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Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j-4 can significantly induce the apoptosis of MDA-MB-231 cells (IC 50  = 2.68 ± 0.27 μM). In further studies, 12j-4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j-4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors.

Phylogeny of hard ticks (Ixodidae) remains unresolved. Mitochondrial genomes (mitogenomes) are increasingly used to resolve phylogenetic controversies, but remain unavailable for the entire large Hyalomma genus. Hyalomma asiaticum is a parasitic tick distributed throughout the Asia. As a result of great morphological variability, two subspecies have been recognised historically; until a morphological data-based synonymization was proposed. However, this hypothesis was never tested using molecular data. Therefore, objectives of this study were to: 1. sequence the first Hyalomma mitogenome; 2. scrutinise the proposed synonymization using molecular data, i.e. complete mitogenomes of both subspecies: H. a. asiaticum and kozlovi; 3. conduct phylogenomic and comparative analyses of all available Ixodidae mitogenomes. Results corroborate the proposed synonymization: the two mitogenomes are almost identical (99.6%). Genomic features of both mitogenomes are standard for Metastriata; which includes the presence of two control regions and all three \"Tick-Box\" motifs. Gene order and strand distribution are perfectly conserved for the entire Metastriata group. Suspecting compositional biases, we conducted phylogenetic analyses (29 almost complete mitogenomes) using homogeneous and heterogeneous (CAT) models of substitution. The results were congruent, apart from the deep-level topology of prostriate ticks (Ixodes): the homogeneous model produced a monophyletic Ixodes, but the CAT model produced a paraphyletic Ixodes (and thereby Prostriata), divided into Australasian and non-Australasian clades. This topology implies that all metastriate ticks have evolved from the ancestor of the non-Australian branch of prostriate ticks. Metastriata was divided into three clades: 1. Amblyomminae and Rhipicephalinae (Rhipicephalus, Hyalomma, Dermacentor); 2. Haemaphysalinae and Bothriocrotoninae, plus Amblyomma sphenodonti; 3. Amblyomma elaphense, basal to all Metastriata. We conclude that mitogenomes have the potential to resolve the long-standing debate about the evolutionary history of ticks, but heterogeneous evolutionary models should be used to alleviate the effects of compositional heterogeneity on deep-level relationships.

Our research examines the concept of geographic proximity, particularly proximity to knowledge, market and labor resources in China, to understand how the embedded spatial context of a region influences the preferences of enterprises investing in China. Using a sample of Taiwanese enterprises investing in China from 2007–2011, we find that proximity to knowledge and labor resources have a significant negative influence on the location choice of Taiwanese enterprises, whereas proximity to market has a significant positive influence. Furthermore, we find that the influence of proximity on location choice changes with different industry characteristics.

The different donors of eight rice bacterial blight (BB) major resistant (MR) genes, Xa3, Xa4, xa5, Xa7, Xa10, Xa11, Xa14 and Xa23, were inoculated with two Chinese Xoo strains, strain IV and strain V, respectively. The strain IV was a predominant pathotype in south China, while the strain V was a severe virulentstrain. Two susceptible sterile lines and two susceptible inbred rice were employed to study the effect of geneticbackground on expression of resistance to BB for Xa4, xa5, Xa7 and Xa23. The application value of twodominant resistant genes Xa7 and Xa23 on hybrid rice was also evaluated. The results indicated that the resistance inheritance behaviors of most of the MR genes to the Xoo strains were similar and only a few genes show contradictory reaction in different donors,which suggests that the genetic background would produce an effect on the resistant expression of some R genes. Four resistant donors, IRBB4, IRBB5, IRBB7 and CBB23, were crossed with four susceptible cultivars, WufengA, JitianA, Jingang30 and IR24, respectively, using the resistant donors as male parent. The analysis of F1 populations revealed that the recessive resistance gene xa5 and dominant resistance gene Xa23 conformed to recessive and dominant expression model, respectively, while the other two dominant resistance genes, Xa4 and Xa7, conformed to dominant expression model only in some of F1 populations but not for others. In conclusion, expression of resistance for xa5 and Xa23 was independent of genetic background, while Xa4 and Xa7 show specific behaviors of resistance related to the receptor background. This study also suggests that Xa7 is not suitable for application in hybrid rice, for the F1 generation of its cross with two male sterile lines were highly susceptible, and Xa23 (CBB23) had important value in improving BB resistance of hybridrice, as the F1 generations from its cross with 4 susceptible parents, including sterile lines and inbred rice, were all show highly resistant.

目的：探讨在肾功能正常或轻度受损（肾小球滤过率≥60 ml/（min·1.73 m2））人群中矿物质代谢紊乱与钙化性主动脉瓣疾病的发生和严重性是否相关。创新点：以具有代表性和临床价值的肾功能正常或轻度受损人群为研究对象，首次尝试通过骨转换生物标志物检测探讨钙化性主动脉瓣疾病的可能机制。方法：入选260例经超声心动图诊断钙化性主动脉瓣疾病患者（164例钙化性主动脉瓣硬化，96例钙化性主动脉瓣狭窄）和164例年龄及性别匹配对照组人群，检测矿物质代谢和骨转换生化标志物，应用多因素回归分析矿物质代谢与钙化性主动脉瓣疾病的发生和严重性的关系，并初步探讨可能机制。结果显示，从对照组到钙化性主动脉瓣硬化至狭窄患者，血钙、血磷、碱性磷酸酶和甲状旁腺素（iPTH）水平进行性升高，25羟-维生素 D（25-OHD）水平进行性降低，各组间差异具有统计学显著性（P 结论：矿物质代谢紊乱与钙化性主动脉瓣疾病的发生和严重性密切相关，异常骨转换可能是其发生机制。

Objective： Coronary collateral circulation is an alternative source of blood supply to myocardium in the presence of advanced coronary artery disease. We sought to determine which clinical and angiographic variables are associated with collateral development in patients with stable angina and chronic total coronary occlusion. Methods： Demographic variables, biochemical measurements, and angiographic findings were collected from 478 patients with stable angina and chronic total coronary occlusion. The presence and extent of collaterals supplying the distal aspect of a total coronary occlusion from the contra-lateral vessel were graded from 0 to 3 according to the Rentrop scoring system. Results： Low （Rentrop score of 0 or 1） and high （Rentrop score of 2 or 3） coronary collateralizations were detected in 186 and 292 patients, respectively. Despite similar age, cigarette smoking, and medical treatment, patients with low collateralization were female in a higher proportion and less hypertensive, and had higher rates of type 2 diabetes and dyslipidemia than those with high coUateralization （for all comparisons, P〈0.05）. In addition, patients with low collateralization exhibited more single-vessel disease, less right coronary artery occlusion, more impaired renal function, and higher serum levels of high-sensitivity C-reactive protein （hsCRP） compared with those with high col- lateralization. Multivariate analysis revealed that age of 〉65 years, female gender, diabetes, no history of hypertension dyslipidemia, moderate to severe renal dysfunction, single-vessel disease, and elevated hsCRP levels were inde- pendently associated with low coronary collateralization. Conclusions： Coronary collateralization was reduced in almost 40% of stable angina patients with chronic total occlusion, which was related to clinical and angiographic factors. The impact of coronary collateralization on outcomes after revascularization needs further investigation.

Objective： Advanced glycation end-products （AGEs） exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs （RAGE）. This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE （sRAGE） and RAGE expressions in the rat kidney. Methods： Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment （10 mg/kg for 24 weeks）. Serum sRAGE and glycated albumin （GA） levels were measured with enzyme-linked immunosorbent assay （ELISA） and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE （esRAGE）, and sRAGE were determined with reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting. Results： Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in ac- cumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. Conclusions： Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.

Optimal control of greenhouse climate is one of the key techniques in digital agriculture. Greenhouse climate, a nonlinear and uncertain system, consists of several major environmental factors such as temperature, humidity, light intensity, and CO2 concentration. Due to the complex coupled correlations, it is a challenge to achieve coordination control of greenhouse environmental factors. This paper proposes a model-free coordination control approach for greenhouse environmental factors based on Q-learning. Coordination control policy is found through systematic interaction with the dynamic environment to achieve optimal control for greenhouse climate with the control cost constraints. In order to decrease systematic trial-and-error risk and reduce the computational complexity in Q-learning algorithm, case-based reasoning (CBR) is seamlessly incorporated into the Q-learning process. The experimental results demonstrate that this approach is practical, highly effective and efficient.

Aim： To investigate the mechanisms underlying the protective effects of sodium tanshinone IIA sulfonate （STS） in an ischemia- reperfusion （I/R）-induced rat myocardial injury model. Methods： Male SD rats were iv injected with STS, STS＋LY294002, or saline （NS） for 15 d. Then the hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Cardiac function, infarction size and area at risk were assessed. Cell apoptosis was evaluated with TUNEL staining, DNA laddering and measuring caspase-3 activity. In addition, isolated cardiomyocytes of neonatal rats were pretreated with the above drugs, then exposed to H202 （200 μmol/L） for I h. Cell apoptosis was detected using flow cytometric assay. The levels of p-Akt, p-FOXO3A and Bim were examined with immunoblotting. Results： Compared to NS group, administration of STS （20 mg/kg） significantly reduced myocardial infarct size （40.28%＋5.36% in STS group vs 59.52%±7.28% in NS group）, and improved the myocardial function as demonstrated by the increased values of dp/dt LVDP and coronary flow at different reperfusion time stages. Furthermore, STS significantly decreased the rate of apoptotic cells （15.11%±3.71% in STS group vs 38.21%±7.83% in NS group）, and reduced caspase-3 activity to nearly a quarter of that in NS group. Moreover, STS significantly increased the phosphorylation of Akt and its downstream target FOXO3A, and decreased the expression of pro-apoptotic gene Bim. Co-treatment with the PI3K inhibitor LY294002 （40 mg/kg） partially countered the protective effects induced by STS treatment. In isolated cardiomyocytes, STS exerted similar protective effects as shown in the ex vivo I/R model. Conclusion： STS pretreatment reduces infarct size and improves cardiac function in an I/R-induced rat myocardial injury model via activation of Akt/FOXO3A/Bim-mediated signal pathway.

BACKGROUND: This meta-analysis aimed to determine whether extracorporeal cardiopulmonary resuscitation(ECPR), compared with conventional cardiopulmonary resuscitation(CCPR), improves outcomes in adult patients with cardiac arrest(CA).DATA RESOURCES: Pub Med, EMBASE, Web of Science, and China Biological Medicine Database were searched for relevant articles. The baseline information and outcome data(survival, good neurological outcome at discharge, at 3–6 months, and at 1 year after CA) were collected and extracted by two authors. Pooled risk ratios(RRs) and 95% confidence intervals(CIs) were calculated using Review Manager 5.3.RESULTS: In six studies 2 260 patients were enrolled to study the survival rate to discharge and longterm neurological outcome published since 2000. A signi? cant effect of ECPR was observed on survival rate to discharge compared to CCPR in CA patients(RR 2.37, 95%CI 1.63–3.45, P<0.001), and patients who underwent ECPR had a better long-term neurological outcome than those who received CCPR(RR 2.79, 95%CI 1.96–3.97, P<0.001). In subgroup analysis, there was a significant difference in survival to discharge favoring ECPR over CCPR group in OHCA patients(RR 2.69, 95%CI 1.48–4.91, P=0.001). However, no signi? cant difference was found in IHCA patients(RR 1.84, 95%CI 0.91–3.73, P=0.09).CONCLUSION: ECPR showed a bene? cial effect on survival rate to discharge and long-term neurological outcome over CCPR in adult patients with CA.