Elucidation of the pluripotent potential of bovine embryonic lineages facilitates the establishment of formative stem cell lines.

The establishment of epiblast-derived pluripotent stem cells (PSCs) from cattle, which are important domestic animals that provide humans with milk and meat while also serving as bioreactors for producing valuable proteins, poses a challenge due to the unclear molecular signaling required for embryonic epiblast development and maintenance of PSC self-renewal. Here, we selected six key stages of bovine embryo development (E5, E6, E7, E10, E12, and E14) to track changes in pluripotency and the dependence on signaling pathways via modified single-cell transcription sequencing technology. The remarkable similarity of the gene expression patterns between cattle and pigs during embryonic lineage development contributed to the successful establishment of bovine epiblast stem cells (bEpiSCs) using 3i/LAF (WNTi, GSK3ßi, SRCi, LIF, Activin A, and FGF2) culture system. The generated bEpiSCs exhibited consistent expression patterns of formative epiblast pluripotency genes and maintained clonal morphology, normal karyotypes, and proliferative capacity for more than 112 passages. Moreover, these cells exhibited high-efficiency teratoma formation as well as the ability to differentiate into various cell lineages. The potential of bEpiSCs for myogenic differentiation, primordial germ cell like cells (PGCLCs) induction, and as donor cells for cell nuclear transfer was also assessed, indicating their promise in advancing cell-cultured meat production, gene editing, and animal breeding.

Integrating Shared Socioeconomic Pathway-informed adaptation into temperature-related mortality projections under climate change.

The extent to which populations will successfully adapt to continued warming temperatures will be a crucial factor in determining future health burdens. Previous health impact assessments of future temperature-related mortality burdens mostly disregard adaptation or make simplistic assumptions. We apply a novel evidence-based approach to model adaptation that takes into account the fact that adaptation potential is likely to vary at different temperatures. Temporal changes in age-specific mortality risk associated with low and high temperatures were characterised for Scotland between 1974 and 2018 using temperature-specific RR ratios to reflect past changes in adaptive capacity. Three scenarios of future adaption were constructed consistent with the SSPs. These adaptation projections were combined with climate and population projections to estimate the mortality burdens attributable to high (above the 90th percentile of the historical temperature distribution) and low (below the 10th percentile) temperatures up to 2080 under five RCP-SSP scenarios. A decomposition analysis was conducted to attribute the change in the mortality burden into adaptation, climate and population. In 1980-2000, the heat burden (21 deaths/year) was smaller than the colder burden (312 deaths/year). In the 2060-2080 period, the heat burden was projected to be the highest under RCP8.5-SSP5 (1285 deaths/year), and the cold burden was the highest under RCP4.5-SSP4 (320 deaths/year). The net burden was lowest under RCP2.6-SSP1 and highest under RCP8.5-SSP5. Improvements in adaptation was the largest factor reducing the cold burden under RCP2.6-SSP1 whilst temperature increase was the biggest factor contributing to the high heat burdens under RCP8.5-SSP5. Ambient heat will become a more important health determinant than cold in Scotland under all climate change and socio-economic scenarios. Adaptive capacity will not fully counter projected increases in heat deaths, underscoring the need for more ambitious climate mitigation measures for Scotland and elsewhere.

The accuracy of the FIT in detecting advanced neoplasm is highest in young people aged 40 to 49 years: an analysis based on sex and age.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers and is associated with high incidence and mortality rates worldwide. CRC has caused a tremendous loss of human health and wealth. The incidence and mortality of colorectal carcinoma are increasing in young adults. Early cancer detection and prevention are made possible through screening. At present, the faecal immunochemical test (FIT) is a noninvasive method that can be used for the large-scale clinical screening of CRC status. Therefore, this study, based on CRC screening results in Tianjin from 2012 to 2020, was conducted to analyse the major differences in diagnostic performance parameters according to sex and age. METHODS: This study was based on 39,991 colonoscopies performed for individuals in the Tianjin CRC screening program from 2012 to 2020. Of these individuals, they had complete FIT and colonoscopy results. The differences in FIT results were analysed by sex and age. RESULTS: According to this study, males were generally more likely to develop advanced neoplasms (ANs) than females, and the prevalence increased with age. Males with negative FIT results were more likely to have advanced neoplasms than females with positive results. The accuracy of the FIT in detecting ANs in each age group was 54.9%, 45.5%, 48.6% and 49.5% in the 40-49, 50-59, 60-69, and ≥ 70 age groups, respectively. CONCLUSIONS: The FIT detected ANs with highest accuracy in the 40-49 age group. Our research can provide guidance to formulate CRC screening strategies.

Early life PM2.5 exposure, childhood cognitive ability and mortality between age 11 and 86: A record-linkage life-course study from Scotland.

BACKGROUND: Living in areas with high air pollution concentrations is associated with all-cause and cause-specific mortality. Exposure in sensitive developmental periods might be long-lasting but studies with very long follow-up are rare, and mediating pathways between early life exposure and life-course mortality are not fully understood. METHODS: Data were drawn from the Scottish Longitudinal Study Birth Cohort of 1936, a representative record-linkage study comprising 5% of the Scottish population born in 1936. Participants had valid age 11 cognitive ability test scores along with linked mortality data until age 86. Fine particle (PM2.5) concentrations estimated with the EMEP4UK atmospheric chemistry transport model were linked to participants' residential address derived from the National Identity Register in 1939 (age 3). Confounder-adjusted Cox regression estimated associations between PM2.5 and mortality; regression-based causal mediation analysis explored mediation through childhood cognitive ability. RESULTS: The final sample consisted of 2734 individuals with 1608 deaths registered during the 1,833,517 person-months at risk follow-up time. Higher early life PM2.5 exposure increased the risk of all-cause mortality (HR = 1.03, 95% CI: 1.01-1.04 per 10 µg m-3 increment), associations were stronger for mortality between age 65 and 86. PM2.5 increased the risk of cancer-related mortality (HR = 1.05, 95% CI: 1.02-1.08), especially for lung cancer among females (HR = 1.11, 95% CI: 1.02-1.21), but not for cardiovascular and respiratory diseases. Higher PM2.5 in early life (≥50 µg m-3) was associated with lower childhood cognitive ability, which, in turn, increased the risk of all-cause mortality and mediated 25% of the total associations. CONCLUSIONS: In our life-course study with 75-year of continuous mortality records, we found that exposure to air pollution in early life was associated with higher mortality in late adulthood, and that childhood cognitive ability partly mediated this relationship. Findings suggest that past air pollution concentrations will likely impact health and longevity for decades to come.

Potential impacts of spatial restrictions on tobacco retail availability in China: a simulation study in Shanghai.

OBJECTIVES: Regulating tobacco retail availability provides promising new opportunities for effective tobacco control. This study simulates the potential impacts of introducing spatial restrictions on the availability of tobacco in Shanghai, the largest city in China. METHODS: Twelve stakeholder-informed simulation scenarios under four types of spatial restrictions were considered: (1) capping, (2) ban of sales, (3) minimum spacing and (4) school-buffer exclusion zone. Tobacco retailer data for Shanghai (n=19 413) were used. The main outcome was per cent reduction in retail availability measured by population-weighted kernel density estimation across neighbourhoods, and impacts on social inequality in availability were estimated using the Kruskal-Wallis test and effect size estimation. All analyses were further stratified by three levels of urbanity to examine geographical disparities in overall effectiveness and equity of the simulation scenarios. RESULTS: All simulation scenarios have the potential to reduce availability, with overall reductions ranging from 8.60% to 85.45%. Compared with the baseline, the effect size regarding the association between availability and neighbourhood deprivation quintiles suggests that the most effective scenario, '500 m minimum spacing' between retailers, increased the social inequality in availability (p<0.001). Conversely, school-buffer scenarios were both effective and equitable. Additionally, the effectiveness and the equity impact of scenarios varied by urbanity level. CONCLUSION: Spatial restrictions offer potential new policy opportunities to reduce retail availability, but some may increase social inequality in accessing tobacco. For effective tobacco control, policymakers should consider the overall and equity impacts of spatial restrictions when developing comprehensive tobacco retail regulations.

Sulforaphane suppresses paraquat-induced oxidative damage in bovine in vitro-matured oocytes through Nrf2 transduction pathway.

Sulforaphane (SFN), a bioactive phytocompound extracted from cruciferous plants, has received increasing attention due to its vital cytoprotective role in eliminating oxidative free radical through activation of nuclear factor erythroid 2-related factor (Nrf2)-mediated signal transduction pathway. This study aims at a better insight into the protective benefit of SFN in attenuating paraquat (PQ)-caused impairment in bovine in vitro-matured oocytes and the possible mechanisms involved therein. Results showed that addition of 1 µM SFN during oocyte maturation obtained higher proportions of matured oocytes and in vitro-fertilized embryos. SFN application attenuated the toxicological effects of PQ on bovine oocytes, as manifested by enhanced extending capability of cumulus cell and increased extrusion proportion of first polar body. Following incubation with SFN, oocytes exposed to PQ exhibited reduced intracellular ROS and lipid accumulation levels, and elevated T-SOD and GSH contents. SFN also effectively inhibited PQ-mediated increase in BAX and CASPASE-3 protein expressions. Besides, SFN promoted the transcription of NRF2 and its downstream antioxidative-related genes GCLC, GCLM, HO-1, NQO-1, and TXN1 in a PQ-exposed environment, indicating that SFN prevents PQ-caused cytotoxicity through activation of Nrf2 signal transduction pathway. The mechanisms underlying the role of SFN against PQ-induced injury included the inhibition of TXNIP protein and restoration of the global O-GlcNAc level. Collectively, these findings provide novel evidence for the protective role of SFN in alleviating PQ-caused injury, and suggest that SFN application may be an efficacious intervention strategy against PQ cytotoxicity.

GEospatial aNalysis of ExtRacorporeal membrane oxygenATion in Europe (GENERATE).

INTRODUCTION: A cross-sectional survey GENERATE (GEospatial aNalysis of ExtRacorporeal membrane oxygenATion in Europe) initiated on behalf of the European chapter of the Extracorporeal Life Support Organization (EuroELSO), aims to provide a systematic, detailed description of contemporary Extracorporeal Life Support (ECLS) provision in Europe, map the spatial distribution of ECLS centers, and the accessibility of ECLS. METHODS: Structured data collection forms were used to create a narrative description of ECLS provision in EuroELSO affiliated countries. This consisted of both center-specific data and relevant national infrastructure. Data was provided by a network of local and national representatives. Spatial accessibility analysis was conducted where appropriate geographical data were available. RESULTS: 281 centers from 37 countries affiliated to EuroELSO were included in the geospatial analysis and demonstrate heterogeneous patterns of ECLS provision. Accessibility of ECLS services within 1 hour of drive-time is available for 50% of the adult population in 8 of 37 countries (21.6%). This proportion is reached within 2 hours in 21 of 37 countries (56.8%) and within 3 hours in 24 of 37 countries (64.9%). For pediatric centers, accessibility is similar with 9 of 37 countries (24.3%) reached the covering of 50% of the population aged 0-14 within 1 hour and 23 of 37 countries (62.2%) within 2 hours and 3 hours. CONCLUSIONS: ECLS services are accessible in most of the European countries, but their provision differs across the continent. There is still no solid evidence given regarding the optimal ECLS provision model. The spatial disparity in ECLS provision demonstrated in our analysis requires governments, healthcare professionals and policy makers to consider how to develop existing provision to accommodate the anticipated increase in need for time critical access to this advanced support modality.

Cold-Inducible RNA-Binding Protein Prevents an Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase.

RATIONALE: The stress response of heart rate, which is determined by the plasticity of the sinoatrial node (SAN), is essential for cardiac function and survival in mammals. As an RNA-binding protein, CIRP (cold-inducible RNA-binding protein) can act as a stress regulator. Previously, we have documented that CIRP regulates cardiac electrophysiology at posttranscriptional level, suggesting its role in SAN plasticity, especially upon stress conditions. OBJECTIVE: Our aim was to clarify the role of CIRP in SAN plasticity and heart rate regulation under stress conditions. METHODS AND RESULTS: Telemetric ECG monitoring demonstrated an excessive acceleration of heart rate under isoprenaline stimulation in conscious CIRP-KO (knockout) rats. Patch-clamp analysis and confocal microscopic Ca2+ imaging of isolated SAN cells demonstrated that isoprenaline stimulation induced a faster spontaneous firing rate in CIRP-KO SAN cells than that in WT (wild type) SAN cells. A higher concentration of cAMP-the key mediator of pacemaker activity-was detected in CIRP-KO SAN tissues than in WT SAN tissues. RNA sequencing and quantitative real-time polymerase chain reaction analyses of single cells revealed that the 4B and 4D subtypes of PDE (phosphodiesterase), which controls cAMP degradation, were significantly decreased in CIRP-KO SAN cells. A PDE4 inhibitor (rolipram) abolished the difference in beating rate resulting from CIRP deficiency. The mechanistic study showed that CIRP stabilized the mRNA of Pde4b and Pde4d by direct mRNA binding, thereby regulating the protein expression of PDE4B and PDE4D at posttranscriptional level. CONCLUSIONS: CIRP acts as an mRNA stabilizer of specific PDEs to control the cAMP concentration in SAN, maintaining the appropriate heart rate stress response.

A Cross-sectional Analysis of Socio-spatial Patterning of Tobacco Retail in Shanghai, China.

INTRODUCTION: International evidence from high-income countries demonstrates that the availability of tobacco tends to be greater in more urban and more deprived neighborhoods. However, little is known about the socio-spatial disparities in other settings, including megacities in China. This study investigated the patterning of tobacco retailers across Shanghai by types of tobacco retailers, including the relationship with levels of urbanity and neighborhood deprivation. AIMS AND METHODS: Tobacco retailer data (n = 19 413) was extracted from a web-scraped Points-of-Interest database. For all communities (n = 5432) across Shanghai, neighborhood tobacco retail availability was calculated using population-weighted kernel density estimation and grouped by quintiles of neighborhood deprivation and a 3-level urban classification. Associations were analyzed using the Kruskal-Wallis tests and epsilon squared. RESULTS: Across Shanghai, tobacco retail availability decreased from more urbanized areas to less urbanized areas. There was a statistical difference (p < .001) in the availability of tobacco retail across quintiles of deprivation, with the highest availability in the less deprived neighborhoods, and the lowest availability in the most deprived neighborhoods. However, this trend was reversed in the urban center, where retail availability was greatest in the most deprived areas. Convenience stores were the most common type of tobacco retailer across the city, while tobacco-only outlets were most strongly associated with levels of neighborhood deprivation. CONCLUSIONS: The results show an association between tobacco retail availability and neighborhood deprivation, which varied with levels of urbanity and types of tobacco retailers. These findings provide supportive evidence for further interventions that target reducing inequalities in exposure to tobacco retail. IMPLICATIONS: This is the first study to examine the relationship between tobacco retail availability and neighborhood deprivation in the context of Chinese megacities. Using data from Shanghai, China, we found a significant non-linear association between tobacco retail availability and neighborhood deprivation across the city. It is plausible that the socio-spatial disparities in tobacco retail availability at the neighborhood level may be a key factor explaining differences in smoking behaviors between sociodemographic groups. The findings emphasize the need for greater efforts in regulating neighborhood-level tobacco retailing in China.

Telomere is shortened in patients with irritable bowel syndrome in the Chinese population.

BACKGROUND AND AIM: Telomere shortening is an accepted indicator of aging. Many studies have investigated an association between leukocyte telomere length (LTL) and psychiatric disorders. Mental or psychological factors could be an important cause of irritable bowel syndrome (IBS). However, there are currently few research evaluating correlations between LTL and IBS. METHODS: We examined associations between LTL and IBS using quantitative polymerase chain reaction in independent cohorts, including 205 patients with IBS and 189 healthy controls. Furthermore, we examined whether mental or psychological factors, types of IBS, duration of IBS and antidepressants had an association with LTL in patients with IBS. RESULTS: Among total samples, patients with IBS presented shorter LTL when compared to healthy controls (P < 0.0001). Moreover, in subgroup analyses of patients with IBS, not only the LTL in patients with IBS caused by mental or psychological factors was shorter (P < 0.0001), but also in patients with IBS that were caused by other factors (P = 0.0082). Furthermore, LTL in patients with IBS who had taken antidepressants for more than 1 month was longer than that in patients with IBS who did not take antidepressants or took for less than 1 month (P < 0.0001). CONCLUSIONS: This is the first study to describe the relationship between LTL and IBS. This study showed significantly shorter telomeres in patients with IBS. Our findings suggest that LTL may hold the potential to serve as a predictor of IBS diagnosis.

Temperature-related mortality and associated vulnerabilities: evidence from Scotland using extended time-series datasets.

BACKGROUND: Adverse health impacts have been found under extreme temperatures in many parts of the world. The majority of such research to date for the UK has been conducted on populations in England, whilst the impacts of ambient temperature on health outcomes in Scottish populations remain largely unknown. METHODS: This study uses time-series regression analysis with distributed lag non-linear models to characterise acute relationships between daily mean ambient temperature and mortality in Scotland including the four largest cities (Aberdeen, Dundee, Edinburgh and Glasgow) and three regions during 1974-2018. Increases in mortality risk under extreme cold and heat in individual cities and regions were aggregated using multivariate meta-analysis. Cold results are summarised by comparing the relative risk (RR) of death at the 1st percentile of localised temperature distributions compared to the 10th percentile, and heat effects as the RR at the 99th compared to the 90th percentile. RESULTS: Adverse cold effects were observed in all cities and regions, and heat effects were apparent in all cities and regions except northern Scotland. Aggregate all-cause mortality risk in Scotland was estimated to increase by 10% (95% confidence interval, CI: 7%, 13%) under extreme cold and 4% (CI: 2%, 5%) under extreme heat. People in urban areas experienced higher mortality risk under extreme cold and heat than those in rural regions. The elderly had the highest RR under both extreme cold and heat. Males experienced greater cold effects than females, whereas the reverse was true with heat effects, particularly among the elderly. Those who were unmarried had higher RR than those married under extreme heat, and the effect remained after controlling for age. The younger population living in the most deprived areas experienced higher cold and heat effects than in less deprived areas. Deaths from respiratory diseases were most sensitive to both cold and heat exposures, although mortality risk for cardiovascular diseases was also heightened, particularly in the elderly. Cold effects were lower in the most recent 15 years, which may be linked to policies and actions in preventing the vulnerable population from cold impacts. No temporal trend was found with the heat effect. CONCLUSIONS: This study assesses mortality risk associated with extreme temperatures in Scotland and identifies those groups who would benefit most from targeted actions to reduce cold- and heat-related mortalities.

A study of the moving rate of positive results for use in a patient-based real-time quality control program on a procalcitonin point-of-care testing analyzer.

OBJECTIVE: To establish an applicable and highly sensitive patient-based real-time quality control (PBRTQC) program based on a data model constructed with patients' results of a procalcitonin point-of-care testing (POCT) analyzer. METHODS: Patients' results were retrospectively collected within one year. The Excel software was used to establish quality control (QC) programs of the moving average (MA) and the moving rate of positive results (MR). A Monte Carlo simulation was used to introduce positive and negative biases between 0.01 and 1 ng/ml at random points of the testing data set. Different parameters were used to detect the biases, and the detection efficiency was expressed using the median number of patient samples affected until error detection (MNPed). After comparing the MNPeds of different programs, MA and MR programs with appropriate parameters were selected, and validation plots were generated using MNPeds and maximum number of the patient samples affected (MAX). ß curves were generated using the power function of the programs, the performances were compared with that of the conventional QC program. RESULTS: Neither the conventional QC nor MA program was sensitive to small bias, While MR program can detect the minimum positive bias of 0.06 ng/ml and negative of 0.4 ng/ml at an average daily run size of 10 specimens, with FRs < 1.0%, ßs < 1%. CONCLUSION: The MR program, which is more sensitive to small biases than conventional QC and MA programs, with low FR and ß. As such, it can be used as a PBRTQC program with high performance.

Disruption of O-GlcNAcylation Homeostasis Induced Ovarian Granulosa Cell Injury in Bovine.

O-linked ß-N-acetylglucosamine (O-GlcNAc) modification is a ubiquitous, reversible, and highly dynamic post-translational modification, which takes charge of almost all biological processes examined. However, little information is available regarding the molecular regulation of O-GlcNAcylation in granulosa cell function and glucose metabolism. This study focused on the impact of disrupted O-GlcNAc cycling on the proliferation and apoptosis of bovine granulosa cells, and further aimed to determine how this influenced glucose metabolism. Pharmacological inhibition of OGT with benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside (BADGP) led to decreased cellular O-GlcNAc levels, as well as OGT and OGA protein expressions, whereas increasing O-GlcNAc levels with the OGA inhibitor, O-(2-acetamido-2-deoxy-D-gluco-pyranosylidene) (PUGNAc), resulted in elevated OGA protein expression and decreased OGT protein expression in granulosa cells. Dysregulated O-GlcNAc cycling reduced cell viability, downregulated the proliferation-related genes of CDC42 and PCNA transcripts, upregulated the pro-apoptotic genes of BAX and CASPASE-3 mRNA and the ratio of BAX/BCL-2, and increased the apoptotic rate. Glycolytic enzyme activities of hexokinase and pyruvate kinase, metabolite contents of pyruvate and lactate, mitochondrial membrane potential, ATP levels, and intermediate metabolic enzyme activities of succinate dehydrogenase and malate dehydrogenase involved in the tricarboxylic acid cycle, were significantly impaired in response to altered O-GlcNAc levels. Moreover, inhibition of OGT significantly increased the expression level of thioredoxin-interacting protein (TXNIP), but repression of OGA had no effect. Collectively, our results suggest that perturbation of O-GlcNAc cycling has a profound effect on granulosa cell function and glucose metabolism.

Integrin ß5 enhances the malignancy of human colorectal cancer by increasing the TGF-ß signaling.

Increased integrin ß5 (ITGB5) expression is associated with the progression and metastasis of several types of cancers. However, whether upregulated ITGB5 expression can act as a prognostic factor for colorectal cancer (CRC) remains controversial. In this study, we aimed to identify the role ITGB5 plays during the pathogenesis of human CRC and explore the underlying molecular mechanism. Here, we show that ITGB5 expression is upregulated in CRC and is significantly associated with exacerbated CRC malignancy and an unfavourable overall survival rate among CRC patients. ITGB5 silencing significantly inhibited the proliferation and invasion of human CRC cell lines (HCT116 and HT29) in vitro and suppressed the growth and metastasis of implanted CRC tumours in vivo. Mechanistically, upregulated ITGB5 expression enhanced transforming growth factor ß/Smad signalling and facilitated the epithelial-mesenchymal transition in CRC cells. Together, such findings indicate that ITGB5 acts as an oncogenic factor to enhance the malignancy of CRC and suggest that ITGB5 may be a therapeutic target.

Design, synthesis, and structure-activity relationship of PD-1/PD-L1 inhibitors with a benzo[d]isoxazole scaffold.

Blocking the programmed cell death protein 1 (PD-1) and programmed death-ligand (PD-L1) interaction has emerged as one of the most promising treatments for cancer immunotherapy. A novel series of compounds bearing a benzo[d]isoxazole scaffold was developed as PD-1/PD-L1 inhibitors, among them, compound P20 exhibited the most potent inhibitory activity, with an IC50 value of 26.8 nM. The preliminary structure-activity relationship was also investigated. The docking analysis of compound P20 with the PD-L1 dimer complex (PDB ID: 5j89) indicated that compound P20 was bound to the PD-L1 dimer with high affinity. These results suggest that compound P20 is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction.

Design, synthesis, and biological evaluation of 1-methyl-1H-pyrazolo[4,3-b]pyridine derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signalling pathway is a promising tumour immunotherapeutic approach, and small molecule drugs have more advantages than monoclonal antibody macromolecules in clinical applications. Therefore, a series of 1-methyl-1H-pyrazolo[4,3-b]pyridine derivatives as PD-1/PD-L1 interaction novel small-molecule inhibitors were designed employing a ring fusion strategy. The inhibitory activity of compounds was evaluated by the HTRF assay, among which D38 was identified as the most potent PD-1/PD-L1 interaction inhibitor with an IC50 value of 9.6 nM. Furthermore, D38 exhibited prominent inhibitory activity against the PD-1/PD-L1 interaction with an EC50 value of 1.61 µM in a coculture model of PD-L1/TCR activator-expressing CHO cells and PD-1-expressing Jurkat cells. In addition, the preliminary structure-activity relationships (SARs) of compounds were elucidated, and the binding mode of D38 with the PD-L1 dimer was analysed by molecular docking. Overall, D38 could be employed as a prospective lead compound of PD-1/PD-L1 interaction inhibitors for further development.

Effect of healthcare system reforms on job satisfaction among village clinic doctors in China.

BACKGROUND: Village clinic doctors (VCDs) are part of the health service force in rural China. VCDs' job satisfaction (JS) is important to the stability of the three-tiered health service system. Since 2009, the Chinese government launched a new health care system reform (NHCSR) which affected VCDs significantly. This study aimed to analysing the effect of NHCSR on JS among VCDs. METHODS: All the data came from three surveys in Shandong Province conducted in 2012, 2015 and 2018. In 2012, an originally designed questionnaire was used to conduct a baseline survey of 405 VCDs from 27 townships in nine counties. In 2015 and 2018, 519 and 223 VCDs in the same counties were surveyed with the same questionnaire. Descriptive analysis and ANOVA were used to analyse the level and changes in VCDs' JS. RESULTS: The mean scores of VCDs' total JS were 2.664 ± 1.069, 3.121 ± 0.931 and 2.676 ± 1.044 in 2012, 2015 and 2018, respectively, with a significant difference (F = 28.732, P < 0.001). The mean scores of the medical practice environment and the job itself showed a continuous downward trend. The trends of the mean scores for job reward, internal work environment and organizational management were consistent with the trend for total JS. CONCLUSION: The NHCSR had a partly negative impact on VCDs' JS. Policy-makers should pay more attention to VCDs' job reward and medical practice environment. With the implementation of new reform policies, VCDs' JS should be the subject of more systematic and detailed research.

Factors Influencing Severity of Medication-Related Osteonecrosis of the Jaw: A Retrospective Study.

PURPOSE: The progression of medication-related osteonecrosis of the jaw (MRONJ) is influenced by many factors. This study aimed to identify the clinical risk factors associated with severe MRONJ (stage 3). PATIENTS AND METHODS: The data of patients with MRONJ who were hospitalized between July 2013 and December 2019 were retrospectively analyzed. Demographic and clinical factors were the independent variables, and the clinical stage of MRONJ lesions was the dependent variable. Multivariate logistic regression analysis was performed to identify the risk factors for advanced stage disease (MRONJ stage 3). RESULTS: A total of 79 patients (with 93 MRONJ lesions) were included. In multivariate regression analysis, the risk factors associated with stage 3 MRONJ were age ≤65 years (odds ratio [OR] = 3.968, 95% confidence interval [CI]: 1.280-12.301; P = .017); chemotherapy (OR = 3.687, 95% CI: 1.048-12.972; P = .042); preoperative MRONJ duration ≥12 months (OR = 7.616, 95% CI: 1.865-31.110; P = .005); lesion location in maxilla (OR = 1.150, 95% CI: 1.006-1.315; P = .041); lesion location in posterior jaw, that is, in molar area (OR = 1.384, 95% CI; 1.118-1.715; P = .003); and serum albumin <40 g/L (OR = 6.257, 95% CI: 1.313-29.815; P = .021). CONCLUSIONS: Age ≤65 years, chemotherapy, preoperative MRONJ duration ≥12 months, lesion location in maxilla, lesion location in the molar area, and serum albumin <40 g/L may increase the risk for severe MRONJ.

A WSN Layer-Cluster Key Management Scheme Based on Quadratic Polynomial and Lagrange Interpolation Polynomial.

Since current key management schemes are mainly designed for static and planar networks, they are not very suitable for the layer-cluster wireless sensor networks (WSNs), a WSN layer-cluster key management scheme based on quadratic polynomial and Lagrange interpolation polynomial is proposed, in which the main idea of this scheme along the research line of broadcast identity authentication, session key, group key, network key and personal key. Specifically, authentication key can be established on the basis of Fourier series for identity authentication; session key is established by a multiple asymmetric quadratic polynomial, in which session key information is encrypted by the authentication key to ensure the security of intermediate interactive information; based on the former two keys, group key is established on the basis of Lagrange interpolation polynomial, in which the nodes of the cluster are not directly involved; the generation and management of network key is similar to the group key, in which the establishment idea is to regard the BS and all cluster heads as a group; the generation and management of personal key is also similar to the group key, the difference is that the personal key can be obtained by cluster nodes through getting the Lagrange interpolation polynomial coefficients based on their own random key information. It is analyzed that the proposed layer-cluster key management scheme can guarantee the identity of network nodes firstly through forward authentication and reverse authentication, and session key, group key and network key will guarantee the independence of the keys' management and avoids the problem of single point failure compared with LEAP protocol, and personal key will guarantee the privacy of network.

Design, Synthesis and Biological Evaluation of Phenyl Urea Derivatives as IDO1 Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives i12, i23, i24 as showed potent IDO1 inhibition, with IC50 values of 0.1-0.6 µM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound i12 within IDO1. Compound i12 was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound i12 had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound i12 orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of i12-treated mice showed no obvious reduction compared with the control group. Overall, compound i12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.