Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors.

The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates. One of the A2AR/A2BR dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2-118. The structures revealed a common binding mode on A2AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.

Optimal peritoneal cancer index cutoff point for predicting surgical resectability of pseudomyxoma peritonei in treatment-naive patients.

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.

Effect of different nutrients on blood glucose, inflammatory response and oxidative stress in gestational diabetes mellitus: a network meta-analysis.

We searched PubMed, Web of Science, Embase, The Cochrane Library, China Biomedical Literature Database and other databases from inception to June 2023. The included studies were randomised controlled trials (RCT). The studies were screened by four authors, divided into two independent pairs. A total of eighteen studies were included, including 1362 patients, involving twelve intervention measures. The different nutrients had a significant effect on improving blood glucose, reducing inflammation levels and reducing oxidative stress compared with placebo (P < 0.05). Cumulative probability ranking showed that vitamin A + vitamin D + vitamin E ranked first in lowering fasting blood glucose (standardised mean difference (SMD) = 41.30, 95 % CI (2.07, 825.60)) and postprandial 2-h blood glucose (SMD = 15.19, 95 % CI (4.16, 55.53)). In terms of insulin resistance index, the first highest probability ranking is vitamin D (SMD = 5.12, 95 % CI (0.76, 34.54)). In terms of reducing the high-sensitivity C-reactive protein level, the first in probability ranking is VE (SMD = 2.58, 95 % CI (1.87,3.55)). The results of cumulative probability ranking showed that Mg + Zn + Ca + VD ranked first in reducing TNF-α (SMD = 1.90, 95% CI (0.40, 9.08)) and IL-6 (SMD = 1.83, 95 % CI (0.37, 9.12)). In terms of reducing malondialdehyde levels, the first ranked probability is VB1 (SMD = 4.99, 95 % CI (1.85, 13.46)). Cumulative probability ranking results showed that Ca + VD ranked first in reducing total antioxidant capacity (SMD = 0.66,95 % CI (0.38, 1.15)) and glutathione (SMD = 1.39, 95 % CI (0.43, 4.56)). In conclusion, nutritional interventions have significant effects on improving blood glucose, inflammatory levels and oxidative stress in patients with gestational diabetes. Due to the high uncertainty in the results and differences in the number and quality of studies included, the reliability of the conclusions still needs to be validated by conducting large-sample, high-quality RCT studies.

Structural insight into CD93 recognition by IGFBP7.

The CD93/IGFBP7 axis proteins are key factors expressed in endothelial cells (EC) that mediate EC angiogenesis and migration. Their upregulation contributes to tumor vascular abnormality and a blockade of this interaction promotes a favorable tumor microenvironment for therapeutic interventions. However, the interactions of these proteins with each other remain unclear. In this study, we determined a partial structure of the human CD93-IGFBP7 complex comprising the EGF1 domain of CD93 and the IB domain of IGFBP7. Mutagenesis studies confirmed interactions and specificities. Cellular and mouse tumor studies demonstrated the physiological relevance of the CD93-IGFBP7 interaction in EC angiogenesis. Our study provides leads for the development of therapeutic agents to precisely disrupt unwanted CD93-IGFBP7 signaling in the tumor microenvironment. Additionally, analysis of the CD93 full-length architecture provides insights into how CD93 protrudes on the cell surface and forms a flexible platform for binding to IGFBP7 and other ligands.

Bland-Altman agreement analysis between CT predicted and surgical peritoneal cancer index in pseudomyxoma peritonei of appendiceal origin.

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.

The Most Popular Commercial Weight Management Apps in the Chinese App Store: Analysis of Quality, Features, and Behavior Change Techniques.

BACKGROUND: Many smartphone apps designed to assist individuals in managing their weight are accessible, but the assessment of app quality and features has predominantly taken place in Western countries. Nevertheless, there is a scarcity of research evaluating weight management apps in China, which highlights the need for further investigation in this area. OBJECTIVE: This study aims to conduct a comprehensive search for the most popular commercial Chinese smartphone apps focused on weight management and assess their quality, behavior change techniques (BCTs), and content-related features using appropriate evaluation scales. Additionally, the study sought to investigate the associations between the quality of various domains within weight management apps and the number of incorporated BCTs and app features. METHODS: In April 2023, data on weight management apps from the iOS and Android app stores were downloaded from the Qimai Data platform. Subsequently, a total of 35 weight management apps were subjected to screening and analysis by 2 researchers. The features and quality of the apps were independently assessed by 6 professionals specializing in nutrition management and health behavioral change using the Mobile Application Rating Scale (MARS). Two registered dietitians, who had experience in app development and coding BCTs, applied the established 26-item BCT taxonomy to verify the presence of BCTs. Mean (SD) scores and their distributions were calculated for each section and item. Spearman correlations were used to assess the relationship between an app's quality and its technical features, as well as the number of incorporated BCTs. RESULTS: The data set included a total of 35 apps, with 8 available in the Android Store, 10 in the Apple Store, and 17 in both. The overall quality, with a mean MARS score of 3.44 (SD 0.44), showed that functionality was the highest scoring domain (mean 4.18, SD 0.37), followed by aesthetics (mean 3.43, SD 0.42), engagement (mean 3.26, SD 0.64), and information (mean 2.91, SD 0.52), which had the lowest score. The mean number of BCTs in the analyzed apps was 9.17 (range 2-18 BCTs/app). The most common BCTs were "prompt review of behavioral goals" and "provide instruction," present in 31 apps (89%). This was followed by "prompt self-monitoring of behavior" in 30 apps (86%), "prompt specific goal setting" in 29 apps (83%), and "provide feedback on performance" in 27 apps (77%). The most prevalent features in the analyzed apps were the need for web access (35/35, 100%), monitoring/tracking (30/35, 86%), goal setting (29/35, 83%), and sending alerts (28/35, 80%). The study also revealed strong positive correlations among the number of BCTs incorporated, app quality, and app features. This suggests that apps with a higher number of BCTs tend to have better overall quality and more features. CONCLUSIONS: The study found that the overall quality of weight management apps in China is moderate, with a particular weakness in the quality of information provided. The most prevalent BCTs in these apps were reviewing behavioral goals, providing guidance, self-monitoring of behavior, goal setting, and offering performance feedback. The most common features were the need for web access, monitoring and tracking, goal setting, and sending alerts. Notably, higher-quality weight management apps in China tended to incorporate more BCTs and features. These findings can be valuable for developers looking to improve weight management apps and enhance their potential to drive behavioral change in weight management.

Determination of the water vapor transmission rate of cellulose-based papers by multiple headspace extraction analysis.

This paper presents a multiple headspace extraction (MHE) analysis technique to determine the water vapor transmission rate of cellulose-based papers. The water vapor passing through the sample in a closed headspace vial is determined by MHE-gas chromatography. The results show that the employed method offers good precision (the relative standard deviation < 3.49 %) and good accuracy. The method is rapid and accurate, and is promising for the determination of the water vapor transmission rate of cellulose-based papers in future studies.

Effect of different analgesic treatments on the pulmonary function in elderly hip fracture patients: A prospective study.

BACKGROUND: To investigate the effect of different analgesic methods on lungs in elderly patients with hip fractures. METHODS: A prospective study was conducted on 78 elderly hip fracture patients undergoing spinal anesthesia for surgery, where 3 analgesic methods were used: postoperative Patient-controlled intravenous analgesia pump (PCIA) (group I), pre and postoperative PCIA (group II), and preoperative fascia iliaca compartment block (FICB) + postoperative PCIA (group III). The following indicators were monitored at admission (T1), on the day of surgery before anesthesia (T2), and 7 days after surgery (T3): heart rate (HR), respiratory rate (RR), forced expiratory volume during the first second, arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), C-reactive protein (CRP), and interleukin 6 (IL-6). Pulmonary complications such as pulmonary atelectasis and respiratory insufficiency were analyzed. RESULTS: The HR, RR, forced expiratory volume during the first second, PaO2, PaCO2, IL-6, and CRP levels at T1 after fracture did not significantly differ among the 3 groups (P > .05). After different analgesic treatments post-admission, all indicators at T2 were significantly higher in group I than in groups II and III (P < .05), while there was no significant difference between groups II and III (P > .05). At T3, there were no significant differences in RR, HR, PaO2, PaCO2, and CRP levels among the groups (P > .05), but IL-6 levels at T3 were significantly higher in group I than in groups II and III (P < .05). CONCLUSION: The use of effective pain relief during surgery can help protect the lung function of elderly patients with hip fractures. When using PCIA with FICB before surgery, respiratory performance may be better protected compared to using unsustained analgesia. This could be due to a decrease in the levels of inflammatory markers such as CRP and interleukin-6.

Structural insight into CD93 recognition by IGFBP7.

The CD93/IGFBP7 axis are key factors expressed in endothelial cells (EC) that mediate EC angiogenesis and migration. Upregulation of them contributes to tumor vascular abnormality and blockade of this interaction promotes a favorable tumor microenvironment for therapeutic interventions. However, how these two proteins associated to each other remains unclear. In this study, we solved the human CD93-IGFBP7 complex structure to elucidate the interaction between the EGF 1 domain of CD93 and the IB domain of IGFBP7. Mutagenesis studies confirmed the binding interactions and specificities. Cellular and mouse tumor studies demonstrated the physiological relevance of the CD93-IGFBP7 interaction in EC angiogenesis. Our study provides hints for development of therapeutic agents to precisely disrupt unwanted CD93-IGFBP7 signaling in the tumor microenvironment. Additionally, analysis of the CD93 full-length architecture provides insights into how CD93 protrudes on the cell surface and forms a flexible platform for binding to IGFBP7 and other ligands.

Cryo-EM structure of the human adenosine A2B receptor-Gs signaling complex.

The human adenosine A2B receptor (A2BR) is a class A G protein-coupled receptor that is involved in several major physiological and pathological processes throughout the body. A2BR recognizes its ligands adenosine and NECA with relatively low affinity, but the detailed mechanism for its ligand recognition and signaling is still elusive. Here, we present two structures determined by cryo-electron microscopy of A2BR bound to its agonists NECA and BAY60-6583, each coupled to an engineered Gs protein. The structures reveal conserved orthosteric binding pockets with subtle differences, whereas the selectivity or specificity can mainly be attributed to regions extended from the orthosteric pocket. We also found that BAY60-6583 occupies a secondary pocket, where residues V2506.51 and N2737.36 were two key determinants for its selectivity against A2BR. This study offers a better understanding of ligand selectivity for the adenosine receptor family and provides a structural template for further development of A2BR ligands for related diseases.

Experimental Study of Diamond-like Carbon Film on Aermet100 Steel and First-Principles Calculation of Interfacial Adhesion.

Three different types of surface-modified layers of N, C, and N+C are successfully prepared on AerMet100 steel by plasma-assisted thermochemical treatment, and diamond-like carbon (DLC) films are formed on the top surfaces of the latter two. The results show that the DLC films produced by prenitriding and then carburizing (N+C) exhibit a smoother and finer morphology and higher sp3 content than that without prenitriding (C). In addition, the wear resistance of the N+C specimen with a high hardness nitrided layer as the support for the outermost DLC films is superior to that of the C specimen. In view of the catalytic effect of the Fe3C phase on the growth of DLC films, the interfacial properties of Fe3C(001)/diamond(111) are investigated using first-principles calculations. On the basis of the most preferred Fe-terminated HCP site model, the effects of alloyed cementite (Fe2MC) on interfacial adhesion of Fe2MC(001)/diamond(111) are also investigated. Furthermore, the mechanisms of interfacial adhesion for two representative dopings (Zr weakened and V enhanced) are revealed in detail. These results are expected to provide a potential promising means for future experimental works on the preparation of high-performance DLC films on alloy steel surfaces by plasma carburizing.

Future Fertility of Patients With No Embryo Transfer in Their First IVF Cycle Attempts.

Objective: We aimed to evaluate the future outcomes of patients undergoing their first IVF (in vitro fertilization) attempt with no oocyte retrieved, no normal zygotes formed, or no embryos available for transfer and to identify factors affecting the live birth rate. Methods: Patients who underwent no transplantable embryo in their first IVF cycles but carried out several consecutive cycles between January 2012 to December 2020 were retrospectively enrolled and divided into three groups:group A (no egg retrieval), group B (no normal zygotes formed), and group C (no embryos available to transfer). The patients were also divided into the live birth group and non-live birth group according to whether they got a live baby or not. The clinical data and the cumulative clinical outcomes of groups were compared. Results: 496 patients met the inclusion criteria and enrolled, with 121 patients with no oocytes retrieved in group A, 138 patients with no normal zygotes formed in group B, and 237 patients with no embryos available to transfer in group C. The age [(34.75(5.82) vs 31.91(5.31), P<0.001; 34.75(5.82) vs 32.25(5.72), P<0.001)] and baseline FSH level [(13.04(8.82) vs 10.52(7.39), P=0.005; 13.04(8.82) vs 9.91(5.95), P<0.001)] of women in group A were significantly higher than those in groups B and C. The stable cumulative live birth rate/patient of three groups achieved 18.18% (after 5 cycles, group A), 28.98% (after 3 cycles, group B) and 20.25% (after 7 cycles, group C). Moreover, the multivariate regression analysis showed that female age and basic FSH were main factors affecting live birth outcome of patients with no embryo transfer in their first IVF cycle attempts. Conclusions: The future clinical outcome may be better in women with no normal zygotes than those with no oocyte retrieved or no available embryo at their first IVF cycle attempts. The main factors influencing the live birth are age and ovarian reserve.

Effects of Anticoagulants and Immune Agents on Pregnancy Outcomes and Offspring Safety in Frozen-Thawed Embryo Transfer Cycles-A Retrospective Cohort Study.

The application of anticoagulants and immune agents in assisted reproduction technology has been in a chaotic state, and no clear conclusion has been reached regarding the effectiveness and safety of this treatment. We aimed to explore the potential association between adjuvant medication and pregnancy outcomes and offspring safety in a retrospective cohort study including 8,873 frozen-thawed embryo transfer cycles. The included cycles were divided into three groups according to the drugs used, namely, the routine treatment group (without anticoagulant agents and immune agents), the anticoagulant agent group, and the immunotherapy group. Among normal ovulatory patients, those who used immune agents had a 1.4-fold increased risk of miscarriage (≤13 weeks), but a 0.8-fold decreased chance of birth (≥28 weeks) compared with the routine treatment group. Among patients with more than 1 embryo transferred, those who used anticoagulant agents showed a 1.2-fold higher risk of multiple birth than those undergoing routine treatment. Among patients without pregnancy complications, anticoagulant treatment was associated with a 2.1-fold increased risk of congenital anomalies. Among young patients (<26 years) with a singleton pregnancy, the neonatal birth weight of the immunotherapy group and the anticoagulant treatment group was 305.4 g and 175.9 g heavier than the routine treatment group, respectively. In conclusion, adjuvant anticoagulants or immune agent treatment in assisted reproductive technology should be used under strict supervision, and the principle of individualized treatment should be followed.

Factors affecting clinical pregnancy in controlled ovarian hyperstimulation with GnRH-a long protocol: a retrospective cross-sectional study.

This retrospective cross-sectional study was to investigate factors affecting clinical pregnancy in patients who received gonadotropin-releasing hormone agonist luteal phase long protocol (GnRH-a long protocol) and underwent fresh in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) embryo transfer cycle. One thousand five hundred and twenty-five patients who received GnRH-a long protocol and underwent fresh IVF/ICSI embryo transfer cycle were enrolled. The clinical pregnancy rate (63.1 vs. 22.4%, p < .05) and live birth rate (53.8 vs. 14.5%, p < .05) were significantly higher while the miscarriage rate (12.5 vs. 35.3%, p < .05) was significantly lower in the two embryo group than those in the one embryo group. The clinical pregnancy rate (48.5 vs. 64.1%, p < .05) and live birth rate (38.4 vs. 55.0%, p < .05) were significantly lower in patients older than 33.5 years than those in younger patients. The clinical pregnancy rate (52 and 60.6 vs. 79.7%, p < .05) and live birth rate (36 and 51.4 vs. 69.6%, p < .05) of the thin and mediate groups were significantly lower than those in the thick group, whereas the ectopic pregnancy rate (11.5 and 1.9 vs. 0%, p < .05) was significantly higher in the thin group than in the mediate and thick group. Multivariate logistic regression analysis showed that age (OR = 0.956, 95% CI [0.931, 0.982], p < .05), number of embryos transferred (OR = 2.491, 95% CI [1.670, 3.715], p < .05) and endometrial thickness on the transplantation day (OR = 1.124, 95% CI [1.067, 1.185], p < .05) were independent factors significantly associated with clinical pregnancy. In conclusion, endometrial thickness (>14.69 mm) on the day of transfer, two cleavage embryos transferred, and female age (≤33.5 years) are independent factors affecting clinical pregnancy outcomes in controlled ovarian hyperstimulation with GnRH-a long protocol for assisted conception. IMPACT STATEMENTWhat is already known on this subject? Fresh embryo transfer cycle with GnRH-a long protocol will result in a higher pregnancy rate in controlled ovarian hyperstimulation cycles.What do the results of this study add? Endometrial thickness on the day of transfer, number of embryos transferred, and female age were independent factors affecting clinical pregnancy outcomes.What are the implications of these findings for clinical practice and/or further research? When performing a fresh IVF/ICSI embryo transfer cycle with GnRH-a long protocol for ovulation induction, the independent affecting factors should be taken into consideration.

Crystal structure of a constitutive active mutant of adenosine A2A receptor.

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 pharmaco-logical studies among class A GPCRs.

The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.

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-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi 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.

Impact of Elevated Progesterone in Late Follicular Phase on Early Pregnancy Outcomes and Live Birth Rate After Fresh Embryo Transfers.

Objective: To investigate the effect of progesterone elevation during late follicular phase on early pregnancy outcomes and live births after fresh embryo transfers. Methods: Patients who underwent IVF/ICSI treatment cycles were retrospectively enrolled. The effect of progesterone elevation was analyzed on early pregnancy outcome and live births after fresh embryo transfers. Results: A total of 2,404 patients were enrolled on the day of HCG triggering (HCG0), 1,584 patients on the day before HCG triggering (HCG-1), and 800 patients 2 days before HCG triggering (HCG-2). With a 1 ng/ml increase in the progesterone level on HCG0 day when the progesterone level was ≥1.5 ng/ml, the clinical pregnancy rate decreased by 60% (95% CI: 0.2-0.7, p = 0.004), the intrauterine pregnancy rate decreased by 70% (95% CI: 0.2-0.7, p = 0.003), and the live birth rate decreased by 70% (95% CI: 0.1-0.7, p = 0.004). With a 1 ng/ml increase in the progesterone level on HCG-1 day, the clinical pregnancy rate decreased by 90% (95% CI: 0.0-0.5, p = 0.003) when the progesterone level was ≥1.6 ng/ml, the intrauterine pregnancy rate decreased by 90% (95% CI: 0.0-0.5, p = 0.001) when the progesterone was ≥1.5 ng/ml, and the live birth rate decreased by 90% (95% CI: 0.0-0.6, p = 0.015) when the progesterone was ≥1.7 ng/ml. On HCG-2 day when the progesterone was ≥1.2 ng/ml, the clinical pregnancy rate decreased by 80% (95% CI: 0.1-0.6, p = 0.003), and the intrauterine pregnancy rate decreased by 70% (95% CI: 0.1-0.7, p = 0.007) with a 1 ng/ml increase in the progesterone level. Conclusion: Elevated progesterone level during the late follicular phase is an independent risk factor affecting the clinical pregnancy rate, intrauterine pregnancy rate, and live birth rate among infertile patients undergoing IVF/ICSI after fresh embryo transfers. When the progesterone level exceeds a certain level, the early pregnancy and live birth rates after fresh embryo transfers show a rapid downward trend.

Structure-Activity Relationship Studies of Hydantoin-Cored Ligands for Smoothened Receptor.

An underside binding site was recently identified in the transmembrane domain of smoothened receptor (SMO). Herein, we report efforts in the exploration of new insights into the interactions between the ligand and SMO. The hydantoin core in the middle of the parent compound was found to be highly conservative in chirality, ring size, and substituents. On each benzene at two ends, a plethora of variations, particularly halogen substitutions, were introduced and investigated. Analysis of the structure-activity relationship revealed miscellaneous halogen effects. The ligands with double halogen substituents exhibit remarkably enhanced potency, providing promising candidates that potentially overcome the common drug resistance and useful heavy-atom labeled chemical tools for co-crystallization studies of SMO.

Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis.

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.