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Anaerobic digestion is the most prevalent stabilization method used in treating waste activated sludge. However, the digested sludge produced has always been difficult to dehydrate. In this study, mesophilic anaerobic digested sludge and thermophilic anaerobic digested sludge were used to compare the dewatering capacity of two chemical coagulants: high-performance polyaluminum chloride (HPAC) and FeCl3. For mesophilic anaerobic digestion, 5% g/g total suspended solids (TSS) was the optimal dose of FeCl3 and HPAC to improve dewaterability. In addition, HPAC was superior to ferric chloride in the removal of loosely bound extracellular polymeric substances (LB-EPS) and tightly bound extracellular polymeric substances (TB-EPS). For thermophilic anaerobic sludge, HPAC is more effective compared with FeCl3 in improving the dewaterability. FeCl3 could effectively remove TB-EPS, while HPAC had better removal efficiency on soluble extracellular polymeric substances (S-EPS) and LB-EPS. Both chemical coagulants have greater potential to degrade EPS during thermophilic anaerobic digestion sludge treatment. The results of the supernatants characterization after conditioning illustrated that FeCl3 and HPAC have similar removal efficiency on organic matter, but HPAC could remove additional small molecular weight compounds, particularly when conditioning with the thermophilic anaerobic sludge; however, there was no apparent changes when using FeCl3. [ABSTRACT FROM AUTHOR]

Aims: To estimate the effectiveness of metformin on glycaemic parameters among participants with incident prediabetes attending Australian general practices. Methods: This retrospective cohort study used electronic health records of regular participants (3+ visits in two consecutive years) attending 383 Australian general practices (MedicineInsight). Participants with 'incident' prediabetes (newly recorded diagnosis between 2012 and 2017) and their glycaemic parameters (haemoglobin A1c [HbA1c] or fasting blood glucose [FBG]) at 6‐, 12‐, and 18–24 months post diagnosis (unexposed) or post‐management with metformin (treatment) were identified from the database. We estimated the average treatment effect (ATE) of metformin management on glycaemic parameters using both linear regression and augmented inverse probability weighting. Results: Of the 4770 investigated participants with 'incident' prediabetes, 10.2% were managed with metformin. Participants on metformin had higher HbA1c levels at the baseline than those unexposed (mean 45 mmol/mol [6.2%] and 41 mmol/mol [5.9%], respectively), but no differences were observed at 6–12 months (mmol/mol ATE 0.0, 95% CI −0.4; 0.7) or 12–18 months (ATE −0.3, 95% CI −1.2; 0.3). However, participants on metformin had lower mean HbA1c mmol/mol at 18–24 months (ATE −1.1, 95% CI −2.0; 0.1) than those unexposed. Consistent results were observed for FBG (ATE at 6–12 months −0.14 [95% CI −0.25; −0.04], 12–18 months 0.02 [95% CI −0.08; 0.13] and 18–24 months −0.07 [95% CI −0.25; 0.12]). Conclusion: The higher HbA1c and FBG baseline levels among participants with 'incident' prediabetes managed with metformin improved after 6–12 months of starting pharmacological management, and the effect persisted for up to 24 months. Management with metformin could prevent further deterioration of glycaemic levels. [ABSTRACT FROM AUTHOR]

Approach and docking with space tether system has the advantages of less system complexity and lower cost compared with conventional rendezvous and docking which are usually essential operations in on-orbit service of spacecraft. This paper deals with the relative dynamics and control of the tethered on-orbit service satellite for the process of approach and docking by retrieving tether. Considering the system safety, it is necessary to keep the pitch angle constant or it varying in a small range during the approach. Therefore, we propose a control law for tether retrieval. Specifically, the relative dynamics equations are established to analyze the effects of orbit eccentricity, orbit altitude, and tether length rate on the system dynamics as well as investigate the property of pitch motion. Then the retrieval control law with constant pitch angle constraint is proposed using the dynamic inverse method based on the dynamics analyses. We further discuss the feasible region of orbit eccentricity and constant pitch angle for the control law to retrieve the tether. The numerical simulation experiments show that the proposed law can realize stable retrieval while maintaining a constant pitch angle. [ABSTRACT FROM AUTHOR]

The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists. [Display omitted] • The structure and physiological function of TGR5 were analyzed in this review. • The mechanisms of TGR5-mediated effects in various diseases were summarized. • Different structural types of TGR5 agonists were also reviewed. • The challenges and prospects in the development of TGR5 agonists were introduced. [ABSTRACT FROM AUTHOR]

Background: Continuous glucose monitors (CGMs) can measure interstitial fluid glucose levels to provide comprehensive real-time glucose profile among people with type 2 diabetes. These can accurately detect glucose levels, hyperglycaemia and hypoglycaemia events compared with conventional self-monitoring. Increased application of CGMs provides a valuable opportunity to evaluate glucose control on oral anti-diabetic medications. This review will compare the efficacy and safety of oral anti-diabetic medications among patients with type 2 diabetes, evaluated by CGM. Methods: The following databases will be searched: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus and grey literature (ClinicalTrials.gov, PsycEXTRA, ProQuest Dissertations, Google Scholar and Theses Global) for the identification of studies. The review will include and summarise evidence from randomised clinical trials that use CGMs for blood glucose management in adults (aged ≥ 18 years), published in English between January 2000 and May 2021 without any restrictions of countries. Reference list of all selected articles will independently be screened to identify additional studies left out in the initial search. Primary outcomes will be HbA1c (≤ 7.0%), time spent with hypoglycaemia (< 70 mg/dl) or hyperglycaemia (≥ 180 mg/dl). Secondary outcomes will be change in weight, blood pressure and related comorbidities (cardiovascular mortality, heart failure events, myocardial infarction and stroke). Study selection, data extraction and quality assessment will be conducted independently by at least two reviewers. A third reviewer will determine and resolve discrepancies. At least two independent reviewers will cross-check data synthesis. The quality of evidence of the review will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Tool. Discussion: The review is anticipated to provide up to date evidence for further studies and clinic practices regarding glycaemic control, hypoglycaemia, and hyperglycaemia issues. The results will be published in a peer-reviewed journal. Trial registration: PROSPERO CRD42020188399. [ABSTRACT FROM AUTHOR]

Electromigration (EM) of metal interconnects is the continuous reliability concern for high-density integration beyond 5-nm technology, especially for the buried power rails in vertically stacked device structure. In this work, EM reliability of alternative metal interconnects based on complementary FET (CFET) is investigated by kinetic Monte Carlo (KMC) method. The microscopic evolutions of void formation in power rails can be well reproduced by considering the coupled effects of thermal and stress distribution during the EM simulation. The influences of grain boundary in different metal materials on EM lifetime are analyzed to provide the optimal strategy of process integration. Thermal-aware EM reliability is further predicted, indicating the importance of self-heating on EM evaluation of power rails in CFET. [ABSTRACT FROM AUTHOR]

Aims. To investigate the epidemiology of diabetes diagnosis and screening in Australian general practice. Methods. Cross-sectional study using electronic health records of 1,522,622 patients aged 18+ years attending 544 Australian general practices (MedicineInsight database). The prevalence of diagnosed diabetes and diabetes screening was explored using all recorded diagnoses, laboratory results, and prescriptions between 2016 and 2018. Their relationship with patient sociodemographic and clinical characteristics was also investigated. Results. Overall, 7.5% (95% CI 7.3, 7.8) of adults had diabetes diagnosis, 0.7% (95% CI 0.6, 0.7) prediabetes, and 0.3% (95% CI 0.3, 0.3) unrecorded diabetes/prediabetes (elevated glucose levels without a recorded diagnosis). Patients with unrecorded diabetes/prediabetes had clinical characteristics similar to those with recorded diabetes, except for a lower prevalence of overweight/obesity (55.5% and 69.9%, respectively). Dyslipidaemia was 1.8 times higher (36.2% vs. 19.7%), and hypertension was 15% more likely (38.6% vs. 33.8%) among patients with prediabetes than with diabetes. Diabetes screening (last three years) among people at high risk of diabetes was 55.2% (95% CI 52.7, 57.7), with lower rates among young or elderly males. Conclusions. Unrecorded diabetes/prediabetes is infrequent in Australian general practice, but prediabetes diagnosis was also lower than expected. Diabetes screening among high-risk individuals can be improved, especially in men, to enhance earlier diabetes diagnosis and management. [ABSTRACT FROM AUTHOR]

Objective. Panax ginseng and Atractylodes macrocephala Koidz. (AMK) are widely used in treating various diseases; however, research is insufficient on measuring the relationship that exists by combining this drug pair using the copula function. Methods. In this study, 279 traditional Chinese medicine prescriptions containing the Panax ginseng and AMK drug pair were extracted from the prescription database for three types of screened indications, namely, diabetes mellitus, diarrhea, and insomnia. Following the principle of dose conversion, each dynasty unit was uniformly converted into a modern unit. Then, the kernel density distribution of Panax ginseng and AMK was fitted with their empirical distribution functions. Finally, the optimal copula function was selected from the copula function family as a t-copula function. Results. The empirical distribution and probability density functions of Panax ginseng and AMK were obtained. From the results, their Kendall rank correlation coefficients with indications of diabetes mellitus, insomnia, and diarrhea were 0.8689, 0.7858, and 0.7403, whereas their Spearman rank correlation coefficients were 0.9563, 0.9276, and 0.8958. Results also indicated that the use of the t-copula function can better reflect the correlation between Panax ginseng and AMK doses. Conclusion. From the three indications, the dose between Panax ginseng and AMK was positively correlated. This study, therefore, confirms the medicinal principle of Chinese medicine "combining" from the perspective of mathematical statistics. Results from this study are practical to evaluate the correlation between the drug pair doses, Panax ginseng and AMK, using the copula function model, which provides a new model for the scientific explanation of compatibility for Chinese medicines. This study also provides a methodological basis for more drug measurement studies and clinical medications. [ABSTRACT FROM AUTHOR]

As technology nodes continue to shrink, the impact of aging problems on devices has become increasingly important. One significant aging problem that affects device characteristics and circuit performance is Negative Bias Temperature Instability (NBTI). Under small-size conditions, fluctuations in device parameters such as threshold voltage due to aging are not negligible. To capture these fluctuations, an improved statistical model has been proposed. The time-dependent statistical model accounts for the average change in the number of charged defects due to NBTI and enables the evaluation of degradation fluctuations over time. The model prediction of the threshold voltage degradation of devices in advanced technology is verified with different measured data. Furthermore, the model is implemented with the Open Model Interface (OMI) for the circuit-level degradation simulation, taking advantage of OMI's convenience and compatibility with different circuit simulators. The integration of the proposed model into the OMI benefits in predicting the degradations difference among the transistors in the circuits, reducing the overestimation of aging degradation compared to the methods that assume every transistor experiences the same and worst degradation. • An improved statistical model to capture device parameter fluctuations due to aging. • The average change in the number of charged defects due to Negative Bias Temperature Instability. • Integrating model into Open Model Interface for the compatibility with different simulators. • Reducing overestimation of degradation during aging evaulation at circuit level. [ABSTRACT FROM AUTHOR]

Piceatannol (Pice), a natural analog of resveratrol, has been identified as an anticancer agent in various cancers by modulating the expression of microRNAs (miRNAs/miRs). However, the molecular mechanisms underlying the anticancer effects of Pice in osteosarcoma (OS) cells remain unclear. Thus, we hypothesized that Pice exerts anticancer effects on OS cells via the regulation of miRNA expression. Herein, we performed a MTT assay and flow cytometric analysis to determine cell viability and apoptosis in OS cells treated with Pice, respectively. Our results showed that Pice inhibits proliferation in a dose-dependent manner induces the apoptosis of OS cells. More importantly, miRNA microarray analysis identified that Pice alters miRNA expression profiles in human OS cells after treatment with Pice, and miR-21 was the most significantly downregulated. In addition, the therapeutic effects of Pice on OS cells were weakened by restoration of miR-21. In addition, we further verified that phosphatase and tensin homolog (PTEN), a tumor suppressor gene, is the functional target of miR-21 and Pice blocks the PTEN/AKT signaling pathway through inhibiting miR-21 expression in OS cells. Our findings suggested that Pice may exert anticancer effects on OS cells via mediating the miR-21/PTEN/AKT signaling pathway and could be considered to be a potential anticancer agent for treating OS. [ABSTRACT FROM AUTHOR]

Background: Continuous glucose monitorings (CGMs) have been used to manage diabetes with reasonable glucose control amongst patients with type 2 diabetes (T2D) in recent decades. CGMs measure interstitial fluid glucose levels to provide information about glucose levels, which identify fluctuation that would not have been identified with conventional self-monitoring. Self-monitoring of blood glucose (SMBG) is a classical tool to measure glycaemic changes. However, the effectiveness of glucose control, hypoglycemia, weight change, quality of life and user satisfaction, are needed to evaluate and compare CGMs and SMBG amongst adults with T2D. Methods: The review will compare the various forms of CGM systems (i.e flash CGM, real-time CGM, retrospective CGM) versus SMBG or usual intervention regarding diabetes management amongst adults with T2D. The following databases will be searched: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus and grey literature (ClinicalTrials.gov, PsycEXTRA, ProQuest Dissertations, Google Scholar and Theses Global) for the identification of studies. The studies involving adults (aged ≥ 18 years old) will be included. We will only include and summarise randomised clinical trials (RCTs) with respect to authors, publication type, year, status and type of devices. Studies published in English between February 2010 and March 2020, will be included as the field of CGMs amongst T2D patients has emerged over the last decade. Primary outcomes will be HbA1c (glycosylated haemoglobin level) (mmol/L), body weight (kg), time spent with hypoglycaemia (< 70 mg/dl) or hyperglycaemia (≥ 180 mg/dl), blood pressure (< 140/90 mmHg is considered as good management) and quality of life (understanding and feeling of living situation based on culture and value system). Secondary outcome measures will be user satisfaction (patient or treatment/intervention satisfaction or satisfaction scale) and barriers (physical and mental difficulties or issues). Study selection, data extraction and risk of bias assessment will be conducted independently by at least two reviewers. A third reviewer will determine and resolve discrepancies. Moreover, the quality of the evidence of the review will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation tool (GRADE). Discussion: The review will synthesise evidence on the comparison between using CGMs and SMBG. The results will support researchers and health professionals to determine the most effective methods/technologies in the overall diabetes management. Systematic review registration: PROSPERO CRD42020149212 [ABSTRACT FROM AUTHOR]

A novel low-cost gas atomisation technology producing spherical titanium powder (wire induction heating gas atomisation, WIGA) has been developed for additive manufacturing. Combined with the gas atomisation principle, the characteristics of WIGA were analysed. The effects of the gas pressure, metal temperature and the wire-feeding speed on the particle size of the titanium powder were studied. The results indicated that the decreases in mass median particle diameter (D50) and the increases in efficiency of fine size powders occurred with the increase in gas atomisation pressure and melting temperature and with the decrease of wire-feed speed. The optimum parameters are that the main gas pressure (P0) is 4.0 MPa, the degree of superheat of the metal melt is 350°C and the wire-feed speed is 50 mm s−1. On the condition, the D50 of titanium powder was 40.2 μm and powder morphology was spherical. Satellites rarely existed on the surface of particles. [ABSTRACT FROM AUTHOR]

CuAgZr alloy is known for its high strength and high conductivity, which are reasons for its wide application. In this work, CuAgZr powder alloys were produced by high-pressure argon gas atomisation. The results indicate that the surface morphology of the powder is a cellular crystal structure with a pentagonal crystal structure, with a ‘rose-like’ lattice and cross-shaped dendrites. A three-dimensional model of the primary dendritic changes in the CuAgZr alloy powder with different powder diameters was established by studying the surface morphology and internal microstructure of the powder. The relationship between the powder diameter and the powder cooling rate was established as the function of the primary dendritic length (PDL), the primary dendritic volume fraction (PDVF), the secondary dendrite arm spacing (SDAS) and the secondary dendritic volume fraction (SDVF). A confidence validation was performed, and the function fitting error is within 10%. The results establish that the function is meaningful. [ABSTRACT FROM AUTHOR]

Serious eye damage and eye irritation have been authenticated to be significant human health issues in various fields such as ophthalmic pharmaceuticals. Due to the shortcomings of traditional animal testing methods, in silico methods have advanced to study eye toxicity. The models for predicting serious eye damage and eye irritation potential of compounds were developed using 2299 and 5214 compounds, respectively. The 40 global single models and 40 local models were developed by combining 5 molecular description methods and 4 machine learning methods. The 40 active learning models were developed by adopting uncertainty-based active learning strategies and taking local models as initial models. The 110 global consensus models based on 40 global single models were developed using a consensus strategy. Active learning models and global consensus models performed high prediction accuracy. The test accuracy of the best serious eye damage model and eye irritation model reached 0.972 and 0.959, respectively. The applicability domains for all models were calculated to verify the rationality of prediction effect. In addition, 8 structural alerts probably causing serious eye damage or eye irritation were sought out. The prediction models and structural alerts contributed to providing hazard identification and assessing chemical safety. [Display omitted] • The test accuracy of damage models and irritation models reached 0.972 and 0.959. • Global models, local models, active learning models, consensus models were developed. • 40 uncertainty-based active learning models derived from 40 local models were useful. • 110 global consensus models generally performed better than 40 global single models. • The 8 structural alerts probably causing eye damage or irritation were identified. [ABSTRACT FROM AUTHOR]

Methanosaeta strains are frequently involved in the granule formation during methanogenic wastewater treatment. To investigate the impact of Methanosaeta on granulation and performance of upflow anaerobic sludge blanket (UASB) reactors, three 1-L working volume reactors noted as R1, R2, and R3 were operated fed with a synthetic wastewater containing sodium acetate and glucose. R1 was inoculated with 1-L activated sludge, while R2 and R3 were inoculated with 200-mL concentrated pre-grown Methanosaeta harundinacea 6Ac culture and 800 mL of activated sludge. Additionally, R3 was daily dosed with 0.5 mL/L of acetyl ether extract of 6Ac spent culture containing its quorum sensing signal carboxyl acyl homoserine lactone (AHL). Compared to R1, R2 and R3 had a higher and more constant chemical oxygen demand (COD) removal efficiency and alkaline pH (8.2) during the granulation phase, particularly, R3 maintained approximately 90 % COD removal. Moreover, R3 formed the best granules, and microscopic images showed fluorescent Methanosaeta-like filaments dominating in the R3 granules, but rod cells dominating in the R2 granules. Analysis of 16S rRNA gene libraries showed increased diversity of methanogen species like Methanosarcina and Methanospirillum in R2 and R3, and increased bacteria diversity in R3 that included the syntrophic propionate degrader Syntrophobacter. Quantitative PCR determined that 6Ac made up more than 22 % of the total prokaryotes in R3, but only 3.6 % in R2. The carboxyl AHL was detected in R3. This work indicates that AHL-facilitated filaments of Methanosaeta contribute to the granulation and performance of UASB reactors, likely through immobilizing other functional microorganisms. [ABSTRACT FROM AUTHOR]

The effect of pH (4.0, 5.0, and 6.0) on acidification and fermentation of fruit and vegetable wastes was investigated using batch and semi-continuous experiments under mesophilic condition. Results showed that fermentation types change with pH variation. The pH of acidification system containing fruit and vegetable wastes could automatically decrease to 3.0 ~ 4.0. At this pH range, a stable ethanol production was observed, at which ethanol-type fermentation was obtained. Based on the results, the fermentation types were classified into ethanol-type, mixed acid-type, propionic acid-type, and butyric acid-type fermentations, which occurred at pH 4.0 ~ 4.5, 4.5 ~ 5.0, 5.0 ~ 5.5, and 5.5 ~ 6.5, respectively. [ABSTRACT FROM AUTHOR]

CD47 is a macrophage-specific immune checkpoint protein acting by inhibiting phagocytosis. However, the underlying mechanism maintaining CD47 protein stability in cancer is not clear. Here we show that CD47 undergoes degradation via endocytosis/lysosome pathway. The lysosome protein RAGA interacts with and promotes CD47 lysosome localization and degradation. Disruption of RAGA blocks CD47 degradation, leading to CD47 accumulation, high plasma membrane/intracellular CD47 expression ratio and reduced phagocytic clearance of cancer cells. RAGA deficiency promotes tumor growth due to the accumulation of CD47, which sensitizes the tumor to CD47 blockade. Clinical analysis shows that RAGA and CD47 proteins are negatively correlated in lung adenocarcinoma patient samples. High RAGA protein level is related to longer patient survival. In addition, RAGAhighCD47low patients show the longest overall survival. Our study thereby not only reveals a mechanism by which RAGA regulates CD47 lysosome degradation, but also suggests RAGA is a potential diagnostic biomarker of lung adenocarcinoma. The lysosome protein RAGA interacts with and promotes lysosome localization and degradation of the macrophage-specific immune checkpoint protein CD47, with possible relevance to lung adenocarcinoma [ABSTRACT FROM AUTHOR]

Highlights: [•] The leading computational techniques for drug design and discovery are reviewed. [•] Successful applications of computational techniques are provided. [•] A novel drug–target binding kinetics calculation approach is introduced. [ABSTRACT FROM AUTHOR]

Water is an important component in living systems and deserves better understanding in chemistry and biology. However, due to the difficulty of investigating the water functions in protein structures, it is usually ignored in computational modeling, especially in the field of computer-aided drug design. Here, using the potential of mean forces (PMFs) approach, we constructed a water PMF (wPMF) based on 3946 non-redundant high resolution crystal structures. The extracted wPMF potential was first used to investigate the structure pattern of water and analyze the residue hydrophilicity. Then, the relationship between wPMF score and the B factor value of crystal waters was studied. It was found that wPMF agrees well with some previously reported experimental observations. In addition, the wPMF score was also tested in parallel with 3D-RISM to measure the ability of retrieving experimentally observed waters, and showed comparable performance but with much less computational cost. In the end, we proposed a grid-based clustering scheme together with a distance weighted wPMF score to further extend wPMF to predict the potential hydration sites of protein structure. From the test, this approach can predict the hydration site at the accuracy about 80% when the calculated score lower than −4.0. It also allows the assessment of whether or not a given water molecule should be targeted for displacement in ligand design. Overall, the wPMF presented here provides an optional solution to many water related computational modeling problems, some of which can be highly valuable as part of a rational drug design strategy. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient. Due to the wider receptor selectivity and lower target-based toxicity, compared with orthosteric ligands, allosteric modulators are expected to play a larger role in pharmaceutical research and development. However, current difficulties, such as a low affinity and unknown structural features of potential allosteric small-molecules, usually obstruct the discovery of allosteric modulators. In this study, we compared known allosteric modulators with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators generally contain more hydrophobic scaffolds and have a higher structural rigidity, i.e., less rotatable bonds and more rings. Based on this analysis, an empirical rule was defined to determine the structural requirements for an allosteric modulator. It was found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this “allosteric-like” filter, which shows good discriminatory power in identifying allosteric modulators. Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds. [Copyright &y& Elsevier]

Skin sensitization is an important toxic endpoint in the risk assessment of chemicals. In this paper, structure-activity relationships analysis was performed on the skin sensitization potential of 357 compounds with local lymph node assay data. Structural fragments were extracted by GASTON (GrAph/Sequence/Tree extractiON) from the training set. Eight fragments with accuracy significantly higher than 0.73 ( p < 0.1) were retained to make up an indicator descriptor fragment. The fragment descriptor and eight other physicochemical descriptors closely related to the endpoint were calculated to construct the recursive partitioning tree (RP tree) for classification. The balanced accuracy of the training set, test set I, and test set II in the leave-one-out model were 0.846, 0.800, and 0.809, respectively. The results highlight that fragment-based RP tree is a preferable method for identifying skin sensitizers. Moreover, the selected fragments provide useful structural information for exploring sensitization mechanisms, and RP tree creates a graphic tree to identify the most important properties associated with skin sensitization. They can provide some guidance for designing of drugs with lower sensitization level. [ABSTRACT FROM AUTHOR]

The dominant reaction pathway changes with the composition of the supported PdAu nanoalloys, and the water promotion effect is component-dependent. [Display omitted] • Maximize the synergistic effect of PdAu catalysts on TiO 2 (101) for CO 2 reduction. • CO 2 adsorption has a volcanic relationship with activity in "CO 2 HYD" pathway. • Activity is related to adsorption energy of CHO and CO in "RWGS + CO HYD" pathway. • The mechanism of water promotion is composition-dependent. To provide insight into how to realize maximization of the synergistic effect of supported PdAu catalysts, we have performed first-principles calculations for CO 2 reduction over PdAu/TiO 2 (1 0 1). The results indicate that introducing a secondary metal (Au) to supported Pd catalyst and controlling Au concentration can affect the binding energy of reactants and also alter the dominant reaction pathway. The energetically preferred path for CO 2 reduction on Pd 8-x Au x /TiO 2 changes from the formate pathway (referred to as the "CO 2 HYD" pathway) (x = 0–3) to the reverse water-gas shift and CO hydrogenation ("RWGS + CO HYD") pathway (x = 4–6). Notably, the CO 2 reduction activity shows a volcano trend as a function of the binding energy of the initial reactant CO 2 * in the "CO 2 HYD" pathway or the adsorption energy difference between CHO* and CO* in the "RWGS + CO HYD" pathway. In addition, there is a component-dependent relationship between the water-promotion-effect and the nanoalloy structure. This work proposes fundamental insights into the effect of nanoalloy composition and water promotion in maximizing the synergy of PdAu catalysts for CO 2 reduction, providing facile descriptors for the activity of reaction pathways, and offering important guidance for rational design of supported nanoalloy catalysts. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC50 =74μM). Selected compounds for concentration–response studies showed prominent inhibitory activities with IC50 values ranging from 0.74μM to 3.17μM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC50 values less than 1μM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases. [Copyright &y& Elsevier]

Abstract: Sixteen novel 4-triazole-modified zanamivir (1) analogues were synthesized using the click reactions, and their inhibitory activities against avian influenza virus (AIV, H5N1) were determined. Compound 3b exerts promising inhibitory activity with EC50 of 6.4μM, which is very close to that of zanamivir (EC50 =2.8μM). Molecular modeling provided the information about the binding model between inhibitors and neuraminidase, which are in good agreement with inhibitory activities. [Copyright &y& Elsevier]

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure–activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q 2 of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor–enzyme interaction should be useful in developing novel potent NA inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics (MD) simulations, automated docking, and 3D-QSAR analyses were performed in this study on 21 COX-2/5-LOX dual inhibitors, namely, 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (DHDMBF) analogues. A 3D-model of 5-LOX was built based on the high-resolution X-ray structure of rabbit reticulocyte 15-lipoxygenase. Molecular docking was then applied to locate the binding orientations and conformations of DHDMBF analogues with COX-2 and 5-LOX, respectively, leading to highly predictive CoMFA models constructed on the basis of the binding conformations with q 2 values of 0.782 and 0.634 for COX-2 and 5-LOX, respectively. In addition, CoMFA field distributions were found in good agreement with the structural characteristics of the corresponding binding sites. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature with a moderately bulky group at R2 position and a rather negatively charged group around the position of the carbonyl group of DHDMBFs. Therefore, the final 3D-QSAR models and the information of the inhibitor–enzyme interaction should be useful in developing new NSAIDs as anti-inflammation drugs with favorable safety profile. [Copyright &y& Elsevier]

Microenvironmental factors regulate stem cell fate. Fibronectin (FN), a key extracellular matrix component of the microenvironment, has been linked to various stem cell behaviors. However, how FN controls self-renewal, proliferation, and homeostasis of limbal stem cells remains unclear. Our study investigated the roles of FN in the self-renewal of rabbit limbal epithelial stem cells (rLESCs) by assessing rLESC proliferation and stemness in the presence and absence of FN. We further examined the effect of FN on non-canonical Wnt signaling during rLESC proliferation by evaluating the expression of cell cycle regulators. We found that rLESC proliferation increased after FN treatment and that 12.5 μg/cm2 FN maintained rLESC stemness. FN facilitated rLESC self-renewal by promoting Wnt11 and Fzd7 interaction. Furthermore, FN modulated cell cycle regulators to enhance rLESC proliferation via the upregulation of ROCK1 and ROCK2. Our study provides new insights into the mechanism through which FN regulates the self-renewal of rLESCs; specifically, this occurs via stimulation of the Wnt11/Fzd7/ROCK non-canonical Wnt pathway. The roles of FN in the self-renewal of limbal epithelial stem cells should be further investigated for the potential treatment of limbal deficiency. • FN improves the self-renewal of rabbit limbal epithelial stem cells (rLESCs). • rLESC proliferation is enhanced through modulating ROCK1/2 and cell cycle regulators. • FN regulates rLESC self-renewal by stimulating the Wnt11/Fzd7/ROCK non-canonical Wnt pathway. [ABSTRACT FROM AUTHOR]

Background: This study investigated the association between Anti-Müllerian Hormone (AMH) and relevant metabolic parameters and assessed its predictive value in the clinical diagnosis of polycystic ovarian syndrome (PCOS). Methods: A total of 421 women aged 20–37 years were allocated to the PCOS (n = 168) and control (n = 253) groups, and their metabolic and hormonal parameters were compared. Spearman correlation analysis was conducted to investigate associations, binary logistic regression was used to determine PCOS risk factors, and receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of AMH in diagnosing PCOS. Results: The PCOS group demonstrated significantly higher blood lipid, luteinizing hormone (LH), and AMH levels than the control group. Glucose and lipid metabolism and hormonal disorders in the PCOS group were more significant than in the control group among individuals with and without obesity. LH, TSTO, and AMH were identified as independent risk factors for PCOS. AMH along with LH, and antral follicle count demonstrated a high predictive value for diagnosing PCOS. Conclusion: AMH exhibited robust diagnostic use for identifying PCOS and could be considered a marker for screening PCOS to improve PCOS diagnostic accuracy. Attention should be paid to the effect of glucose and lipid metabolism on the hormonal and related parameters of PCOS populations. [ABSTRACT FROM AUTHOR]

In this work, the thiol modified silica nanostructures (SiO2-SH) were doped into polymer-dispersed liquid crystal (PDLC) films. The SEM was used to observe the morphology of the polymer microstructure. The electro-optical (E-O) property test was determined by a liquid crystal parameter tester. The SEM images suggested that the SiO2-SH nanoparticles can react with acrylate groups to form the polymer matrix. The saturation voltage decreased by half in the sample when the dosage of the SiO2-SH nanoparticles was 7.5 wt%, which may be due to the reduced anchoring strength of the polymer matrix incorporated with silicon nanoparticles resulting from the lower surface energy and the enhanced steric repulsions of LC droplets and polymer matrix. In addition, the preparation conditions like polymerisation temperatures and UV light intensity also effectively regulated the E-O properties and polymer microstructure of the PDLC film with silica nanostructure. Thus, the results showed that the E-O properties and the polymer morphology of PDLC films with silicon nanostructures can be effectively regulated by doping SiO2-SH nanoparticles and regulating the preparation conditions such as the polymerisation temperature and UV light intensity. This work can provide practical guidance for modulating the properties of PDLC films. [ABSTRACT FROM AUTHOR]

We aimed to compare the prevalence of modifiable and non-modifiable coronary heart disease (CHD) risk factors among those with premature CHD and healthy individuals. PubMed, CINAHL, Embase, and Web of Science databases were searched (review protocol is registered in PROSPERO CRD42020173216). The quality of studies was assessed using the National Heart, Lung and Blood Institute tool for cross-sectional, cohort and case-control studies. Meta-analyses were performed using Review Manager 5.3. Effect sizes for categorical and continuous variables, odds ratio (OR) and mean differences (MD)/standardised mean differences (SMD) with 95% confidence intervals (CI) were reported. A total of n=208 primary studies were included in this review. Individuals presenting with premature CHD (PCHD, age ≤65 years) had higher mean body mass index (MD 0.54 kg/m2, 95% CI 0.24, 0.83), total cholesterol (SMD 0.27, 95% CI 0.17, 0.38), triglycerides (SMD 0.50, 95% CI 0.41, 0.60) and lower high-density lipoprotein cholesterol (SMD 0.79, 95% CI: −0.91, −0.68) compared with healthy individuals. Individuals presenting with PCHD were more likely to be smokers (OR 2.88, 95% CI 2.51, 3.31), consumed excessive alcohol (OR 1.40, 95% CI 1.05, 1.86), had higher mean lipoprotein (a) levels (SMD 0.41, 95% CI 0.28, 0.54), and had a positive family history of CHD (OR 3.65, 95% CI 2.87, 4.66) compared with healthy individuals. Also, they were more likely to be obese (OR 1.59, 95% CI 1.32, 1.91), and to have had dyslipidaemia (OR 2.74, 95% CI 2.18, 3.45), hypertension (OR 2.80, 95% CI 2.28, 3.45), and type 2 diabetes mellitus (OR 2.93, 95% CI 2.50, 3.45) compared with healthy individuals. This meta-analysis confirms current knowledge of risk factors for PCHD, and identifying these early may reduce CHD in young adults. [ABSTRACT FROM AUTHOR]

Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468's prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model's predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data. [ABSTRACT FROM AUTHOR]

Aim: To explore the current status of Chinese nurses' willingness to work during the COVID‐19 pandemic and the factors that influence them. Background: The demand for front‐line nurses continues to grow during the COVID‐19 pandemic, but their willingness varies significantly. Therefore, it is crucial to explore nurses' willingness to report for front‐line work. Methods: A cross‐sectional study of 1,310 nurses from six tertiary hospitals was conducted. The participants completed self‐administered online questionnaires. Results: A total of 90.5% of nurses reported that they would like to voluntarily participate in front‐line work. Those with previous training, higher self‐efficacy scores, and lower perceived risk and self‐worth scores were more likely to participate in front‐line work, while nurses, who had 11–15 years of work experience and were worried about their family and the lack of family support, were less likely to be involved in front‐line work. Conclusion: This study found that the vast majority of nurses were willing to participate in front‐line work and affirmed the positive effects of previous infection prevention training, self‐efficacy and self‐worth. Implications for Nursing Management: This research emphasizes the necessity of infection prevention training and provides evidence for further emergency workforce deployment and incentives. [ABSTRACT FROM AUTHOR]

[Display omitted] • The superiority of ethanol-path anaerobic digestion was clarified via various means. • Liquid product presents higher recovery potential than gas product in carbon flux view. • The dominant microorganisms in the anaerobic digestion system are identified. To rapidly treat and stably utilize great quantities of fruit and vegetable waste (FVW), the strategies in anaerobic digestion pattern have been constantly improved. In this work, the efficiencies and capacities of carbon conversion in different FVW anaerobic digestion systems were studied. Compared to butyrate-path (BD) two-phase and single-phase anaerobic digestion (SD), the ethanol-path two-phase anaerobic digestion (ED) system showed the highest rate of converting insoluble into soluble carbon formation (82.2%) and methane yield conversed from soluble carbon which is 0.14 gCOD CH4 (gVSS d)−1. It was also found that the coexistence of Bacillus and Methanococcus in the methanogenic phase maintained fatty acids and methane generation. The advantage of carbon conversion efficiency in ED can be elucidated from the highest acetification rate (704.10 mgCOD (L h)−1) which means more converted acetate can be smoothly used for methane generation. Compared to methanogenesis converted from butyrate and propionate, the thermodynamic condition of methanogenesis converted from ethanol was more feasible. Also, the highest capacity of max methane production (197773.7 mL) of ED was simulated. ED might be an efficient and advantageous option for FVW methane digestion. Furthermore, comparison of acidogenic product and methane in conversion efficiency revealed that fatty acids should think as ideal anaerobic product rather than methane. [ABSTRACT FROM AUTHOR]

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape. [ABSTRACT FROM AUTHOR]

Lipophilicity is a fundamental physical property that significantly affects various aspects of drug behavior, including solubility, permeability, metabolism, distribution, protein binding, and toxicity. Accurate prediction of lipophilicity, measured by the logD7.4 value (the distribution coefficient between n-octanol and buffer at physiological pH 7.4), is crucial for successful drug discovery and design. However, the limited availability of data for logD modeling poses a significant challenge to achieving satisfactory generalization capability. To address this challenge, we have developed a novel logD7.4 prediction model called RTlogD, which leverages knowledge from multiple sources. RTlogD combines pre-training on a chromatographic retention time (RT) dataset since the RT is influenced by lipophilicity. Additionally, microscopic pKa values are incorporated as atomic features, providing valuable insights into ionizable sites and ionization capacity. Furthermore, logP is integrated as an auxiliary task within a multitask learning framework. We conducted ablation studies and presented a detailed analysis, showcasing the effectiveness and interpretability of RT, pKa, and logP in the RTlogD model. Notably, our RTlogD model demonstrated superior performance compared to commonly used algorithms and prediction tools. These results underscore the potential of the RTlogD model to improve the accuracy and generalization of logD prediction in drug discovery and design. In summary, the RTlogD model addresses the challenge of limited data availability in logD modeling by leveraging knowledge from RT, microscopic pKa, and logP. Incorporating these factors enhances the predictive capabilities of our model, and it holds promise for real-world applications in drug discovery and design scenarios. [ABSTRACT FROM AUTHOR]

We aimed to systematically compare literature on prevalence of modifiable and non-modifiable risk factors for early compared to late-onset coronary heart disease (CHD). PubMed, CINAHL, Embase, and Web of Science databases were searched (review protocol registered in PROSPERO CRD42020173216). Study quality was assessed using the National Heart, Lung and Blood Institute tool for observational and case-control studies. Review Manager 5.3 was used for meta-analysis. Effect sizes were expressed as odds ratio (OR) and mean differences (MD)/standardised MD (SMD) with 95% confidence intervals (CI) for categorical and continuous variables. Individuals presenting with early-onset CHD (age <65 years) compared to late-onset CHD had higher mean body mass index (MD 1.07 kg/m2; 95% CI 0.31−1.83), total cholesterol (SMD 0.43; 95% CI 0.23−0.62), low-density lipoprotein (SMD 0.26; 95% CI 0.15−0.36) and triglycerides (SMD 0.50; 95% CI 0.22−0.68) with lower high-density lipoprotein-cholesterol (SMD 0.26; 95% CI -0.42−-0.11). They were more likely to be smokers (OR 1.76, 95% CI 1.39−2.22) and have a positive family history of CHD (OR 2.08, 95% CI 1.74−2.48). They had lower mean systolic blood pressure (MD 4.07 mmHg; 95% CI -7.36−-0.78) and were less likely to have hypertension (OR 0.47, 95% CI 0.39−0.57), diabetes mellitus (OR 0.56, 95% CI 0.51−0.61) or stroke (OR 0.31, 95% CI 0.24−0.42). A focus on weight management and smoking cessation and aggressive management of dyslipidaemia in young adults may reduce the risk of early-onset CHD. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA) vaccine is revolutionizing the methodology of immunization in cancer. However, mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport, rapid clearance, catalytic hydrolysis, insufficient cellular entry and endosome entrapment. Herein, we design a mRNA nanovaccine based on intelligent design to overcome these obstacles. Highly efficient nanovaccines are carried out with machine learning techniques from datasets of various nanocarriers, ensuring successful delivery of mRNA antigen and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to targets. It activates stimulator of interferon genes (STING), promotes mRNA-encoded antigen presentation and boosts antitumour immunity in vivo , thus inhibiting tumour growth and ensuring long-term survival of tumour-bearing mice. This work provides a feasible and safe strategy to facilitate STING agonist-synergized mRNA immunization, with great translational potential for enhancing cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Lipophilicity is a fundamental physical property that significantly affects various aspects of drug behavior, including solubility, permeability, metabolism, distribution, protein binding, and toxicity. Accurate prediction of lipophilicity, measured by the logD7.4 value (the distribution coefficient between n-octanol and buffer at physiological pH 7.4), is crucial for successful drug discovery and design. However, the limited availability of data for logD modeling poses a significant challenge to achieving satisfactory generalization capability. To address this challenge, we have developed a novel logD7.4 prediction model called RTlogD, which leverages knowledge from multiple sources. RTlogD combines pre-training on a chromatographic retention time (RT) dataset since the RT is influenced by lipophilicity. Additionally, microscopic pKa values are incorporated as atomic features, providing valuable insights into ionizable sites and ionization capacity. Furthermore, logP is integrated as an auxiliary task within a multitask learning framework. We conducted ablation studies and presented a detailed analysis, showcasing the effectiveness and interpretability of RT, pKa, and logP in the RTlogD model. Notably, our RTlogD model demonstrated superior performance compared to commonly used algorithms and prediction tools. These results underscore the potential of the RTlogD model to improve the accuracy and generalization of logD prediction in drug discovery and design. In summary, the RTlogD model addresses the challenge of limited data availability in logD modeling by leveraging knowledge from RT, microscopic pKa, and logP. Incorporating these factors enhances the predictive capabilities of our model, and it holds promise for real-world applications in drug discovery and design scenarios. [ABSTRACT FROM AUTHOR]

This study aims to explore the early experiences of frontline nurses at the beginning of the COVID‐19 pandemic in China as expressed through social media posts. This study used an explanatory sequential mixed‐method design. Text mining was used for sentiment analysis. The chi‐square test was used to compare the differences in the composition ratio of sentiment classification of posts in different months. Word frequency was statistically analyzed. Further thematic analysis was also performed. The primary sentiments of the posts were discovered to be positive and neutral. The number of posts containing positive emotions was the lowest in January, peaked in March, and gradually declined in April 2020. The following nurse‐oriented narrative themes were developed: "To see and be seen," "Moving forward amid adversity and support," and "Returning to everyday life and constructing meaning." The sentiments of Chinese nurses in response to the pandemic fluctuated, with positive emotions in the early stage, but it could not be sustained. This study recommends nurses could be encouraged to engage in expressive writing while adhering to ethical guidelines. [ABSTRACT FROM AUTHOR]

Background: We aimed to systematically examine literature on the prevalence of known modifiable and nonmodifiable risk factors for premature coronary heart disease (PCHD) in women compared with men. Materials and Methods: PubMed, CINAHL, Embase, and Web of Science databases were searched. Review protocol is registered in PROSPERO (CRD42020173216). Quality was assessed using the National Heart, Lung, and Blood Institute tool. Review Manager 5.3 was used for meta-analysis. Effect sizes were expressed as odds ratio (OR) and mean differences/standardized mean differences (SMD) with 95% confidence intervals (CIs) for categorical and continuous variables. Results: In this PCHD cohort (age <65 years), the mean age of presentation in women was 3 years older than men. Women had higher total cholesterol (SMD 0.11; 95% CI 0.00 to 0.23) and higher high-density lipoprotein cholesterol (SMD 0.49; 95% CI 0.29 to 0.69). Women were more likely to have hypertension (OR 1.51, 95% CI 1.42 to 1.60), diabetes mellitus (OR 1.78, 95% CI 1.55 to 2.04), obesity (OR 1.33, 95% CI 1.24 to 1.42), metabolic syndrome (OR 3.73, 95% CI 1.60 to 8.69), stroke (OR 1.63, 95% CI 1.51 to 1.77), peripheral vascular disorder (OR 1.67, 95% CI 1.43 to 1.96), and depression (OR 2.29, 95% CI 1.96 to 2.67). Women were less likely to be smokers (OR 0.60, 95% CI 0.55 to 0.66), have reported alcohol intake (OR 0.36, 95% CI 0.33 to 0.40), and reported use of illicit drug (OR 0.32, 95% CI 0.16 to 0.62). Conclusions: Risk factor profile in PCHD has a clear sex difference that supports early, aggressive, holistic, but sex-specific, approach to prevention. [ABSTRACT FROM AUTHOR]

C(sp3)−H oxyfunctionalization, the insertion of an O‐atom into C(sp3)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp3)−H oxyfunctionalization has the potential to overcome limitations inherent to small‐molecule‐mediated approaches by delivering catalyst‐controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α‐ketoglutarate‐dependent iron dioxygenases that catalyze the site‐ and stereodivergent oxyfunctionalization of secondary and tertiary C(sp3)−H bonds, providing concise synthetic routes towards four types of 92 α‐ and β‐hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks. [ABSTRACT FROM AUTHOR]

C(sp3)−H oxyfunctionalization, the insertion of an O‐atom into C(sp3)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp3)−H oxyfunctionalization has the potential to overcome limitations inherent to small‐molecule‐mediated approaches by delivering catalyst‐controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α‐ketoglutarate‐dependent iron dioxygenases that catalyze the site‐ and stereodivergent oxyfunctionalization of secondary and tertiary C(sp3)−H bonds, providing concise synthetic routes towards four types of 92 α‐ and β‐hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks. [ABSTRACT FROM AUTHOR]

Aims and Objective: This qualitative review summarises and synthesises the available evidence on subjective experiences of clinical nurses who cared for patients with COVID‐19. Background: Nurses are first responders and play a vital role in emerging infectious disease epidemics such as the COVID‐19 pandemic. In this context, they also face many difficulties and challenges related, for example to the imbalance between extensive demands and low control over work tasks. Design and Method: A systematic review of qualitative studies and meta‐synthesis focused on the experiences of clinical nurses caring for patients with COVID‐19 during the pandemic was carried out. Results: A total of 279 findings were extracted, aggregated into 21 categories and combined into seven synthesised findings, namely (1) professional nursing practice during the pandemic, (2) support systems, (3) somatic sensations and psychological experiences, (4) difficulties and challenges, (5) coping strategies and behaviour, (6) impact on life, profession and values, and (7) needs and expectations for the future. Conclusion: Nurses encountered considerable difficulties and challenges in caring for patients with COVID‐19. Nurses caring for patients with COVID‐19 need more support from organisations, families and society. It is essential to explore positive coping strategies suitable for working in different cultural backgrounds. Policymakers and decision‐makers should pay attention to the experiences and voices of nurses. Relevance to Clinical Practice: It is critical for nurse managers to consider how to enhance the support system and help nurses develop adaptive coping strategies in response to COVID‐19. Nurses' experiences and voices are valuable in improving health emergency response systems. Patient or Public Contribution: There was no patient or public contribution. [ABSTRACT FROM AUTHOR]

WTAP, a highly conserved Wilms' tumor 1 interacting protein, is involved in a variety of biological processes. However, functional studies of WTAP in planarians have not been reported. In this study, we examined the spatiotemporal expression pattern of planarian DjWTAP and investigated its functions in planarians regeneration and homeostasis. Knocking-down DjWTAP resulted in severe morphological defects leading to lethality within 20 days. Silencing DjWTAP promoted the proliferation of PiwiA+ cells but impaired the lineage differentiation of epidermal, neural, digestive, and excretory cell types, suggesting a critical role for DjWTAP in stem cell self-renewal and differentiation in planarian. To further investigate the mechanisms underlying the defective differentiation, RNA-seq was employed to determine the transcriptomic alterations upon DjWTAP RNA interference. Histone 4 (H4), Histone-lysine N -methyltransferase-SETMAR like, and TNF receptor-associated factor 6 (TRAF6), were significantly upregulated in response to DjWTAP RNAi. Knocking-down TRAF6 largely rescued the defective tissue homeostasis and regeneration resulted from DjWTAP knockdown in planarians, suggesting that DjWTAP maintains planarian regeneration and homeostasis via TRAF6. [ABSTRACT FROM AUTHOR]

WTAP, a highly conserved Wilms' tumor 1 interacting protein, is involved in a variety of biological processes. However, functional studies of WTAP in planarians have not been reported. In this study, we examined the spatiotemporal expression pattern of planarian DjWTAP and investigated its functions in planarians regeneration and homeostasis. Knocking-down DjWTAP resulted in severe morphological defects leading to lethality within 20 days. Silencing DjWTAP promoted the proliferation of PiwiA+ cells but impaired the lineage differentiation of epidermal, neural, digestive, and excretory cell types, suggesting a critical role for DjWTAP in stem cell self-renewal and differentiation in planarian. To further investigate the mechanisms underlying the defective differentiation, RNA-seq was employed to determine the transcriptomic alterations upon DjWTAP RNA interference. Histone 4 (H4), Histone-lysine N -methyltransferase-SETMAR like, and TNF receptor-associated factor 6 (TRAF6), were significantly upregulated in response to DjWTAP RNAi. Knocking-down TRAF6 largely rescued the defective tissue homeostasis and regeneration resulted from DjWTAP knockdown in planarians, suggesting that DjWTAP maintains planarian regeneration and homeostasis via TRAF6. [ABSTRACT FROM AUTHOR]

A site‐selective electrochemical benzylic C(sp3)−H oxidation reaction of aryl alkanes has been reported for synthesis of the desired products. This method significantly expands the scope and enhances the selectivity of aryl aldehydes and fluorinated ethers. Electricity is used as a sustainable oxidant and promote H2 evolution. This protocol is eco‐friendly and easy to handle as it uses a simple undivided cell in mild conditions without employing any catalyst and oxidant. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion angles of rotatable bonds by an interpretable autoregressive method and reconstructs the 3D conformations from them, which keeps structural validity during reconstruction. Another advancement of our method over other conformational generation methods is the ability to use energy to guide the conformation generation. In addition, we propose a new message-passing mechanism that applies the Transformer to the graph to solve the difficulty of remote message passing. Tora3D shows superior performance to prior computational models in the trade-off between accuracy and efficiency, and ensures conformational validity, accuracy, and diversity in an interpretable way. Overall, Tora3D can be used for the quick generation of diverse molecular conformations and 3D-based molecular representation, contributing to a wide range of downstream drug design tasks. [ABSTRACT FROM AUTHOR]

The development of mild, efficient, and enantioselective methods for preparing chiral building blocks from simple, renewable carbon units has been a long‐term goal of the sustainable chemical industry. Mandelate derivatives are valuable pharmaceutical intermediates and chiral resolving agents, but their manufacture relies heavily on highly toxic cyanide. Herein, we report (S)‐4‐hydroxymandelate synthase (HmaS)‐centered biocatalytic cascades for the synthesis of mandelates from benzaldehydes and glycine. We show that HmaS can be engineered to perform R‐selective hydroxylation by single‐point mutation, empowering the stereodivergent synthesis of both (S)‐ and (R)‐mandelate derivatives. These biocatalytic cascades enabled the production of various mandelate derivatives with high atom economy as well as excellent yields (up to 98 %) and ee values (up to >99 %). This methodology offers an effective cyanide‐free technology for greener and sustainable production of mandelate derivatives. [ABSTRACT FROM AUTHOR]