Silver-Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion.

Given the prevalence of heterocyclic scaffolds in drug-related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene-mediated dearomative N-N bond cleavage leading to skeletal hopping between indazole and 1,2-dihydroquinazoline via a highly selective single-carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene-substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late-stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C-N bond.

[Value of single-phase gonadotropin-releasing hormone stimulation test in diagnosis of central precocious puberty in girls with different levels of body mass index]. / 单时相GnRHæ¿€å‘è¯•éªŒå¯¹ä¸åŒä½“é‡æŒ‡æ•°å¥³ç«¥ä¸­æž¢æ€§æ€§æ—©ç†Ÿè¯Šæ–­ä»·å€¼çš„ç ”ç©¶.

OBJECTIVES: To investigate the value of single-phase gonadotropin releasing hormone (GnRH) stimulation test in the diagnosis of central precocious puberty (CPP) in girls with different levels of body mass index (BMI). METHODS: A retrospective analysis was performed for the data of 760 girls with breast development before 7.5 years of age who attended the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2023. According to the results of GnRH stimulation test and clinical manifestations, they were divided into a CPP group (297 girls) and a non-CPP group (463 girls). According to the values of BMI, the girls were divided into a normal weight group (540 girls), an overweight group (116 girls), and an obese group (104 girls). The receiver operating characteristic (ROC) curve was used to investigate the value of single-phase GnRH stimulation test in the diagnosis of CPP in girls with different levels of BMI. RESULTS: Luteinizing hormone (LH)/follicle-stimulating hormone at 30 minutes after GnRH stimulation had an area under the curve (AUC) of 0.985 in the diagnosis of CPP, which was higher than the AUC at 0, 60, and 90 minutes (P<0.05). LH at 30 minutes had a similar diagnostic value to LH at 60 minutes (P>0.05). LH at 30 minutes was negatively correlated with BMI and BMI-Z value (P<0.05).The AUC for diagnosing CPP in normal weight, overweight, and obese girls at 30 minutes LH was 0.952, 0.965, and 0.954, respectively (P<0.05). CONCLUSIONS: The 30-minute GnRH stimulation test has a good value in the diagnosis of CPP in girls with different levels of BMI and is expected to replace the traditional GnRH stimulation test, but the influence of BMI on LH level should be taken seriously.

Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities.

Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4ΔCD8 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4ΔCD8 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies.

Seven-layer analysis model of an optical waveguide excitation fluorescence microscopy.

In this paper, an optical waveguide evanescent field fluorescence microscopy is studied. Based on Maxwell's equation, a seven-layer theoretical analysis model is developed for the evaluation of an optical waveguide excitation fluorescence microscopy. The optical waveguide excitation fluorescence microscopy structure is systematically and comprehensively analysed at the wavelengths of 488, 532 and 646 nm for fluorescent dyes. The analysis results provide some useful suggestions, which will be beneficial to the research of an optical waveguide evanescent field fluorescence microscopy.

DTCO optimizes critical path nets to improve chip performance with timing-aware OPC in deep ultraviolet lithography.

Design technology co-optimization (DTCO) is a potential approach to tackle the escalating expenses and complexities associated with pitch scaling. This strategy offers a promising solution by minimizing the required design dimensions and mitigating the pitch scaling trend. It is worth noting that lithography has played a significant role in dimensional scaling over time. This paper proposes a DTCO flow to reduce the impact of the process variation (PV) band and edge placement error (EPE). First, we performed the digital back-end design of the high-performance processor and got the test layout; second, we executed timing analysis on the test layout to get the critical path net that affects the chip performance; third, we proposed the timing-aware optimized optical proximity correction (OPC) method to optimize the PV band and EPE by adjusting the weights of critical path net merit points, optimizing the generation of the sub-resolution assistant feature, giving tighter EPE specs for merit points on the critical path net, and placing denser merit points as well as denser breakpoints for the critical path net to obtain greater freedom in the OPC process. Finally, it is verified that our proposed DTCO process can significantly reduce the EPE and lead to a slight decrease in the PV band of the chip while maintaining the same process windows.

Impact of Ultrasonication on the Self-Assembly Behavior and Gel Properties of Bovine Bone Collagen I.

This study deliberated the effect of ultrasonic treatment on collagen self-assembly behavior and collagen fibril gel properties. Bovine bone collagen I which had undergone ultrasonic treatment with different power (0-400 W) and duration (0-60 min) was analyzed. SDS-PAGE and spectroscopic analysis revealed that ultrasonic treatment decreased collagen molecular order degree and the number of hydrogen bonds, stretching collagen telopeptide regions while maintaining the integrity of the collagen triple-helical structure. Ultrasonic treatment (p ≤ 200 W, t ≤ 15 min) dispersed the collagen aggregates more evenly, and accelerated collagen self-assembly rate with a decreased but more homogeneous fibril diameter (82.78 ± 16.47-115.52 ± 19.51 nm) and D-periodicity lengths (62.1 ± 2.9-66.5 ± 1.8 nm) than that of the untreated collagen (119.15 ± 27.89 nm; 66.5 ± 1.8 nm). Meanwhile, ultrasonic treatment (p ≤ 200 W, t ≤ 15 min) decreased the viscoelasticity index and gel strength, enhancing thermal stability and promoting specific surface area and porosity of collagen fibril gels than that of the untreated collagen fibril gel. These results testified that collagen self-assembly behavior and collagen fibril gel properties can be regulated by ultrasonic treatment through multi-hierarchical structural alteration. This study provided a new approach for controlling in vitro collagen fibrillogenesis process so as to manufacture novel desirable collagen-based biomaterials with propitious performances for further valorization.

Remote cyclic compression ameliorates myocardial infarction injury in rats via AMPK-dependent pathway.

BACKGROUND: Remote ischemic conditioning (RIC) displays a cardioprotective role in acute myocardial infarction (AMI). Since interruption of blood vessel is not an essential trigger of remote cardioprotection, tissue compression may play a prominent part in the effect. The purpose of this study was to confirm the protective effect of tissue compression on AMI and the underlying mechanisms. METHODS AND RESULTS: Rat model of AMI was induced by ligation of the left anterior descending coronary artery. Remote cyclic compression (RCC) on forelimb was applied to AMI rats for 3 days after the operation. RCC postconditioning displayed cardioprotective effects against AMI injury by limiting infarct size, alleviating cardiac dysfunction, and suppressing cardiomyocyte apoptosis. In addition, RCC postconditioning induced myocardial autophagy as evidenced by increased LC3-II and Beclin-1 and reduced mTOR levels. Furthermore, RCC treatment upregulated AMPK phosphorylation in the context of AMI hearts. AMPK inhibitor Compound C administration markedly abrogated RCC-mediated cardioprotective effect, as evidenced by decreased infarct size and cardiac function. CONCLUSION: Our results indicated that RCC postconditioning could attenuate AMI injury through inhibiting apoptosis and promoting autophagy via AMPK signaling pathway. The research provided a novel perspective for studying the cardioprotection of RIC and possible therapeutic strategy for managing AMI injury.

Integrated opto-mechanical cantilever sensor with a rib waveguide.

An integrated opto-mechanical cantilever sensor with a rib waveguide is reported in this paper. The device consists of a rib waveguide cantilever with buried waveguides on silicon. The rib cantilever is introduced to match better with the buried waveguide, further for increasing the interface coupling efficiency. With this configuration, single-mode operating can be achieved in transverse direction without decreasing the width of optical waveguide cantilever. The system sensitivity is 1.1 µm-1 which is increased by about 21%, compared with the conventional structure.

An integrated optical waveguide micro-cantilever system for chip-based AFM.

An optical waveguide cantilever system with a tip is introduced as the displacement detection system of chip-based atomic force microscopy (AFM) system. A chip-based AFM on optical waveguide is demonstrated with sensitivity of up to 4.0 × 10-2 nm-1 , which is mainly constructed by a 210 nm thick optical waveguide cantilever with a nano-tip. The nano-tip is a height of 1.2 µm and diameter of 140 nm. This integrated on-chip system provides a displacement range of approximately ±0.4 µm, which makes it possible for the device to be used for AFM imaging and pays the way for further performance improvement.

Effect of injection of different doses of isoproterenol on the hearts of mice.

BACKGROUND: Heart failure (HF) is one of the diseases that seriously threaten human health today and its mechanisms are very complex. Our study aims to confirm the optimal dose ISO-induced chronic heart failure mice model for better study of HF-related mechanisms and treatments in the future. METHODS: C57BL/6 mice were used to establish mice model of chronic heart failure. We injected isoproterenol subcutaneously in a dose gradient of 250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg and 50 mg/kg. Echocardiography and ELISA were performed to figure out the occurrence of HF. We also supplemented the echocardiographic changes in mice over 30 days. RESULTS: Except group S and group E, echocardiographic abnormalities were found in other groups, suggesting a decrease in cardiac function. Except group S, myofibrolysis were found in the hearts of mice in other groups. Brain natriuretic peptide was significantly increased in groups B and D, and C-reactive protein was significantly increased in each group. CONCLUSION: Our research finally found that the HFrEF mice model created by injection at a dose of 100 mg/kg for 7 days was the most suitable and a relatively stable chronic heart failure model could be obtained by placing it for 21 days.

Non-coplanar misalignment optical waveguide cantilever sensor with a monotonic response in a large operation range.

This paper reports a non-coplanar misalignment optical waveguide cantilever sensor realizing a monotonic response with a large operation range. A 1×2 Y-branch optical power splitter cantilever structure was designed, and one of the branches was reduced in thickness at the end, as a non-coplanar structure with respect to another. The misalignment coupling of the two branches due to the thickness of one branch leads to a monotonic response of an optical waveguide cantilever sensor. The simulation results showed a monotonic response with a sensitivity of 6×10-4 n m -1 in a large operation range of -1 to 1 µm.

Asymmetric Double Hydroxycarbonylation of Alkynes to Chiral Succinic Acids Enabled by Palladium Relay Catalysis.

A Pd-catalyzed asymmetric double hydroxycarbonylation of terminal alkynes was developed by using relay catalysis, providing a highly efficient route to chiral succinic acids (41 examples, 76-94 %, 94-99 % ee). Key to success was the combinatorial use of a Pd precursor with two distinct phosphine ligands in one pot. The synthetic utilities of this protocol were showcased in the facile synthesis of key intermediates for chiral pharmaceuticals.

Electroacupuncture interventions alleviates myocardial ischemia reperfusion injury through regulating gut microbiota in rats.

Electroacupuncture (EA) intervention has a remarkable cardioprotection against myocardial ischemia reperfusion injury (MIRI). Recently, it has been suggested that the gut microbiota plays an important role in regulating the progression and prognosis of MIRI. The purpose of this study was to illustrate the relationship between gut microbiota and cardioprotection of EA on MIRI. We conducted a MIRI model by ligating the left anterior descending coronary artery for 30 min followed by reperfusion in male Sprague Dawley rats, which then received 7 days of EA intervention. Echocardiography was employed to evaluate left ventricular function. Fecal samples were collected for microbial analysis by 16S rDNA high-throughput sequencing. Blood samples and myocardium were collected for inflammatory cytokine detection by enzyme linked immunosorbent assay (ELISA) and Western blot. Hematoxylin & eosin (HE) staining and immunofluorescence of ileum tissue were performed for intestinal damage evaluation. After 7 days of EA intervention, the left ventricular function was improved with significantly increased ejection fraction and fractional shortening. Furthermore, we found that EA intervention reversed the changed gut microbiota induced by MIRI, including Clostridiales, RF39, S24-7, Desulfovibrio, and Allobaculum, improved the impaired gut barrier, reduced the production and circulation of lipopolysaccharide (LPS), inhibited the level of interleukin 6 (IL-6) and interleukin 12 (IL-12) in periphery and decreased the expression of Toll like receptor 4 (TLR4) and IL-6 in myocardium. EA intervention could improve the impaired gut mucosal barrier and reduce the production and circulation of LPS after MIRI through regulating gut microbiota, thus inhibiting the circulation and myocardium inflammation and finally exerted the cardioprotective effect.

Long-Term and Short-Term Prognostic Value of Circulating Soluble Suppression of Tumorigenicity-2 Concentration in Chronic Heart Failure: A Systematic Review and Meta-Analysis.

INTRODUCTION: Soluble suppression of tumorigenicity-2 (sST2) has been considered as a prognostic factor of cardiovascular disease. However, the prognostic value of sST2 concentration in chronic heart failure remains to be summarized. METHODS: We searched PubMed, Embase, and Web of Science for eligible studies up to January 1, 2020. Data extracted from articles and provided by authors were used in agreement with the PRISMA statement. The endpoints were all-cause mortality (ACM), cardiovascular mortality (CVM)/heart failure-related hospitalization (HFH), and all-cause mortality (ACM)/heart failure-related readmission (HFR). RESULTS: A total of 11 studies with 5,121 participants were included in this analysis. Higher concentration of sST2 predicted the incidence of long-term ACM (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.02-1.04), long-term ACM/HFR (HR: 1.42, CI: 1.27-1.59), and long-term CVM/HFH (HR: 2.25, CI: 1.82-2.79), regardless of short-term ACM/HFR (HR: 2.31, CI: 0.71-7.49). CONCLUSION: Higher sST2 concentration at baseline is associated with increasing risk of long-term ACM, ACM/HFR, and CVM/HFH and can be a tool for the prognosis of chronic heart failure.

Recent progress in transition-metal-catalyzed hydrocyanation of nonpolar alkenes and alkynes.

Hydrocyanation is a powerful method for the preparation of nitriles which are versatile building blocks for the synthesis of amines, acids and amides. This review summarizes the research on transition-metal-catalyzed (asymmetric) hydrocyanation of nonpolar (or non-activated) alkenes and alkynes in the last decade. These studies involve the extension of HCN surrogates and unsaturated substrates, catalyst development as well as the improvement of the activity and multiple selectivities. The remaining challenges and personal future perspectives are presented at the end.

Decoupling and detecting angular motion errors based on a line laser sensor for motion platforms.

Efficient measurement of a line laser sensor can be achieved by combining it with a multi-axis platform. However, the measuring results are significantly affected by the precision of the platform. To provide a criterion for verifying and compensating for the geometric errors of a platform, a measuring method based on a line laser sensor for angular motion errors is proposed for the first time to the best of our knowledge in this work. The principles of separating and simultaneously detecting the yaw, roll, and pitch errors are elaborated. Based on this, the detection model is built for a three-dimensional platform. Under such an experimental condition, the stability and accuracy of the line laser sensor is tested, and the experimental results revealed small deviations of 3 µm and 10 µm in z axis and x axis, respectively. Ultimately, a series of experiments is performed to verify the feasibility and repeatability of the method. The yaw experimental results indicate that the trend and rule of error conform to the measured value by a laser interferometer, and the maximum variation value is 0.0075 mrad.

Clinical Events Associated with Acupuncture Intervention for the Treatment of Chronic Inflammation Associated Disorders.

Acupuncture is a key component of Chinese medicine. It describes a series of procedures involving the stimulation of skin through penetration of fine, single-use, sterile needles that result in the release of neurotransmitters. Although its use is on the growing trend, considerable controversy surrounds its value as a therapy. Standard randomized controlled trials that adhere to the accepted criteria should be conducted in the future to ensure the effectiveness of acupuncture. This article summarizes the current evidence regarding the use of acupuncture. It includes a description of the history, mode of operation, treatment of a variety of chronic disorders related to inflammation, and future directions for acupuncture use. Published clinical trials support the view that acupuncture is a possible candidate for the treatment of several chronic inflammation-related disorders.

Intestinal Lamina Propria CD4+ T Cells Promote Bactericidal Activity of Macrophages via Galectin-9 and Tim-3 Interaction during Salmonella enterica Serovar Typhimurium Infection.

The intestinal immune system is crucial for protection from pathogenic infection and maintenance of mucosal homeostasis. We studied the intestinal immune microenvironment in a Salmonella enterica serovar Typhimurium intestinal infection mouse model. Intestinal lamina propria macrophages are the main effector cells in innate resistance to intracellular microbial pathogens. We found that S Typhimurium infection augmented Tim-3 expression on intestinal lamina propria CD4+ T cells and enhanced galectin-9 expression on F4/80+ CD11b+ macrophages. Moreover, CD4+ T cells promoted the activation and bactericidal activity of intestinal F4/80+ CD11b+ macrophages via the Tim-3/galectin-9 interaction during S Typhimurium infection. Blocking the Tim-3/galectin-9 interaction with α-lactose significantly attenuated the bactericidal activity of intracellular S Typhimurium by macrophages. Furthermore, the Tim-3/galectin-9 interaction promoted the formation and activation of inflammasomes, which led to caspase-1 cleavage and interleukin 1ß (IL-1ß) secretion. The secretion of active IL-1ß further improved bactericidal activity of macrophages and galectin-9 expression on macrophages. These results demonstrated the critical role of the cross talk between CD4+ T cells and macrophages, particularly the Tim-3/galectin-9 interaction, in antimicrobial immunity and the control of intestinal pathogenic infections.

[Peri-operation treatment for patients with hemophilia A in children with intracranial malignant tumor: a report of 2 cases].

Hemophilia A is aninherited bleeding disorder, lack of coagulation factor VIII (FVIII), and if combined with intracranial malignant tumor, the operation risk is very high. Department of Pediatric Surgery in Peking University First Hospital used coagulation factor replacement therapy, succeeded in the operation of 2 cases of intracranial malignant tumor with hemophilia A in children, with no abnormal bleeding events. The establishment of the multi subject cooperation group before operation, good preoperative preparation, enough alternative factors, and close postoperative monitoring, are the key to the successful treatment.

Adverse reactions of piperacillin: A literature review of case reports.

Aim: This study aimed to summarize case reports of adverse drug reactions (ADRs) caused by piperacillin and explore their effects on human organs in real-world settings. Method: Case reports of piperacillin ADRs were collected by searching databases such as PubMed, Embase, Web of Science, CNKI, WanFang, and VIP from inception to December 2022. Results: A total of 170 patients were ultimately included. The results revealed that ADRs caused by piperacillin were primarily associated with the entire body, followed by the blood system, skin and soft tissues, and the nervous system. The most frequently reported cases included anaphylactic shock, drug fever, rash, and thrombocytopenia. The most severe ADRs were identified as anaphylactic shock and bullous epidermal necrolysis. Furthermore, a comparison was made between systemic adverse reactions caused by piperacillin as a single drug and two composite preparations of piperacillin/ß-lactamase inhibitor. ADRs not mentioned in the instructions included convulsions or hallucinations and Kounis syndrome (KS). Conclusion: This review suggests that the most severe ADRs associated with piperacillin are toxic epidermal necrolysis and anaphylactic shock. Rare ADRs caused by piperacillin, such as myoclonic jerks, hallucinations, and KS, were identified. The most common symptom with domestic preparations of piperacillin/sulbactam and piperacillin sodium was dyspnea.