Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 µM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.

Advanced understanding of the polybrominated diphenyl ethers (PBDEs): Insights from total environment to intoxication.

Polybrominated diphenyl ethers (PBDEs) are brominated compounds connected by ester bonds between two benzene rings. There are 209 congeners of PBDEs, classified according to the number and position of the bromine atoms. Due to their low cost and superior flame retardant properties, PBDEs have been extensively used as flame retardants in electronic products, plastics, textiles, and other materials since the 1970s. PBDEs are classified as persistent organic pollutants (POPs) under the Stockholm Convention because of their environmental persistence, bioaccumulation, and toxicity to both humans and wildlife. Due to their extensive use and significant quantities, PBDEs have been detected across a range of environments and biological organisms. These compounds are known to cause damage to the metabolic system, exhibit neurotoxicity, and pose reproductive hazards. This review investigates the environmental distribution and human exposure pathways of PBDEs. Using China-a country with significant PBDE use-as an example, it highlights substantial regional and temporal variations in PBDE concentrations and notes that certain environmental levels may pose risks to human health. The article then examines the toxic effects and mechanisms of PBDEs on several major target organs, summarizing recent research and the specific mechanisms underlying these toxic effects from multiple toxicological perspectives. This review enhances our understanding of PBDEs' environmental distribution, exposure pathways, and toxic mechanisms, offering valuable insights for further research and management strategies.

Research advances on CaMKs-mediated neurodevelopmental injury.

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study.

The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM2.5) exposure. The possible mediating role of plasma proteins on the causative link between PM2.5 exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM2.5 exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM2.5 exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM2.5 and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM2.5 on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM2.5-induced stroke.

The immune cells have complex causal regulation effects on cancers.

BACKGROUND: There was a large body of evidence linking immune cells to cancer risk. However, the causal relationship between immune cells, cancer, and what genes play an important role is unclear. METHODS: In this study, we performed comprehensive two-sample Mendelian randomization analysis (TSMR) to determine the causal relationship between immune cells and common cancers. We also performed Multimarker Analysis of Genomic Annotation (MAGMA) on immune cells causally associated with cancer to identify their relevant genes and used data summary-based MR (SMR) analysis to investigate the causal relationship between their gene expression, methylation, and cancer, and further used drug prediction and molecular docking to validate the medicinal value of the targets. Finally, reverse TSMR analysis was performed on cancer and immune cells to rule out reverse causality. RESULTS: After FDR correction (PFDR < 0.05), the results showed that 2 immune cells were associated with lung cancer risk, and 1 immune cell was significantly associated with pancreatic cancer risk. The expression of OSBPL10, CHD4, SMDT1, PHETA2, and NAGA was positively and causally related to the risk of lung cancer by SMR analysis and HEIDI test. We also found that increased expression of ANP32E decreased the risk of pancreatic cancer and that the methylation level of OSBPL10, CHD4, SULF2, CENPM, and CYP2D6 had a causal association with lung cancer. The methylation level of FCGR3A was causally associated with pancreatic cancer. The results of molecular docking indicated a strong affinity between the drugs and proteins that possessed existing structural information. CONCLUSION: This data-driven Mendelian randomization (MR) study demonstrates the causal role of immune cells in cancers. In addition, this study identifies candidate genes that may be potential anti-cancer drug targets.

[Differences in the Elderly Care Service Demand,Preference,and Tendency Between Urban and Rural Areas in the Pearl River Delta].

Objective To understand the differences in the demand,preference,and tendency for elderly care services between urban and rural areas in the Pearl River Delta (PRD),and to provide reference for the planning and balanced allocation of elderly care resources in urban and rural areas. Methods Using the multi-stage stratified random sampling method,we selected 7 community health service centers in 2 prefecture-level cities in the PRD and conducted a questionnaire survey on the elderly care service demand,preference,and tendency among 1919 regular residents aged 60 years and above who attended the centers. Results A total of 641 urban elderly residents (33.4%) and 1278 rural elderly residents (66.6%) were surveyed in the PRD.The urban and rural elderly residents showed differences in the child number (χ2=43.379,P<0.001),willingness to purchase socialized elderly care services (χ2=104.141,P<0.001),and attitudes to the concept of raising child to avoid elderly hardship (χ2=65.632,P<0.001).The proportion (71.8%) of rural elderly residents who prefer family-based elderly care was higher than that (57.1%) of urban elderly residents (χ2=41.373,P<0.001).The proportion (62.2%) of urban elderly residents clearly expressing their willingness to choose institutions for elderly care was higher than that (44.0%) of rural elderly residents (χ2=57.007,P<0.001).Compared with family-based elderly care,the willingness to choose institutional or community-based in-house elderly care was low among the urban elderly residents with surplus monthly household income or balanced income and expenditure;urban males,those with college education background or above,and those who purchased socialized elderly care services tended to prefer community-based in-house elderly care.In rural areas,the elderly residents who had local household registry were prone to choose institutional or community-based in-house elderly care,while those who had more than one child and those who were satisfied with the current living conditions were less willing to choose community-based in-house elderly care. Conclusions It is suggested that the urban-rural differences in the elderly care service demand,preference and tendency should be fully considered in the planning and allocation of urban and rural elderly care resources.Efforts remain to be made to develop diversified social elderly care services tailored to the characteristics of urban and rural areas.

Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian randomization and colocalization analyses.

To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [ß] = -0.288, 95% confidence interval [CI]: -0.534 - -0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW ß = 1.564, 95% CI: 0.155 - 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW ß = -1.654, 95% CI: -3.063 - -0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio ß = -0.082, 95% CI: -0.165 - 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW ß = 0.042, 95% CI: 0.007 - 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW ß = -0.200, 95% CI: -0.579 - 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW ß = -0.089, 95% CI: -0.166 - -0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, ß was 0.540 (95% CI: 0.040-1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.

Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.

Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (ß = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (ß = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (ß = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (ß = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (ß = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (ß = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (ß = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (ß = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (ß = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (PH4 = 0.836) and E. hallii (PH4 = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.

Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate.

A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, (S)-17b, demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, (S)-17b exhibited excellent in vivo antitumor activity. In addition, compound (S)-17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC50 value of 34.6 µΜ. This novel compound (S)-17b may serve as a new drug candidate for further investigation.

Significance of Melt Pool Structure on the Hydrogen Embrittlement Behavior of a Selective Laser-Melted 316L Austenitic Stainless Steel.

The hydrogen embrittlement (HE) behavior of a selective laser-melted (SLM) 316L austenitic stainless steel has been investigated by hydrogen charging experiments and slow strain rate tensile tests (SSRTs) at room temperature. The results revealed that compared to the samples without H, the ultimate tensile strength (UTS) and elongation (EL) of specimens were decreased from 572 MPa to 552 MPa and from 60% to 36%, respectively, after 4 h of electrochemical hydrogenation with a current density of 100 mA/cm2. The negative effects of hydrogen charging were more pronounced on the samples' ductility than on their strength. A quasi in situ EBSD observation proved that there was little phase transformation in the samples but an increased density of low angle grain boundaries, after 4 h H charging. After strain was applied, the surface of the H-sample displayed many hydrogen-induced cracks along the melt pool boundaries (MPBs) showing that these MPBs were the preferred areas for the gathering and transferring of hydrogen.

In-Hospital Emergency Treatment Delay Among Chinese Patients with Acute Ischaemic Stroke: Relation to Hospital Arrivals and Implications for Triage Pathways.

Introduction: Timely access to emergency treatment during in-hospital care phase is critical for managing the onset of acute ischaemic stroke (AIS), particularly in developing countries. We aimed to explore in-hospital emergency treatment delay and the relation of door-to-needle (DTN) time to ambulance arrivals vs walk-in arrivals. Methods: Data were collected from 1276 Chinese AIS patients admitted to a general, tertiary-level hospital for intravenous thrombolysis. Information on patients' characteristics and time taken during in-hospital emergency treatment was retrieved from the hospital registry data and medical records. Ambulance arrival was defined as being transported by emergency ambulance services, while walk-in arrival was defined as arriving at hospital by regular vehicle. In-hospital emergency treatment delay occurred when the DTN time exceeded 60 minutes. We performed multivariable logistic regression analysis to explore the association between hospital arrivals (by ambulance vs by walk-in) and treatment delay after adjustment for age, sex, education, marital status, residence, medical insurance, number of symptoms, clinical severity and survival outcome. Results: Over half (53.76%) of patients aged over 60 years. Around one-fifth (20.61%) of patients admitted to hospital through emergency ambulance services, while their counterparts arrived by regular vehicle. Overall, the median time taken from the hospital door to treatment initiation was 86.0 minutes. Patients arrived by ambulance (adjusted odds ratio [aOR] = 1.744, 95% confidence interval [CI] = 1.185-2.566, p = 0.005), had higher socio-economic status (aOR = 1.821, 95% CI = 1.251-2.650; p = 0.002), or paid out-of-pocket (aOR = 2.323, 95% CI = 1.764-3.060; p < 0.001) had an increased likelihood of in-hospital emergency treatment delays. Conclusion: In-hospital emergency treatment delay is common in China, and occurs throughout the entire emergency treatment journey. Having a triage pathway involving hospital arrival by ambulance seems to be more likely to experience in-hospital emergency treatment delay. Further efforts to improve triage pathways may require qualitative evidence on provider- and institutional-level factors associated with in-hospital emergency treatment delay.

Built environment influences on urban climate resilience: Evidence from extreme heat events in Macau.

Systematic understanding of climate resilience in the urban context is essential to improve the adaptive capacity in response to extreme weather events. Although the urban built environment affects climate resilience, empirical evidence on the associations between the built environment and urban climate resilience is rare in the literature. In this study, urban heat resilience (HR) is measured as the land surface temperature (LST) difference in a given urban area between normal and extreme heat event, and it further explores the impact of two-dimensional (2D) and three-dimensional (3D) urban built environment features on HR. Using spatial regression, we find that solar insolation and water density are the dominant factors in determining land surface temperature. However, they do not appear to influence HR significantly. Results indicate that vegetation and urban porosity are crucial both in reducing LST and improving HR during extreme heat events. This study highlights the importance of 2D and 3D urban built environment features in improving HR to extreme heat events.

Rapid Microstructure Homogenization of a Laser Melting Deposition Additive Manufactured Ti-6.5Al-3.5Mo-1.5Zr-0.3Si Alloy by Electropulsing.

The typical microstructure of the laser melting deposition (LMD) additive-manufactured Ti-6.5Al-3.5Mo-1.5Zr-0.3Si alloy (TC11) contains the heat-affected bands (HABs), the narrow bands (NBs) and the melting pools (MPs) that formed due to the reheating and superheating effects during the layer-by-layer manufacturing process. Characterization results indicated that the coarse primary α lath (αp) and transformed ß (ßt) structures were located in the HABs, while the fine basketweave structure was formed inside the MPs. The rapid modifications of microstructure and tensile properties of the LMD-TC11 via electropulsing treatment (EPT) were investigated. The initial heterogeneous microstructure transformed into a complete basketweave structure and the HABs vanished after EPT. Thus, a more homogeneous microstructure was achieved in the EPT sample. The ultrafast microstructural changes were mainly attributed to the solid state phase transformation during electropulsing. The tensile properties of the sample were basically stable, except that the yield strength decreased as EPT voltage increased. This study suggests that EPT could be a promising method to modify the microstructure and mechanical properties of the additive-manufactured alloys in a very short time.

Time Window for Acute Stroke Management: A Cross-Sectional Study Among Community Healthcare Practitioners in Primary Care.

Introduction: Time-to-treatment window is critical for managing acute ischaemic stroke. The community healthcare practitioners (CHPs) who deliver frontline care in the health system play an important role in stroke prevention and treatment. Methods: A multi-stage sampling design was adopted in Guangdong province, China. A total of 997 CHPs who participated in the survey were divided into two groups (the awareness group vs the unawareness group) according to their knowledge on the time window for stroke management. Logistic regression analysis was performed to explore factors associated with the awareness of "time window". Results: Overall, less than half (49.1%) of CHPs were aware of the time window for stroke management. The proportion of CHPs who were able to recognise stroke symptoms were higher in the awareness group (42.7%) than that in the unawareness group (38.8%). Most CHPs (82.9%) in the awareness group had the knowledge about the effectiveness of intravenous thrombolysis in treating acute cerebral infarction, whereas this was perceived by only less than half (43.6%) of CHPs in the unawareness group. Factors associated with the knowledge of time window for stroke management included participation in cerebrovascular disease management training (adjusted odds ratio [aOR]=4.203, 95% CI: 1.707-10.348, p=0.002), awareness of the time frame for CT initiation (aOR=5.214, 95% CI: 1.803-15.078, p=0.002) and for urokinase thrombolysis administration (aOR=11.927, 95% CI: 4.393-32.382, p<0.001), accurate perceptions about the target for blood pressure lowering (aOR=4.181, 95% CI: 1.713-10.207, p=0.002) and blood glucose control (aOR=2.446, 95% CI: 1.019-5.869, p=0.045), and the familiarity with prehospital stroke management principles (aOR=3.593, 95% CI: 1.383-9.332, p=0.009). Conclusion: The CHPs need to enhance their ability to address the acute ischaemic stroke onset promptly to provide effective treatment within the beneficial "time window". This may help improve the stroke chain of survival with better multidisciplinary decision support systems that enable optimal stroke care delivery.

Metabolomics analysis reveals four biomarkers associated with the gouty arthritis progression in patients with sequential stages.

OBJECTIVES: The gouty arthritis (GA) progression was multistage, yet the GA clinical diagnosis guidelines were more inclined to suitable for acute gouty arthritis (AGA), thus neglecting of the progress of GA. This study aimed to identify specific biomarkers that were competent for reflecting the progression of GA and attempted to provide evidence for seasonable intervention of appropriate clinical treatment. METHODS: A total of 547 patients with GA at sequential stages and healthy volunteers were divided into a training set (n = 347) and a validation set (n = 200). Serum metabolic profiles were determined by UHPLC-QTOF-MS-MS untargeted metabolomics, and biomarkers were identified by logistic regression and receiver operating characteristic analysis. Further, UHPLC-QE-MS was applied for accurate quantitative validation of identified potential biomarkers in the validation set samples. RESULTS: After serum metabolic profiles analysis by untargeted metabolomics, 12 metabolites with monotonous change trend were screened, and were verified by targeted metabolomics subsequently. The quantitative results showed the serum concentration of kynurenic acid(KYNA), N1-Methyl-2-pyridone-5-carboxamide(2PY), DL-2-Aminoadipic acid(2AMIA) and 5-hydroxyindole acetic acid(5-HIAA) of patients with sequential stages showed a strictly monotonic trend, and AUC was 0.97, 0.97, 0.96 and 0.95, respectively. CONCLUSIONS: KYNA and 5-HIAA are related to acute inflammation of GA, while 2PY and 2AMIA are related to renal function damage caused by long-term HUA. Therefore, we believe it is inappropriate to use a single biomarker to define the phase of GA. Actually, four biomarkers obtained in this paper should be integratedly adopted to evaluate the progression of GA with sequential stages.

Spatial congruency or mismatch? Analyzing the COVID-19 potential infection risk and urban density as businesses reopen.

Countries worldwide are reopening their businesses despite the continuing COVID-19 crisis and the emergence of new variants. In this context, knowing whether the reopening of businesses at various locations exposes higher risk to the public is essential. Whether urban density correlates with the potential infection risk as concluded by previous studies of the COVID-19 pandemic remains unknown. In this study, taking the Macau Peninsula as a testbed, we first identified business locations for daily activities according to the latest point of interest (POI) data and generated the potential risk surface for COVID-19 infection. Then, using the cellular phone network and urban footprint data, we further analyzed the spatial relationship between COVID-19 potential risk and urban density of population and morphology through visual analytics. Results show that while some degree of spatial congruency exists between medium-risk peaks and urban density hotspots, apparent spatial mismatch exists for high-risk peaks, indicating that the traditional planning control based on urban density is inadequate for mitigating public health risks. POI-based spatial layout and configuration better reflecting business services and associated human activities are recommended in future planning and policy-making for more resilient cities in the post-pandemic era.

[Advances on network pharmacology in ethnomedicine research].

Ethnomedicine is the precious wealth left by ethnic minorities in their struggle against diseases. It is similar to traditional Chinese medicine in a narrow sense and has the characteristics of multi-component,multi-target and multi-channel synergy. Under the guidance of the theory of ethnomedicine,the combination of ethnomedicine and network pharmacology will help to understand the essence of the prevention and treatment of ethnomedicines in a dynamic and holistic manner. This paper reviews the research progress of network pharmacology applied in ethnomedicine,analyses the problems and challenges existing in the application of network pharmacology in ethnomedicine research at present,such as inaccurate data and information,lack of network analysis platform for effective analysis of dose-effect relationship of chemical constituents and weak basic research of ethnomedicine,and puts forward corresponding prospects.

Fatigue and Fracture Behavior of a Cold-Drawn Commercially Pure Aluminum Wire.

Fatigue properties and cracking behavior of cold-drawn commercially pure aluminum wires (CPAWs) widely used as the overhead transmission conductors were investigated. It was found that the fracture surface of the CPAWs shows an obvious four-stage fracture characteristic, i.e., crack initiation, planar crack propagation, 45°-inclined crack propagation and final rapid fracture. The crack growth mechanisms for the CPAWs were found quite different from those for the conventional coarse-grained materials. The cracks in the CPAWs firstly grow along the grain boundaries (Stage I crack growth), and then grow along the plane of maximum shear stress during the last stage of cycling (Stage II crack growth), leading to the distinctive fracture surfaces, i.e., the granular surface in the planar crack propagation region and the coarse fatigue striations in the 45°-inclined crack propagation region. The grain boundary migration was observed in the fatigued CPAWs. The increase in fatigue load enhances the dislocation recovery, increases the grain boundary migration rate, and thus promotes the occurrence of softening and damage localization up to the final failure.

The effect of essential medicines programme on rational use of medicines in China.

OBJECTIVE: Irrational use of medicines is a serious problem in China and has been the primary target of China's national essential medicines programme (NEMP). The aim of this study was to evaluate the effect of the NEMP on rational use of medicines in China. METHODS: A nationwide sample of 3 76 700 prescriptions written by primary care providers from 2007 to 2011 was obtained following a multistage sampling process. Six prescribing indicators were measured: average number of drugs prescribed per prescription, average expenditure per prescription, percentage of prescriptions with antibiotics, with injections, with two or more antibiotics and with corticosteroids. The pre-post with control study design and the difference-in-difference (DID) methodology were employed to evaluate the effect of NEMP. RESULTS: Prescriptions from primary care institutions with the NEMP implementation were better than those without NEMP implementation. Adjusting for the institution's sizes, ownership, economic geographic regions and the year of NEMP implementation, the DID estimator was statistically significant in all prescribing indicators except for the percentage of prescriptions with injection. The number of drugs per prescription decreased by 0.2 per prescription [95% confidence interval (CI): -0.3, -0.1] after the NEMP was implemented; the percentages of prescriptions with antibiotics, with corticosteroids and with two or more antibiotics decreased by 7% (95% CI: -10, -4), 1% (95% CI: -2, 0) and 2% (95% CI: -3, 0), respectively; and the average expenditure per prescription decreased by eight Renminbi Yuan (95% CI: -14, -2). The effect of NEMP on reducing irrational prescribing was greater in public institutions than in private institutions (P < 0.05). CONCLUSIONS: China's NEMP is effective in promoting rational use of medicines, and the effect is greater in public institutions than in private institutions. However, the irrational use is still high, pointing to the need for further reforms to tackle the underlying causes, such as clinical guidelines and patient education.

The Association Between Physical Activity, Mental Status, and Social and Family Support with Five Major Non-Communicable Chronic Diseases Among Elderly People: A Cross-Sectional Study of a Rural Population in Southern China.

BACKGROUND: Non-communicable chronic diseases (NCDs) have become the top threat in China. This study aimed to estimate the prevalence of major NCDs among the elderly population in rural areas in southern China and explore its associated social determinants. METHODS: A multistage cluster random sampling methodology was adopted to select a total of 9245 rural elderly people from 3860 rural households in Guangdong Province. Interviews and physical examinations were performed to collect patient information. Descriptive and logistic regression analyses were conducted to explore factors associated with the presence of major NCDs. RESULTS: Over one-third (38.5%) of the study population suffered from five major NCDs. The grade of activities of daily living (ADL), mental status, and social relationship of elderly people without NCDs were better than those with NCDs. The major factors associated with the presence of NCDs among the elderly people included age (70-79 years group and 80-89 years group), education level (senior high/technical secondary school and junior college and above), mental status (concentration, enrichment and happy life and memory), relationship with neighbours, activities of daily living (ADL) (being able to climb three floors and bend over), physical activity, marital status (bereft), and living conditions (with offspring and family members). CONCLUSIONS: The study identified several social determinants associated with the presence of major NCDs. A higher level of family support and physical exercise might contribute to improved physical condition, mental status, and ADL among the elderly people in rural areas in southern China.