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Due to global attention on student employability, employers are expected to be involved in institutional governance in higher education and quality assurance (QA). Due to the difficulties in recruiting motivated employers to participate in external QA governance and process, this has become a challenging issue in many Asian nations. The paper aims to explore employer legitimacy in Asian national higher education regulations and EQA system according to a four-dimensional diagram of institutional governance model. There are two major findings. First, Asian governments developed QA policies with a focus on employer engagement but the emerging practice is still ineffective. Second, approaches of employer engagement in QA governance vary context to context, such as HK and Malaysia in the excellence mode; Taiwan, Indonesia, Australia, New Zealand belong to advanced type; and China, Thailand, and Vietnam fall in the intermediate category.

Background Type I diabetes occurs when the pancreas can only make limited or minimal insulin. Patients with type 1 diabetes need effective approaches to manage diabetes and maintain their blood-glucose concentration. Recently, continuous glucose monitoring (CGM) has been used to help control blood-glucose levels in patients with type 1 diabetes. Patients with type 2 diabetes may also benefit from CGM on multiple insulin injections, basal insulin, or sulfonylureas. Enzyme-free glucose detection in a neutral environment is the recent development trend of CGM. Materials and Methods Pt/Au alloy electrodes for enzyme-free glucose detection in a neutral environment were formed by electrochemically depositing Pt/Au alloy on a thin polycarbonate (PC) membrane surface with a uniformly distributed micro-hemisphere array. The PC membranes were fabricated using semiconductor microelectromechanical manufacturing processes, precision micro-molding, and hot embossing. Amperometry was used to measure the glucose concentration in PBS (pH 7.4) and artificial human serum. Results The Pt/Au nanoalloy electrode had excellent specificity for glucose detection, according to the experimental results. The device had a sensitivity of 2.82 μA mM−1 cm−2, a linear range of 1.39–13.9 mM, and a detection limit of 0.482 mM. Even though the complex interfering species in human blood can degrade the sensing signal, further experiments conducted in artificial serum confirmed the feasibility of the proposed Pt/Au nanoalloy electrode in clinical applications. Conclusion The proposed Pt/Au nanoalloy electrode can catalyze glucose reactions in neutral solutions with enhancing sensing performance by the synergistic effect of bimetallic materials and increasing detection surface area. This novel glucose biosensor has advantages, such as technology foresight, good detection performance, and high mass production feasibility. Thus, the proposed neutral nonenzymatic glucose sensor can be further used in CGMs., Graphical Abstract

Air pollution may be involved in spreading dengue fever (DF) besides rainfalls and warmer temperatures. While particulate matter (PM), especially those with diameter of 10 μm (PM10) or 2.5 μm or less (PM25), and NO2 increase the risk of coronavirus 2 infection, their roles in triggering DF remain unclear. We explored if air pollution factors predict DF incidence in addition to the classic climate factors. Public databases and DF records of two southern cities in Taiwan were used in regression analyses. Month order, PM10 minimum, PM2.5 minimum, and precipitation days were retained in the enter mode model, and SO2 minimum, O3 maximum, and CO minimum were retained in the stepwise forward mode model in addition to month order, PM10 minimum, PM2.5 minimum, and precipitation days. While PM2.5 minimum showed a negative contribution to the monthly DF incidence, other variables showed the opposite effects. The sustain of month order, PM10 minimum, PM2.5 minimum, and precipitation days in both regression models confirms the role of classic climate factors and illustrates a potential biological role of the air pollutants in the life cycle of mosquito vectors and dengue virus and possibly human immune status. Future DF prevention should concern the contribution of air pollution besides the classic climate factors.

In alignment with the Central Epidemic Center (CECC) measures and Ministry of Education (MOE) policy, Taiwan's universities took actions to ensure campus safely and continued quality of learning. A...

Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM-free rate, and disease-free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow-up of 24.7 months. The 3-year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3-year DM-free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3-year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84-13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13-8.00) were significant independent predictors of a poorer DM-free rate. Weight loss > 10% (HR, 5.53; 95% CI, 1.02-30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery.

Cruciferous vegetables contain high levels of glucosinolates (GSL) and isothiocyanates (ITC). ITC are known to induce glutathione S-transferases (GST) and thus exert their anticarcinogenic effects. This study explored the combined effects of cruciferous vegetable, GSL and ITC intake and GST polymorphisms on breast cancer risk. A total of 737 breast cancer cases and 756 controls were recruited into this case–control study. OR and 95 % CI were assessed by multivariable logistic regression. Higher cruciferous vegetable, GSL and ITC intakes were inversely associated with breast cancer risk, with adjusted OR of 0·48 (95 % CI 0·35, 0·65), 0·54 (95 % CI 0·40, 0·74) and 0·62 (95 % CI 0·45, 0·84), respectively. Compared with women carrying the GSTP1 rs1695 wild AA genotype and high cruciferous vegetable, GSL or ITC intake, carriers of the AA genotype with low cruciferous vegetable, GSL and ITC intake had greater risk of breast cancer, with adjusted OR of 1·43 (95 % CI 1·01, 1·87), 1·34 (95 % CI 1·02, 1·75) and 1·37 (95 % CI 1·05, 1·80), respectively. Persons with the GSTM1-null genotype and lower intake of cruciferous vegetables, GSL and ITC had higher risk of breast cancer than those with the GSTM1-present genotype and higher intake, with OR of 1·42 (95 % CI 1·04, 1·95), 1·43 (95 % CI 1·05, 1·96) and 1·45 (95 % CI 1·06, 1·98), respectively. Among women possessing the GSTT1-present genotype, low intake of cruciferous vegetables, GSL or ITC was associated with higher risk of breast cancer. But these interactions were non-significant. This study indicated that there were no significant interactions between cruciferous vegetable, GSL or ITC intake and GST polymorphisms on breast cancer risk.

Collaboration with caregivers and between disciplines and agencies is a recommended practice in the field of early intervention and early childhood special education (EI/ECSE) as well as required by federal legislation for young children with disabilities. Review of relevant literature suggests that collaboration entails a complex set of principles and practices that are essential for teams and programs to employ if they are to ensure effective and sustained change. Despite the recognized complexity of collaboration in EI/ECSE, few systems frameworks have been proposed that organize the essential components of effective collaboration. We offer a framework that defines the core components of collaboration in EI/ECSE. The proposed system further identifies and operationalizes the infrastructure and practices associated with the components and the levels of action at which these practices operate.

The prevalence of smoking among women in Taiwan is5%, but the incidence of lung cancer remains high. This study determined the association between PMIn total, 21,301 female lung cancer cases nationwide were newly diagnosed between 2012 and 2017. Each case was age-, sex- and calendar year-matched with four controls randomly selected from the general population. Allowing a latent period of 5 years, we estimated the PMThe ORs of lung adenocarcinoma for the third (30.5-35.1 μg/mResidential PM

Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50–60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT3 receptor was found to be >10-fold higher than that of MT1 and MT2 in porcine ciliary epithelium. Aqueous pre-treatment with MT1/MT2 antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT3 antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl− and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT3 receptors.

We have developed a real-time ultrasound needle tracking system based on a fibre-optic hydrophone integrated into an intraoperative needle. The system is intended to track the location of a needle tip during minimally invasive surgical procedures that rely on handheld ultrasound guidance. During these procedures, clear visibility of the needle tip is essential to reach the procedure target and avoid adverse events due to erroneous needle placement. The ultrasound emitted by the handheld probe is detected by the hydrophone and used to draw a cursor marking the position of the needle tip within the B-mode ultrasound image. The tracking accuracy was assessed by comparison to manual labelling of the location of the needle tip within the ultrasound images and found to be ±2.2 mm.

Anti-tumor effect of dietary flavonoids has been sustained by laboratory experiments, but epidemiological studies with breast cancer risk remained inconsistent and insufficient. This study aimed to investigate the associations between total and subclasses of flavonoid and breast cancer risk among Chinese population. This case-control study recruited 1522 eligible breast cancer cases and 1547 frequency-matched control subjects from June 2007 to July 2018 in Guangdong, China. Dietary intake was obtained by face-to-face interview using a validated food frequency questionnaire. Odds ratios and 95% confidence intervals were calculated by multivariable logistic regression models. After adjusting for potential confounders, inverse associations were observed between total flavonoids, anthocyanidins, proanthocyanidins, flavanones, flavones, flavonols and isoflavones and overall breast cancer risk. Comparing the highest versus the lowest quartile, odds ratio (95% confidence interval) was 0.66 (0.54-0.82) for total flavonoids, 0.61 (0.49-0.75) for anthocyanidins, 0.67 (0.54-0.83) for proanthocyanidins, 0.71 (0.57-0.88) for flavanones, 0.48 (0.39-0.60) for flavones, 0.51 (0.41-0.63) for flavonols and 0.67 (0.54-0.83) for isoflavones, respectively. No significant association was found between flavanols, flavan-3-ol monomers, theaflavins and breast cancer risk. Stratified analysis by menopausal status and estrogen receptor/progesterone receptor status showed that the associations of total flavonoids, most flavonoid subclasses with breast cancer risk were generally not modified by menopausal or estrogen receptor/progesterone receptor status. This study indicates that total flavonoids and most flavonoid subclasses intakes were inversely associated with breast cancer risk.

This study aimed to explore the effect of dietary magnesium intake on breast cancer risk both directly and indirectly via its effect on inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). This case-control study recruited 1050 case patients and 1229 control subjects. Inflammatory marker levels of 322 cases and 322 controls, randomly selected, were measured using ELISA, and data on dietary magnesium intake were collected using a food frequency questionnaire. Multivariable logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI), and path analysis was used to investigate the mediating effect. A higher magnesium intake was associated with a lower breast cancer risk (adjusted OR = 0.80, 95% CI = 0.65, 0.99). A positive association was found between the CRP level and breast cancer risk (adjusted OR = 1.43, 95% CI = 1.02–2.01). However, IL-6 was not found to be associated with breast cancer risk. Path analysis revealed that dietary magnesium affected breast cancer risk both directly and indirectly by influencing the CRP level. The results indicate that a direct negative association and an indirect association through influencing the CRP level were observed between dietary magnesium intake and breast cancer risk.

We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identified compounds with broad 3CLpro-inhibitory activity. We also adapted the assay for use in compound screening and in doing so uncovered additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro inhibitors. We observed strong concordance between data emerging from this assay and those obtained from live-virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identified two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested, including 3CLpro enzymes from understudied zoonotic coronaviruses. IMPORTANCE Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We developed and validated a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identified compounds with broad activity against 3CL proteases and uncovered structural insights into features that contribute to their broad activity. Furthermore, we demonstrated that this assay is suitable for identifying chemical inhibitors of proteases from families other than 3CL proteases.

A non-enzymatic glucose detection electrode that can operate in a neutral environment is a key technology for continuous glucose sensing. In this study, semiconductor micro-electromechanical manufacturing processes, precision micro-molding, hot embossing, and electrochemical deposition are integrated to fabricate Pt/Au nano-alloy electrodes for the enzyme-free detection of glucose in a neutral environment. The sensitivity of the proposed neutral enzyme-free glucose sensing scheme is measured to be 2.82 µA mM− 1 cm− 2 with a linear range of 1.39–13.9 mM and a detection limit of 0.482 mM. Further investigations in human serum confirmed the feasibility of the proposed Pt/Au nano alloy electrode in clinical application. This novel glucose biosensor possesses the advantages of technology foresight, good detection performance, and high feasibility of mass production.

Objective:The current study evaluated the associations between different forms and sources of Fe and breast cancer risk in Southern Chinese women.Design:Case–control study. We collected data on the consumption of Fe from different forms and food sources by using a validated FFQ. Multivariable logistic regression and restricted cubic spline (RCS) analysis was used to reveal potential associations between Fe intake and breast cancer risk.Setting:A case-control study of women at three major hospitals in Guangzhou, China.Participants:From June 2007 to March 2019, 1591 breast cancer cases and 1622 age-matched controls were recruited.Results:In quartile analyses, Fe from plants and Fe from white meat intake were inversely associated with breast cancer risk, with OR of 0·65 (95 % CI 0·47, 0·89, Ptrend = 0·006) and 0·76 (95 % CI 0·61, 0·96, Ptrend = 0·014), respectively, comparing the highest with the lowest quartile. No associations were observed between total dietary Fe, heme or non-heme Fe, Fe from meat or red meat and breast cancer risk. RCS analysis demonstrated J-shaped associations between total dietary Fe, non-heme Fe and breast cancer, and reverse L-shaped associations between heme Fe, Fe from meat and Fe from red meat and breast cancer.Conclusion:Fe from plants and white meat were inversely associated with breast cancer risk. Significant non-linear J-shaped associations were found between total dietary Fe, non-heme Fe and breast cancer risk, and reverse L-shaped associations were found between heme Fe, Fe from meat or red meat and breast cancer risk.

Background Although past studies have identified factors associated with individual perceptions of vaccination, limited attention has been paid to the role of personality in individual attitudes toward vaccination. This study aimed to evaluate the effect of personality as measured by the Big Five personality traits on individual attitudes toward vaccination using a nationally representative survey in the United States. Methods A cross-sectional study was conducted with a sample of 3276 American citizens who were aged 18 and above and lived in 50 U.S. states and Washington D.C. from the American National Election Studies. The survey was collected through face-to-face and online interviews using structured questionnaires in 2016. The multistage stratified cluster sampling procedure was used for face-to-face interview, whereas the USPS DSF was used to select the sample for online interview. Multivariable ordinal logistic regression was used to assess how personality traits (extraversion, agreeableness, conscientiousness, emotional stability, and openness to experience) as main explanatory variables influence the outcome variables – individual attitudes toward health benefits of vaccination and support for school vaccination. Results More than two-thirds of respondents perceive health benefit of vaccination and support vaccination requirements for school entry, whereas about one-tenth of respondents have safety concerns about vaccination and oppose the vaccination requirements. After adjusting for ideology, insurance status, and demographic variables, the traits of agreeableness, conscientiousness and emotional stability remain significantly associated with attitude toward vaccination; conscientiousness is significantly associated with support for school vaccination. The odds of reporting health benefits of vaccination associated with one-point increase in agreeableness, conscientiousness and emotional stability are 1.05 (95% confidence intervals [CI] = 1.01–1.08), 1.05 (95% CI = 1.02–1.09) and 1.03 (95% CI = 1.00–1.06), respectively. For a one-point increase in conscientiousness, the odds of supporting school vaccination increase by 1.08 (95% CI = 1.05–1.12). Conclusions People high in agreeableness, conscientiousness and emotional stability are more likely to regard vaccination as beneficial, whereas those high in conscientiousness are more likely to support school-based vaccine requirement. This study highlights the importance of personality in shaping individual attitudes toward vaccination. More research is needed to understand the role of personality in individual health attitudes and behavior.

Personally identifiable information (PII) has become a major target of cyber-attacks, causing severe losses to data breach victims. To protect data breach victims, researchers focus on collecting exposed PII to assess privacy risk and identify at-risk individuals. However, existing studies mostly rely on exposed PII collected from either the dark web or the surface web. Due to the wide exposure of PII on both the dark web and surface web, collecting from only the dark web or the surface web could result in an underestimation of privacy risk. Despite its research and practical value, jointly collecting PII from both sources is a non-trivial task. In this paper, we summarize our effort to systematically identify, collect, and monitor a total of 1,212,004,819 exposed PII records across both the dark web and surface web. Our effort resulted in 5.8 million stolen SSNs, 845,000 stolen credit/debit cards, and 1.2 billion stolen account credentials. From the surface web, we identified and collected over 1.3 million PII records of the victims whose PII is exposed on the dark web. To the best of our knowledge, this is the largest academic collection of exposed PII, which, if properly anonymized, enables various privacy research inquiries, including assessing privacy risk and identifying at-risk populations.

The information privacy of the Internet users has become a major societal concern. The rapid growth of online services increases the risk of unauthorized access to Personally Identifiable Information (PII) of at-risk populations, who are unaware of their PII exposure. To proactively identify online at-risk populations and increase their privacy awareness, it is crucial to conduct a holistic privacy risk assessment across the internet. Current privacy risk assessment studies are limited to a single platform within either the surface web or the dark web. A comprehensive privacy risk assessment requires matching exposed PII on heterogeneous online platforms across the surface web and the dark web. However, due to the incompleteness and inaccuracy of PII records in each platform, linking the exposed PII to users is a non-trivial task. While Entity Resolution (ER) techniques can be used to facilitate this task, they often require ad-hoc, manual rule development and feature engineering. Recently, Deep Learning (DL)-based ER has outperformed manual entity matching rules by automatically extracting prominent features from incomplete or inaccurate records. In this study, we enhance the existing privacy risk assessment with a DL-based ER method, namely Multi-Context Attention (MCA), to comprehensively evaluate individuals' PII exposure across the different online platforms in the dark web and surface web. Evaluation against benchmark ER models indicates the efficacy of MCA. Using MCA on a random sample of data breach victims in the dark web, we are able to identify 4.3% of the victims on the surface web platforms and calculate their privacy risk scores.

We report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors., The essential SARS-CoV-2 3CL protease is of interest as a drug target. Here, the authors identify three 3CL inhibitors and characterize them both in vitro and with a cell-based assay, and they also present the inhibitor-bound 3CL crystal structures, which may allow for the design of improved compounds.

BACKGROUND Neoadjuvant chemotherapy (NAC) has been used in patients with advanced head and neck cancers (HNCs) with the intent of downstaging tumors and suppressing distant metastases. However, to the authors' knowledge, the perioperative impact of NAC has not been systematically explored in patients with HNC. The objective of the current study was to compare perioperative outcomes with surgery upfront compared with patients treated with NAC. METHODS Between March 1, 2016, and March 31, 2019, patients undergoing surgery for HNC with flap reconstruction at The University of Texas MD Anderson Cancer Center in Houston were included. Data were extracted from the prospectively maintained National Surgical Quality Improvement Program database. Postoperative complications, return to operating room, and readmission rates were compared. Univariate and multivariate analyses of length of stay and overall and wound complications were performed. RESULTS A total of 834 patients were analyzed, 687 of whom (82.4%) underwent surgery upfront and 147 of whom (17.6%) received NAC. A total of 631 cases (75.7%) involved the upper aerodigestive tract whereas 203 cases (24.3%) were cutaneous. A total of 317 patients (38.0%) had recurrent disease. The NAC group was younger (P

Zinc ions (Zn2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn2+ concentration ([Zn2+]c), Zrt/Irt-related proteins (ZIPs) and Zn2+ transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn2+]c, respectively, by fluxing Zn2+ across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn2+]c and less investigate the [Zn2+]c at physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn2+]c to different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn2+]c by zinc oxide-nanoparticles (ZnO-NP) at concentrations below 1 μg/ml, which had little cytotoxicity, in cultured human neuroblastoma SH-SY5Y cells and characterized the importance of Zn2+ transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn2+]c transiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels of ZnT1 (mostly at the plasma membrane) and ZIP8 (present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn2+]c, respectively. ZnO-NP treatment reduced the basal levels of reactive oxygen species and Bax/Bcl-2 mRNA ratios; in addition, ZnO-NP decreased the 6-OHDA-induced ROS production, p53 expression, and cell death. Therefore, mild elevations in [Zn2+]c induced by ZnO-NP activate beneficial effects in reducing the 6-OHDA-induced cytotoxic effects. Therefore, brain-delivery of ZnO-NP can be regarded as a potential therapy for neurological disease.

Cruciferous vegetables contain high levels of glucosinolates (GSL) and isothiocyanates (ITC). ITC are known to induce glutathione S-transferases (GST) and thus exert their anticarcinogenic effects. This study explored the combined effects of cruciferous vegetable, GSL and ITC intake and GST polymorphisms on breast cancer risk. A total of 737 breast cancer cases and 756 controls were recruited into this case-control study. OR and 95 % CI were assessed by multivariable logistic regression. Higher cruciferous vegetable, GSL and ITC intakes were inversely associated with breast cancer risk, with adjusted OR of 0·48 (95 % CI 0·35, 0·65), 0·54 (95 % CI 0·40, 0·74) and 0·62 (95 % CI 0·45, 0·84), respectively. Compared with women carrying the GSTP1 rs1695 wild AA genotype and high cruciferous vegetable, GSL or ITC intake, carriers of the AA genotype with low cruciferous vegetable, GSL and ITC intake had greater risk of breast cancer, with adjusted OR of 1·43 (95 % CI 1·01, 1·87), 1·34 (95 % CI 1·02, 1·75) and 1·37 (95 % CI 1·05, 1·80), respectively. Persons with the GSTM1-null genotype and lower intake of cruciferous vegetables, GSL and ITC had higher risk of breast cancer than those with the GSTM1-present genotype and higher intake, with OR of 1·42 (95 % CI 1·04, 1·95), 1·43 (95 % CI 1·05, 1·96) and 1·45 (95 % CI 1·06, 1·98), respectively. Among women possessing the GSTT1-present genotype, low intake of cruciferous vegetables, GSL or ITC was associated with higher risk of breast cancer. But these interactions were non-significant. This study indicated that there were no significant interactions between cruciferous vegetable, GSL or ITC intake and GST polymorphisms on breast cancer risk.

The CHARMM Drude-2013 polarizable force field (FF) was developed to include the explicit treatment of induced electronic polarizability, resulting in a more accurate description of the electrostatic interactions in molecular dynamics (MD) simulations. While the Drude-2013 protein FF has shown success in improving the folding properties of α-helical peptides and to reproduce experimental observables in simulations up to 1 μs, some limitations were noted regarding the stability of β-sheet structures in simulations longer than 100 ns as well as larger deviations from crystal structures in simulations of a number of proteins compared to the additive CHARMM36 protein FF. The origin of the instability has been identified and appears to be primarily due to overestimated atomic polarizabilities and induced dipole-dipole interactions on the Cβ, Cγ, and Cδ side chain atoms. To resolve this and other issues, a number of aspects of the model were revisited, resulting in Drude-2019 protein FF. Backbone parameters were optimized targeting the conformational properties of the (Ala)5 peptide in solution along with gas phase properties of the alanine dipeptide. Dipeptides that contain N-acetylated and N'-methylamidated termini, excluding Gly, Pro, and Ala, were used as models to optimize the atomic polarizabilities and Thole screening factors on selected Cβ, Cγ, and Cδ carbons by targeting quantum mechanical (QM) dipole moments and molecular polarizabilities. In addition, to obtain better conformational properties, side chain χ1 and χ2 dihedral parameters were optimized targeting QM data for the respective side chain dipeptide conformations as well as Protein Data Bank survey data based on the χ1, χ2 sampling from Hamiltonian replica-exchange MD simulations of (Ala)4-X-(Ala)4 in solution, where X is the amino acid of interest. Further improvements include optimizing nonbonded interactions between charged residues to reproduce QM interaction energies of the charged-protein model compounds and experimental osmotic pressures. Validation of the optimized Drude protein FF includes MD simulations of a collection of peptides and proteins including β-sheet structures, as well as transmembrane ion channels. Results showed that the updated Drude-2019 protein FF yields smaller overall root-mean-square differences of proteins as compared to the additive CHARMM36m and Drude-2013 FFs as well as similar or improved agreement with experimental NMR properties, allowing for long time scale simulation studies of proteins and more complex biomolecular systems in conjunction with the remainder of the Drude polarizable FF.

With aging, there are progressive functional declines in multiple organ systems. One of the major physiological problems observed in aged people is skeletal muscle loss. This age-related muscle loss causes muscle weakness and disability, which in turn might reduce the quality of life in older adults and lead to the progression of several diseases, particularly Alzheimer's disease (AD). Some researchers have hypothesized that loss of muscle mass and strength is linked to the risk of developing AD. In addition, unintended weight loss often occurs in AD patients and might reflect dementia severity. However, the causal relationship between muscle atrophy and cognitive deficits in AD is unclear. We found that double transgenic amyloid precursor protein and presenilin 1 (APP/PS1) mice that co-express APP and PS1 at older ages exhibited lower body weight and lean tissue mass than sex- and age-matched wild-type (WT) mice. In addition, muscle atrophy and the extent of memory decline were strongly correlated in APP/PS1 mice. Myostatin levels in the gastrocnemius (GAS) muscle of 12-month-old APP/PS1 mice were elevated. We determined that the cellular and molecular mechanism of muscle atrophy was through the ubiquitin-proteasome pathway. Furthermore, myostatin knockdown in the GAS muscles increased grip strength and muscle mass, leading to memory improvement in myostatin short-hairpin RNA-treated APP/PS1 mice. We conclude that high-level myostatin expression might mediate or trigger muscle atrophy and cognitive deficits.

The quality of the force field is crucial to ensure the accuracy of simulations used in molecular modeling, including computer-aided drug design (CADD). To perform more accurate modeling and simulations of halogenated molecules, in this study the polarizable force field based on the classical Drude oscillator model was extended to both aliphatic and aromatic systems using halogenated ethane and benzene model compounds for the halogens F, Cl, Br, and I. The force field parameters were optimized targeting quantum mechanical dipole moments, water interactions, and molecular polarizabilities as well as experimental observables, including enthalpies of vaporization, molecular volumes, hydration free energies, and dielectric constants. The developed halogenated polarizable force field is capable of reproducing QM relative energies and geometries of both halogen bonds and halogen-hydrogen bond donor interactions at an unprecedented level due to the inclusion of a virtual particle and anisotropic atomic polarizability on the halogen and, notably, the inclusion of Lennard-Jones parameters on the halogen Drude particle. The model was validated on the basis of its ability to accurately reproduce pure solvent properties for halogenated naphthalenes and alkanes, including species analogous to those used as refrigerants. Accordingly, it is anticipated that the model will be applicable for the study of halogenated derivatives in CADD as well as in other chemical and biophysical studies.