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G protein-coupled receptor 4 (GPR4) belongs to the subfamily of proton-sensing GPCRs (psGPCRs), which detect pH changes in extracellular environment and regulate diverse physiological responses. GPR4 was found to be overactivated in acidic tumor microenvironment as well as inflammation sites, with a triad of acidic residues within the transmembrane domain identified as crucial for proton sensing. However, the 3D structure remains unknown, and the roles of other conserved residues within psGPCRs are not well understood. Here we report cryo-electron microscopy (cryo-EM) structures of active zebrafish GPR4 at both pH 6.5 and 8.5, each highlighting a distribution of histidine and acidic residues at the extracellular region. Cell-based assays show that these ionizable residues moderately influence the proton-sensing capacity of zebrafish GPR4, compared to the more significant effects of the triad residues. Furthermore, we reveal a cluster of aromatic residues within the orthosteric pocket that may propagate the signaling to the intercellular region via repacking the aromatic patch at the central region. This study provides a framework for future signaling and functional investigation of psGPCRs. The proton-sensing GPCRs detect extracellular low pH and regulate diverse physiological responses. Here, the authors report cryo-EM structures of GPR4, which provide insight into the structural features of proton sensing mechanism.

Peritoneal cancer index (PCI) is the surgical variable most commonly used to quantify the extent of peritoneal metastases for pseudomyxoma peritonei (PMP) patients. The present study aimed to investigate the agreement between CT predicted and surgical PCI by the Bland–Altman method for PMP of appendiceal origin. A total of 167 PMP patients of appendiceal origin were included between 2016 and 2021. Bland–Altman analysis was performed for both total PCI and selected PCI (regions 2 + 9–12). After the Bland–Altman plot was drawn, the mean bias and its 95% limit of agreements (LoAs) was quantified. Besides, the correlation coefficients between CT-PCI and surgical PCI were also been calculated. The Bland–Altman plot showed the mean bias ± SD between total CT-PCI and surgical PCI as 0.431 ± 3.005, with the LoAs from − 5.459 to 6.321. There were nine points of difference in total PCI exceeded the 95% LoAs, with the rate of 5.39% (9/167). As for selected CT-PCI, Bland–Altman plot showed the mean bias ± SD between selected CT-PCI and surgical PCI as − 0.287 ± 1.955, with the LoAs from − 4.118 to 3.544. There were ten points of difference in selected PCI exceeded the 95% LoAs, with the rate of 5.99% (10/167). The Spearman's rank correlation coefficient between total CT-PCI and surgical PCI was 0.911, P  < 0.001, as for selected CT-PCI and surgical PCI, the coefficient was 0.909, P  < 0.001. Although there was a strong correlation for both total and selected CT-PCI with surgical PCI, however, the agreement is still not good in Bland–Altman analysis, which suggested that CT-PCI cannot predict surgical PCI accurately even in professional PMP treatment centers. In brief explanation, CT makes it difficult to distinguish the borderline between tumor tissue and mucus and to detect tumor lesions in the small intestine regions, which caused overestimation or underestimation by CT-PCI. In the future, a multiple linear regression model based on CT-PCI might accurately predict surgical PCI preoperatively.

Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer’s disease and schizophrenia. However, the lack of understanding on M4R’s activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G i complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G i structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes. The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes.

Background Recently, although studies have investigated the role of NSAIDs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), selection of the ideal drug, the time and route of its administration for the appropriate population remain controversial. Methods A systematic search was done in sources including PubMed, Embase, Web of Science, the Cochrane Library Central, and ClinicalTrials.gov from from August 1, 1990 to August 1, 2017. Randomized controlled trials comparing the prophylactic use of NSAIDs versus a placebo were included. Statistical analysis was performed using the RevMan 5.3 software to assess the outcomes. Results A total of 21 randomized controlled trials were included in the meta-analysis. Our study showed that NSAIDs significantly reduced the incidence of PEP (RR, 0.61, 95%CI,0.52–0.72; p  < 0.00001). The analysis showed that indomethacin administration post-ERCP (RR, 0.47; 95% CI, 0.31–0.70; p  = 0.0002) appeared to be more effective in preventing PEP than indomethacin administration pre-ERCP (RR, 0.59; 95% CI, 0.45–0.79; P  = 0.0003), but there was no significant difference between the high-risk and average-risk population( p  = 0.13). In the diclofenac group, it was noted that administration of diclofenac pre-ERCP (RR, 0.32; 95% CI, 0.16–0.63; p  = 0.001) was more effective than that in post-ERCP (RR, 0.65; 95% CI, 0.27–1.599; p  = 0.35). The relative risk of PEP was 0.63 (95% CI, 0.27–1.50; p  = 0.30) in high-risk patients and 0.41 (95% CI, 0.17–0.98; p  = 0.02) in average-risk patients. With regard to the route of administration, PEP decreased significantly only in patients receiving the drug rectally (RR, 0.53; 95% CI, 0.44–0.63; p  < 0.00001), but not for those who received intramuscularly (RR, 0.74; 95% CI, 0.47–1.17; p  = 0.20), intravenously (RR, 0.97; 95% CI, 0.51–1.83; p  = 0.93), and orally (RR = 0.88; 95% CI, 0.55–0.1.43; p  = 0.62). Conclusions Rectal administration of NSAIDs (both indomethacin and diclofenac) was effective in preventing PEP in unselected patients. A single dose of indomethacin after ERCP might be effective in preventing PEP in both high-risk and average-risk patients. However, diclofenac administered rectally before ERCP might be protective against PEP in high-risk patients compared to a placebo. However, more high quality head-to-head RCTs are required.

Background The peritoneal cancer index (PCI) has been used to predict surgical outcomes for pseudomyxoma peritonei (PMP). The present study aimed to establish the optimal cutoff point for PCI to predict surgical resectability of PMP. Methods A total of 366 PMP patients were included. The patients were divided into low-grade and high-grade groups. Based on the completeness of the cytoreduction (CC) score, both low-grade and high-grade PMP patients were further divided into complete cytoreductive surgery (CRS) and maximal tumor debulking (MTD) subgroups. The ability to predict surgical resectability of total and selected PCI (regions 2 + 9 to 12) was analyzed through receiver operating characteristic (ROC) curves. Results Both total and selected PCI demonstrated excellent discriminative ability in predicting surgical resectability for low-grade PMP patients ( n  = 266), with the ROC-AUC of 0.940 (95% CI : 0.904–0.965) and 0.927 (95% CI : 0.889–0.955). The corresponding optimal cutoff point was 21 and 5, respectively. For high-grade PMP patients ( n  = 100), both total and selected PCI exhibited good performance in predicting surgical resectability, with the ROC-AUC of 0.894 (95% CI : 0.816–0.946) and 0.888 (95% CI : 0.810–0.943); correspondingly, the optimal cutoff point was 25 and 8, respectively. The discriminative ability between total and selected PCI in predicting surgical resectability did not show a statistical difference. Conclusions Both total and selected PCI exhibited good performance and similarity in predicting complete surgical resection for both low-grade and high-grade PMP patients. However, the selected PCI was simpler and time-saving in clinical practice. In the future, new imaging techniques or predictive models may be developed to better predict PCI preoperatively, which might assist in confirming whether complete surgical resection can be achieved.

Exogenous brassinolide (BR) application is a feasible measure to alleviate abiotic stresses on crop productivity. The effects of BR application at the silking-stage on the accumulation, translocation, and remobilization of dry matter (DM) and nutrients (nitrogen, phosphorus, and potassium) of waxy maize exposed to post-silking high temperature (HT) were studied using Jingkenuo2000 (JKN2000, heat-tolerant) and Yunuo7 (YN7, heat-sensitive) as materials. BR application mitigated the penalty of HT on grain yield. HT reduced the post-silking accumulation and increased the translocation of pre-silking DM and nutrients in YN7. In JKN2000, accumulation and remobilization of DM were unaffected by HT. The contribution rate of DM and nutrients translocation to grain yield were unaffected by HT in JKN2000 and increased in YN7. Under HT, the accumulation, translocation, and remobilization of DM were unaffected by BR application, whereas the nitrogen, phosphorus, and potassium response were dependent on hybrids. The harvest index of DM and nutrients in response to HT and BR were different between the two hybrids. In conclusion, BR application relieved the negative effects of HT mainly caused by the increased post-silking accumulation and remobilization of DM and nitrogen, and the alleviation was more obvious in the heat-tolerant hybrid.

A combination of simulation and experimental approaches to optimize the vacuum carburizing process is necessary to replace the costly experimental trial-and-error method in time and resources. In order to accurately predict the microstructure evolution and mechanical properties of the vacuum carburizing process, a multi-field multi-scale coupled model considering the interaction of temperature, diffusion, phase transformation, and stress was established. Meanwhile, the improved model is combined with the heat treatment software COSMAP to realize the simulation of the low-pressure vacuum carburizing process. The low-pressure vacuum carburizing process of 20CrMo gear steel was simulated by COSMAP and compared with the experimental results to verify the model. The results indicated that the model could quantitatively obtain the carbon concentration distribution, Fe-C phase fraction, and hardness distribution. It can be found that the carbon content gradually decreased from the surface to the center. The surface carbon concentration is relatively high only after the carburizing stage. With the increase in diffusion time, the surface carbon concentration decreases, and the carburized layer depth increases. The simulated surface carbon concentration results and experimental results are in good agreement. However, there is an error between calculations and observations for the depth of the carburized layer. The error between simulation and experiment of the depth of carburized layer is less than 6%. The simulated surface hardness is 34 HV lower than the experimental surface hardness. The error of surface hardness is less than 5%, which indicates that the simulation results are reliable. Furthermore, vacuum carburizing processes with different diffusion times were simulated to achieve the carburizing target under specific requirements. The results demonstrated that the optimum process parameters are a carburizing time of 42 min and a diffusion time of 105 min. This provides reference and guidance for the development and optimization of the vacuum carburizing process.

The adenosine A2A receptor (A2AAR) is a prototypical member of the class A subfamily of G-protein-coupled receptors (GPCRs) that is widely distributed in various tissues and organs of the human body, and participates in many important signal-regulation processes. We have previously summarized a common activation pathway of class A GPCRs in which a series of conserved residues/motifs undergo conformational change during extracellular agonist binding and finally induce the coupling of intracellular G protein. Through this mechanism we have successfully predicted several novel constitutive active or inactive mutations for A2AAR. To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097. The mutated I92N forms a hydrophilic interaction network with nearby residues including Trp6.48 of the CWxP motif, which is absent in wild-type A2AAR. Although the mutant structure is similar overall to the previously determined intermediate-state A2AAR structure (PDB ID 3qak) [Xu, Wu, Katritch, Han, Jacobson, Gao, Cherezov & Stevens (2011). Science, 332, 322–327], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmaco­logical studies among class A GPCRs.

Background We aimed to compare the safety and effectiveness of the following procedures after pancreaticoduodenectomy: isolated pancreaticojejunostomy, isolated gastrojejunostomy, and conventional pancreaticojejunostomy. Methods We performed a systematic search of the following databases: PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov until 1 January 2020. Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated using STATA 12.0 statistical software. Results Thirteen studies involving 1942 patients were included in this study. Pooled analysis showed that reoperation rates following isolated pancreaticojejunostomy were lower reoperation than with conventional pancreaticojejunostomy (OR = 0.36, 95% CI: 0.15–0.86, p  = 0.02, respectively), and that isolated pancreaticojejunostomy required longer operation time vs conventional pancreaticojejunostomy (WMD = 43.61, 95% CI: 21.64–65.58, P  = 0.00). Regarding postoperative pancreatic fistula, clinically-relevant postoperative pancreatic fistula, delayed gastric emptying, clinically-relevant delayed gastric emptying, bile leakage, hemorrhage, reoperation, length of postoperative hospital stay, major complications, overall complications, and mortality, we found no significant differences for either isolated pancreaticojejunostomy versus conventional pancreaticojejunostomy or isolated gastrojejunostomy versus conventional pancreaticojejunostomy. Conclusions This study showed that isolated pancreaticojejunostomy was associated with a lower reoperation rate, but required longer operation time vs conventional pancreaticojejunostomy. Considering the limitations, high-quality randomized controlled trials are required.

Abstract Background: The aim of this study is to assess the effect of body mass index (BMI) on outcomes of in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) among polycystic ovarian syndrome (PCOS) and non-PCOS patients. Methods: This was a retrospective cohort study that was performed in the Second Hospital of Hebei Medical University. Patients who were under 35 years old were included in the study and were divided into four groups based on their BMI. The number of retrieved oocytes, implantation rate, clinical pregnancy rate, miscarriage rate and live births among PCOS and non-PCOS patients were compared between different BMIs. Results: IVF/ICSI pregnancies in obese PCOS women had a considerably higher risk of miscarriage and low rate of clinical pregnancy than in non-obese PCOS pregnancies. However, in non-PCOS patient, obesity significantly elevated miscarriage rate but did not affect clinical pregnancy rate. Conclusion: Obesity in PCOS patients led to poor outcomes of IVF/ICSI.