoscope images are also discussed.

¹H, ¹³C and ¹5N backbone and side-chain resonance assignments of a family 36 carbohydrate binding module of xylanase from Paenibacillus campinasensis.

Paenibacillus campinasensis BL11 isolated from black liquor secretes multiple glycoside hydrolases (GHs) against all kinds of polysaccharides. GH consists of a catalytic module and non-catalytic carbohydrate-binding modules (CBMs), in which CBMs append to the catalytic module, mediating specific interactions with insoluble carbohydrates to promote the hydrolysis efficiency of the cognate enzyme. Endo-ß-1,4-xylanase (XylX) is one of the GHs reveals high enzymatic activity in a wide range of pH and thermal endurance, suitable for bioconversion and bio-refinement applications. In this work, we report the resonance assignments of a family 36 CBM (characterized as CBM36) derived from XylX. Our investigations will facilitate molecular structure determination and molecular dynamics analysis of CBMs.