Search

Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states—the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

Ti3SiC2ceramic and SUS430 ferritic stainless steel were welded by the transient liquid phase (TLP) diffusion bonding method using an Al interlayer at 850–1050 °C in vacuum. The evolution of phase and morphology at the interface and bonding strength were systematically investigated. The results show that Ti3SiC2and SUS430 were well bonded at 900–950 °C. Three reaction zones were observed at the interface. At the joint interface area adjacent to alloy, the alloy completely reacted with liquid Al to form Al86Fe14. At Ti3SiC2/Al interface, Ti and Si diffused outward from Ti3SiC2into the molten Al to form Fe3Al + Al5FeSi + TiAl3zone. Adjacent to Ti3SiC2matrix, Ti3Si(Al)C2+ TiCxzone was formed by the loss of Si. The evolution mechanism of TLP-bonded joints was discussed based on the interface microstructure and product phases. In addition, the tensile strength of the joint increased with increasing bonding temperature. The corresponding maximum value of 59.7 MPa was obtained from SUS430/Al (10 μm)/Ti3SiC2joint prepared at 950 °C.

To compare the on‐site diagnostic performance of contrast‐enhanced ultrasound (CEUS), computed tomography (CECT), and magnetic resonance imaging (CEMRI) for hepatocellular carcinoma (HCC) across diverse practice settings. Between May 2019 and April 2022, a total of 2085 patients with 2320 pathologically confirmed focal liver lesions (FLLs) were enrolled. Imaging reports were compared with results from pathology analysis. Diagnostic performance was analyzed in defined size, high‐risk factors for HCC, and hospital volume categories. Three images achieved similar diagnostic performance in classifying HCC from 16 types of FLLs, including HCC ≤2.0 cm. For HCC diagnosis at low‐volume hospitals and HCC with high‐risk factors, the accuracy and specificity of CEUS were comparable to CECT and CEMRI, while the sensitivity of CEUS (77.4 and 89.5%, respectively) was inferior to CEMRI (87.0 and 92.8%, respectively). The diagnostic accuracy of CEUS + CEMRI and CEUS + CECT increased by 7.8 and 6.2% for HCC ≤2.0 cm, 8.0 and 5.0% for HCC with high‐risk factors, and 7.4 and 5.5% for HCC at low‐volume hospitals, respectively, compared with CEMRI/CECT alone. Compared with CECT and CEMRI, CEUS provides adequate diagnostic performance in clinical first‐line applications at high‐volume hospitals. Moreover, a higher diagnostic performance for HCC is achieved by combining CEUS with CECT/CEMRI compared with any single imaging technique.

Ultrasonography is the most widely used technique to diagnose echinococcosis; however, challenges in using this technique and the demand on medical resources, especially in low-income or remote areas, can delay diagnosis. We aimed to develop a deep convolutional neural network (DCNN) model based on ultrasonography to identify echinococcosis and its types, especially alveolar echinococcosis.

Introduction:HNF1B-associated diseases are a group of genetic conditions that affect the kidney as well as other organ systems. Kidney anomalies are the most common symptoms. Other defects may include early-onset diabetes, genital abnormalities, and abnormalities of pancreas and liver function. Renal involvement has emerged as the earliest finding in HNF1Bdisease, even in prenatal life, with the most common feature being hyperechogenic kidneys. Case Presentation:In this study, we present 3 fetuses with bilateral renal hyperechogenicity identified by ultrasound in the second trimester. No pathogenic copy number variations were revealed by amniocentesis with chromosomal microarray analysis (CMA). Heterozygous variants in HNF1Bwere detected in all 3 fetuses by further investigation with exome sequencing (ES). Two pregnancies were terminated, and one was continued to term. Discussion and Conclusion:Because of the known high frequency of HNF1Baberrations in fetal hyperechogenic kidneys, HNF1Bscreening should be an integral part of prenatal diagnosis for such fetuses. ES should be recommended following or concurrently with CMA for rapid prenatal detection. The ES results would improve the diagnostic yield and are beneficial in guiding counseling and management.

Adequate preliminary research is a prerequisite for ensuring the quality of randomized controlled trials (RCTs) on acupuncture. This paper proposes that prior to conducting a new RCT of acupuncture, an evidence-based research (EBR) approach and exploratory studies should be adopted to ensure value and avoid waste of research. EBR, defined as using systematic reviews of relevant clinical studies and obtain the perspectives of end users in a systematic and transparent way to justify research questions and inform trial design, is recommended as the first step before embarking on an acupuncture RCT to ensure its value and rationality. The subsequent exploratory studies can aid researchers in pre-evaluating the effect of acupuncture treatment protocols, identifying key factors that influence the outcome, and test trial feasibility for protocol optimization. This article elucidates the significance and implementation of the EBR approach and exploratory studies, with the aim of providing practical methods to enhance the quality of acupuncture RCTs.

Contrast-enhanced US-guided biopsy of focal liver lesions had a higher diagnostic accuracy than US-guided biopsy, especially for lesions smaller than 2 cm and for hepatocellular carcinoma diagnosis.

Byline: Yan. Zhou, Xiaolin. Xu, Jianmin. Ding, Xiang. Jing, Fengmei. Wang, Yandong. Wang, Peng. Wang Aims: Thermal ablation can evoke an immune response, which may have effects on the prognosis [...]

Systematic and quantitative analysis of the reliability of formally exact methods that in silicocalculate absolute protein–ligand binding free energies remains lacking. Here, we provide, for the first time, evidence-based information on the reliability of these methods by statistically studying 853 cases from 34 different research groups through meta-analysis. The results show that formally exact methods approach chemical accuracy (error = 1.58 kcal/mol), even if people are challenging difficult tasks such as blind drug screening in recent years. The geometrical-pathway-based methods prove to possess a better convergence ability than the alchemical ones, while the latter have a larger application range. We also reveal the importance of always using the latest force fields to guarantee reliability and discuss the pros and cons of turning to an implicit solvent model in absolute binding free-energy calculations. Moreover, based on the meta-analysis, an evidence-based guideline for in silicobinding free-energy calculations is provided.

Acupuncture is used to relieve symptoms, reducing recurrence, and improve the lives of patients with skin diseases.

Russell-Silver syndrome (SRS) is a rare condition characterized by poor growth before and after birth along with multiple physical and psychosocial characteristics such as short stature, characteristic facial features, body asymmetry, feeding difficulties, and learning disabilities. In this study, we report a family with 2 recurrent SRS pregnancies due to a derivative chromosome 15 that is the result of a maternally derived t(11;15) translocation, detected by non-invasive prenatal testing (NIPT). The 2 SRS fetuses were diagnosed by chromosomal microarray analysis, but a balanced, reciprocal translocation of the mother was disclosed by the combination of routine karyotyping and FISH. This study demonstrates that NIPT has the ability to identify submicroscopic copy number variations (CNVs) in fetuses, which in some cases may result from a parent being a balanced rearrangement carrier. Because of the differences in resolution and the various benefits and limitations of each genetic technique, great care must be taken when deciding on which test(s) to employ in family studies.

Objective: To determine whether electroacupuncture (EA) or moxibustion-like stimulation (MLS) can affect the cutaneous and/or systemic hypothalamic–pituitary–adrenal (HPA) axes.Methods: Rats were divided into Control, EA, 37°C MLS and 43.5°C MLS groups. EA and MLS were performed at bilateral ST36 or LI4. The expression of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH) and the glucocorticoid receptor (GR) was detected in local cutaneous tissues at the site of ST36 and LI4 by immunohistochemical staining. In addition, levels of CRF, ACTH and corticosterone (CORT) in cutaneous tissue and plasma were determined.Results: Cutaneous expression of CRF, ACTH and GR significantly increased after EA at ST36, while only GR increased after 43.5°C MLS at ST36. The results of EA and MLS at LI4 were in parallel with those at ST36. In plasma, compared with the control group, the level of CORT increased after EA at ST36, while both ACTH and CORT were markedly increased after 43.5°C MLS. For LI4, plasma CRF and CORT increased after EA, while the levels of all three hormones increased following 43.5°C MLS. Notably, compared with the effect of EA, 43.5°C MLS at ST36 produced a more substantial increase in plasma CORT, and 43.5°C MLS at LI4 induced a more dramatic increase in plasma CRF and CORT.Conclusion: Both EA and 43.5°C MLS can activate the cutaneous and systemic HPA axes of the rat. EA tended to activate the local cutaneous HPA, while 43.5°C MLS was more likely to activate the systemic HPA axis.

ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATPinhibitors have been prescribed for diabetes and KATPactivators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATPchannel activity.SIGNIFICANCE STATEMENTATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATPchannels are important drug targets. Both KATPinhibitors (insulin secretagogues) and KATPactivators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATPstructural pharmacology.

ObjectiveTo analyse the incidence and risk factors of hepatotoxicity induced by antituberculosis (anti-TB) drugs in Renmin Hospital of Wuhan University, and to provide evidence for clinical prevention and treatment of anti-TB drug damage.MethodsA retrospective analysis of patients who received first-line anti-TB drugs from January 2016 to December 2018 in Renmin Hospital of Wuhan University was conducted. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with hepatotoxicity induced by anti-TB drugs.ResultsOf the 1603 patients treated with anti-TB drugs, only 1115 patients met the inclusion criteria and 42 subjects developed anti-TB drug-induced hepatotoxicity (ATDH). Significant differences (p<0.05) were seen in age (p=0.042), hypertension (p=0.021), treatment duration (p=0.000) and therapeutic regimen (p=0.001) between the non-ATDH and ATDH groups. Regression analysis further indicated that treatment duration (OR 1.053, 95% CI 1.031 to 1.076, p=0.000) and therapeutic regimens such as isoniazid (H), rifampicin (R), pyrazinamide (Z) and streptomycin (S) (HRZS) (OR 5.751, 95% CI 2.318 to 14.267, p=0.000), HRZ (OR 3.546, 95% CI 1.449 to 8.676, p=0.006) and RZ (OR 12.243, 95% CI 1.181 to 126.862, p=0.036) were risk factors for ATDH.ConclusionThe incidence of ATDH in this study was 3.77%, which was lower than that of other hospital-based studies. Treatment duration and therapeutic regimen might be potential risk factors for ATDH during anti-TB therapy in hospital. Among these therapeutic combination regimens, HRZS, HRZ and RZ could significantly increase the occurrence of ATDH when used as anti-TB therapy, while isoniazid, rifampicin and ethambutol (HRE) might be safer.

To explore the clinical value of image fusion of contrast‐enhanced ultrasonography (CEUS) and contrast‐enhanced computed tomography (CECT) in the diagnosis of invisible lesions with a size ≤2 cm on conventional ultrasound imaging, and compare it with the clinical value of “first CEUS” . A total of 132 patients with 147 lesions with abnormal blood supply with a size ≤2 cm on CECT were included in this study. “first CEUS” was performed for these lesions. Then “fusion CEUS,” that is, CEUS administered after fusion of US and CECT images, was carried out. The detection rates of the “first CEUS” and “fusion CEUS” were compared. How “fusion CEUS” corrects the misdiagnosis of liver lesions on CECT was analyzed. One hundred nine lesions considered as HCC and 38 lesions considered as benign lesions on CECT were included. The detection rates for the lesions of “first CEUS” and “fusion CEUS” were 71.4% and 96.6%, respectively (P< 0.001). Among the 147 lesions, 68 were with a diameter ≤ 1 cm. The detection rate of “first CEUS” and “fusion CEUS” were 55.9% and 95.6%, respectively (P< 0.001) for the lesions with a size ≤1 cm. “Fusion CEUS” and “first CEUS” corrected the misdiagnosis in 2 lesions on CECT. The “first CEUS” and “fusion CEUS” can improve the lesion conspicuity. Compared with “first CEUS,” “fusion CEUS” has a higher diagnostic ability and hence can detect most of the invisible lesions on the former. Access the CME test hereand search by article title.

The combination of microwave ablation (MWA) and chemodynamic therapy (CDT) presents a promising strategy for complete eradication of residual tumor after MWA. However, it remains challenging and urgent to develop a facile, biocompatible, and imaging‐guided platform for the achievement of this goal. Herein, a minimalist manganese hydrogel (ALG‐Mn hydrogel) is proposed for synergistic MWA and CDT to completely eradicate tumor in vivo. The ALG‐Mn hydrogel is prepared using a simple mixing method and exhibits excellent syringeability, remarkable microwave sensitivity, and potent Fenton‐like activity. By assisting in MWA procedures, the ALG‐Mn hydrogel enables both elimination of primary tumor mass through enhanced MWA efficacy and eradication of potential residual tumor tissues via robust CDT. This approach achieves complete tumor clearance without additional drug loading. Furthermore, the paramagnetic Mn2+component allows real‐time dynamic visualization of the ALG‐Mn hydrogel at the tumor site via magnetic resonance imaging. To the best of knowledge, the proposed ALG‐Mn hydrogel represents the minimalist biocompatible platform for imaging‐guided synergistic MWA and CDT toward achieving complete tumor clearance. A minimalist manganese alginate (ALG‐Mn) hydrogel is developed via a facile one‐pot mixing method for magnetic resonance imaging (MRI)‐guided synergistic microwave ablation (MWA) and chemodynamic therapy (CDT) against tumors. The ALG‐Mn hydrogel‐assisted MWA not only eliminates the primary tumor mass through enhanced MWA, but also eradicates the potential residual tumor tissues via potent CDT, thereby achieving complete tumor clearance.

A multiparametric US predictive model combining attenuation coefficient, alanine aminotransferase level, and international normalized ratio showed good ability to predict metabolic dysfunction–associated steatohepatitis in participants with metabolic dysfunction–associated fatty liver disease.

In this work, we have investigated the near-infrared (NIR) photoluminescence, upconversion (UC), and long-lasting phosphorescence properties of Nd3+/Yb3+-doped Ca2SnO4phosphors. Two-photon NIR quantum cutting (QC) luminescence is observed when the Nd3+–O2–charge-transfer band in Ca2SnO4:Nd3+, Yb3+phosphors was excited, and the theoretical quantum yield is found to be close to 200%. More interestingly, the unique two-photon UC red emission under 808 nm laser diode excitation and NIR QC persistent luminescence can be realized only in Nd3+–Yb3+codoped samples. The energy-transfer mechanism between Nd3+and Yb3+is revealed from the energy level structure and decay measurements. Different cross-relaxation schemes related to 2F5/2–2F7/2of Yb3+and f–f transition of Nd3+are proposed. The results show that multifunctional luminescence properties are achieved in Nd3+-doped Ca2SnO4with the introduction of Yb3+.

Recently, continuous breakthroughs have been made about deep gold prospecting in the Jiaodong gold province area of China. Approximately 5000 t of cumulative gold resources have been explored in Jiaodong, which has thus become an internationally noteworthy gold ore cluster. The gold exploration depth has been increased to about 2000 m from the previous <1000 m. To further explore the mineralization potential of the Jiaodong area at a depth of about 3000 m, the Shandong Institute of Geological Sciences has drilled an exploratory drillhole named “Deep drillhole ZK01” to a depth of 3266 m. Hence, as reported herein, the mineralization characteristics of the Jiaojia metallogenic belt have been successfully documented. ZK01 is, to date, the deepest borehole with an gold intersect in China, and constitutes a significant advance in deep gold prospecting in China. The findings of this study further indicate that the depth interval of 2000 m to 4000 m below the ground surface in the Wuyi Village area incorporates 912 t of inferred gold resources, while the depth interval of 2000 m to 4000 m below the surface across the Jiaodong area possesses about 4000 t of inferred gold resources. The Jiaojia Fault Belt tends to gently dip downward, having dip angles of about 25° and about 20° at vertical depths of 2000 m and 2850 m, respectively. The deep part of the Jiaojia metallogenic belt differs from the shallow and moderately deep parts about fracturing, alteration, mineralization, and tectonic type. The deep zones can generally be categorized from inside outward as cataclastic granite, granitic cataclasite, weakly beresitized granitic cataclasite, beresitized cataclasite, and gouge. These zones exhibit a gradual transitional relation or occur alternately and repeatedly. The mineralization degree of the pyritized cataclastic granite-type ore in the deep part of the Jiaojia metallogenic belt is closely related to the degree of pyrite vein development; that is, the higher the pyrite content, the wider the veins and the higher the gold grade. Compared to the shallow gold ores, the deep-seated gold ores have higher fineness and contain joseite, tetradymite, and native bismuth, suggesting that the deep gold mineralization temperature is higher and that mantle-sourced material may have contributed to this mineralization. ZK01 has also revealed that the deep-seated ore bodies in the Jiaojia metallogenic belt are principally situated above the main fracture plane (gouge) and hosted within the Linglong Granite, contradicting previous findings indicating that the moderately shallow gold ore bodies are usually hosted in the contact zone between the Linglong Granite and Jiaodong Group or meta-gabbro. These new discoveries are particularly significant because they can help correct mineralization prospecting models, determine favorable positions for deep prospecting, and improve metallogenic prediction and resource potential evaluation.

Objective: This study proposed an innovative approach to simplify the multiple psychological scales for children and adolescents by integrating statistical methods and item reflection theory into a structural equation model. Methods: First, a psychological scale for adolescents to replace the existing scales optimized for adults with the Delphi method has been developed. Second, the number of items in the current group of scales has been reduced. Result and Conclusion: A psychological scale for adolescents has been built up that comprehensively reflects their psychological characteristics in terms of mental state, behavioral status, emotion & feeling, relationship, and environmental adaptation. This psychological scale has been simplified and improved its reliability and validity.

The aim of this study was to compare the microstructure of blood vessels and nerve fibers between different acupoints in the rat skin from the perspective of histology.

Sulfonylureas and glinides are commonly used oral insulin secretagogues (ISs) that act on the pancreatic ATP-sensitive potassium (KATP) channel to promote insulin secretion in order to lower the blood glucose level. Physiologically, KATPchannels are inhibited by intracellular ATP and activated by Mg-ADP. Therefore, they sense the cellular energy status to regulate the permeability of potassium ions across the plasma membrane. The pancreatic KATPchannel is composed of the pore-forming Kir6.2 subunits and the regulatory SUR1 subunits. Previous electrophysiological studies have established that ISs bind to the SUR1 subunit and inhibit the channel activity primarily by two mechanisms. First, ISs prevent Mg-ADP activation. Second, ISs inhibit the channel activity of Kir6.2 directly. Several cryo-EM structures of the pancreatic KATPchannel determined recently have provided remarkable structural insights into these two mechanisms.

Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA. In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (< 0.5 mA), and sham EA (non-acupoint). Treatments consisted of five sessions per week, for 2 weeks. Primary outcome measures were visual analog scale (VAS), CPM function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Three hundred one patients with KOA were randomly assigned, among which 271 (90.0%) completed the study (mean age 63.93 years old). One week of EA had a clinically important improvement in VAS and WOMAC but not in CPM function. After 2 weeks treatment, EA improved VAS, CPM, and WOMAC compared with baseline. Compared with sham EA, weak EA (3.8; 95% CI 3.45, 4.15; P< .01) and strong EA (13.54; 95% CI 13.23, 13.85; P< .01) were better in improving CPM function. Compared with weak EA, strong EA was better in enhancing CPM function (9.73; 95% CI 9.44, 10.02; P< .01), as well as in reducing VAS and total WOMAC score. EA should be administered for at least 2 weeks to exert a clinically important effect on improving CPM function of KOA patients. Strong EA is better than weak or sham EA in alleviating pain intensity and inhibiting chronic pain. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-ICR-14005411), registered on 31 October 2014.

To address the gap in understanding precipitation changes in Southeast Asia and to enhance the reliability of climate projections for the region through moisture budget analysis, this study examines the differences among six multi-model ensembles of CMIP6 simulated precipitation in term of moisture budget analysis. It investigates the relative contributions of thermodynamic and dynamic components to seasonal precipitation changes over Southeast Asia under the highest emission scenario, SSP5-8.5. The comparison between ensembles indicates that Good performance model ensembles slightly outperform the combination of all resolution and all category ensembles in reducing the biases. There is no strong evidence showing that good category ensembles outperform the combination of all model ensemble groups in simulating the spatial pattern of historical seasonal precipitation. From the perspective of moisture budget, regions receiving seasonal high rainfall intensity are mainly influenced by the moisture convergence during the monsoon seasons: northeast monsoon (December‒January‒February) and southwest monsoon (June–July–August). By the late 21st century (2081–2100), all model ensemble projections show an increase in December‒January‒February precipitation over the northern Southeast Asia and decreased June‒July‒August rainfall in the southern regions. The moisture budget analysis explained that the seasonal mean rainfall change in Southeast Asia is largely influenced by evaporation and followed by moisture flux convergence. The changes in moisture flux convergence are contributed by both the dynamic and thermodynamic components. Greater inter-model uncertainty was found in the precipitation dynamic component compared to the thermodynamic component suggesting the existence of large discrepancy between the various approaches used by GCMs in describing atmospheric dynamics. The study highlights that the Good model ensemble with middle to low resolution is able to narrow the inter-model uncertainties in terms of the moisture budget analysis compared to the combination of all Good model ensembles.

目的:对全球范围内放化疗所致恶心呕吐指南/专家共识中针灸推荐意见进行总结分析, 为放化疗后恶心呕吐针灸临床实践指南的研制提供依据.方法:系统检索7个数据库,7个指南库及4个行业学会网站.检索时限均为建库至2023年4月1日.由2名研究者独立筛选文献,提取资料后, 采用临床实践指南科学性,透明性,适用性的评级工具 (Scientific, Transparent and Applicable Rankings tool, STAR tool) 评价含针灸推荐意见指南/共识的质量, 并对指南/专家共识中的针灸推荐意见及其证据基础进行分析总结.结果:共纳入56篇放化疗后恶心呕吐防治相关指南/专家共识, 其中22篇指南/专家共识含有针灸推荐意见, 针灸相关推荐意见共34条 (27条推荐, 4条不推荐不反对, 3条反对) .STAR评价(1篇患者指南未进行评价)结果显示无一篇指南/专家共识质量为高, 95.24% (20/21) 指南/专家共识质量中等, 4.76% (1/21) 指南质量低.现有指南/专家共识虽涉及针灸的推荐意见数量可观, 但推荐的针灸治疗方案之间异质性较大, 且多数不描述针灸治疗方案细节如针灸操作,穴位选择,干预时间及介入时机等, 难以指导针灸临床实践.结论:迫切需要依据STAR工具条目研制放化疗后恶心呕吐针灸临床实践指南, 明确针灸方案细节, 提供规范化治疗方案, 以指导针灸临床实践.

Metal-hydride-catalyzed alkene hydroalkylation has been developed as an efficient method for C(sp3)–C(sp3) coupling with broad substrate availability and high functional group compatibility. However, auxiliary groups, a conjugated group or a chelation-directing group, are commonly required to attain high regio- and enantioselectivities. Herein, we reported a ligand-controlled cobalt-hydride-catalyzed regio-, enantio-, and diastereoselective oxyheterocyclic alkene hydroalkylation without chelation-directing groups. This reaction enables the hydroalkylation of conjugated and unconjugated oxyheterocyclic alkenes to deliver C2- or C3-alkylated tetrahydrofuran or tetrahydropyran in uniformly good yields and with high regio- and enantioselectivities. In addition, hydroalkylation of C2-substituted 2,5-dihydrofuran resulted in the simultaneous construction of 1,3-distereocenters, providing convenient access to polysubstituted tetrahydrofuran with multiple enantioenriched C(sp3) centers.

Clinical Practice Guideline on Acupuncture and Moxibustion: Migraine (WFAS 007.9-2023)is a clinical practice guideline officially released by the World Federation of Acupuncture-Moxibustion Societies (WFAS) on October 9, 2023, and is the first international guideline on the treatment of migraine with acupuncture. This international standard was developed under the guidance of rigorous evidence-based methodology, and it contains guideline purpose, scope, applicable population, applicable settings, overview of acupuncture for migraine, guideline development process and recommendations. For promoting the understanding and application of this guideline, this article summarizes a total of 18 recommendations in order to assist clinical decisions for migraine with acupuncture.

A unique, dual-function, photoactivatable anticancer prodrug, RuEuL, has been tailored that features a ruthenium(II) complex linked to a cyclen–europium chelate via a π-conjugated bridge. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. Under evaluation-window irradiation (λirr= one-photon 350 nm or two-photon 700 nm), the drug delivery process can be quantitatively monitored in real-time because of the long-lived red europium emission. Linear relationships between released drug concentration and ESI-MS or luminescence responses are established. Finally, the efficiency of the new prodrug is demonstrated both in vitro RuEuLanticancer prodrug over some existing ones and open the way for decisive improvements in multipurpose prodrugs.

Reactions of two halogenated derivatives of bis(4-hydroxyphenyl)sulphone (BPS, 1), tetrabromobisphenol-S (TBBPS, 2), and tetrachlorobisphenol-S (TCBPS, 3), with piperazine (PZ, 4), were investigated by means of the combinational usage of solvothermal and mechanochemical methods. The resultant organic complexes, [(C6H2OBr2)2SO2]·[(C4H10N2)2CH2] (5), [(C6H2OBr2)2SO2]2·(C4H12N2)2·3(CH3OH) (6), [(C6H2OCl2)2SO2]·[(C4H10N2)2CH2] (7), and [(C6H2OCl2)2SO2]2·(C4H12N2)2·3(CH3OH) (8), were fully characterized by single crystal and powder X-ray diffractions. In the cases of complexes 5and 7that were prepared from solvothermal conditions, a rare metal-free in situligand formation has been observed, in which the new organic molecule 1,2-bispiperazinylmethane was presumably originated from the double C–N coupling of two piperazines on a carbon atom coming from methanol. In addition, the relevant concomitants 6and 8were also isolated from the solutions of 5and 7, respectively. Complexes 6and 8contain 1:1 starting molecules of 2/3with 4assembled into helical structures.

Soluble guanylate cyclase (sGC) is the primary sensor of nitric oxide. It has a central role in nitric oxide signalling and has been implicated in many essential physiological processes and disease conditions. The binding of nitric oxide boosts the enzymatic activity of sGC. However, the mechanism by which nitric oxide activates the enzyme is unclear. Here we report the cryo-electron microscopy structures of the human sGCα1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the nitric oxide sensor module and the catalytic module. Binding of nitric oxide to the β1 haem-nitric oxide and oxygen binding (H-NOX) domain triggers the structural rearrangement of the sensor module and a conformational switch of the transducer module from bending to straightening. The resulting movement of the N termini of the catalytic domains drives structural changes within the catalytic module, which in turn boost the enzymatic activity of sGC.

Many variants of join operations of graphs have been introduced, and their spectral properties have been studied extensively by many researchers. This paper mainly focuses on the Laplacian spectra of some double join operations of graphs. We first introduce the conception of double join matrix and provide a complete information about its eigenvalues and the corresponding eigenvectors. Further, we define four variants of double join operations based on subdivision graph, Q-graph, R-graph and total graph. Applying the result obtained about double join matrices, we give an explicit complete characterization of the Laplacian eigenvalues and the corresponding eigenvectors of four variants in terms of the Laplacian eigenvalues and the eigenvectors of factor graphs. These results generalize some well-known results on the Laplacian spectra of some join operations of graphs.

Glossogyne tenuifoliais a high economic value crop cultivated on Penghu Island, Taiwan. However, there is no extraction optimization of G. tenuifoliareported in the literature. Simplex lattice and central composite design of response surface methodology (RSM) were used in this study to investigate the extraction variables (solvent proportion, extraction temperature, the ratio of liquid to solid and pH) in the extraction of solvent from G. tenuifolia. The total phenolic content (TPC), total flavonoid content (TFC), total triterpenoid content (TTC) and antioxidant capacity of G. tenuifoliawere considered as the response variables, while the solvent proportion, extraction temperature, the ratio of liquid to solid (L/S) and the pH effect were considered for determining the optimal conditions. Quadratic models were used by the RSM optimization approach to obtain the optimal conditions and to predict the relative response variables. ANOVA analysis results exhibited a high coefficient of determination (R2) and adjusted-R2, which indicated that the quadratic models were adequate for the response variables. The results demonstrated that the extract of G. tenuifoliais a good source of antioxidant and has the potential to be applied in various industries.

The low ionic conductivity of solid electrolyte and the poor interfacial compatibility with lithium anode are often restrain the electrochemical performances of the solid-state battery at ambient temperature. Herein, we for the first time applied electrospun Li7La3Zr2O12 (LLZO) fibers and graphite coating simultaneously on polymer solid electrolyte (SE). The composite SE shows uniform composite structure, possesses a high potential window exceeding 4.6V and a high ionic conductivity of 1.59 x 10[?]4 S/cm at ambient temperature. The assembled LiNi0.6Co0.2Mn0.2O2 (NCM622)/SE/Li solid-state battery shows enhanced ambient-temperature electrochemical performance with an initial discharge capacity of 162.6 mAh/g and a retention capacity of 106.1 mAh/g after 200 cycles at a current density of 0.3C. While at 1C, the solid battery were still charged/discharged for 200 cycles with a retention capacity of 100.3 mAh/g. The enhanced ambient-temperature electrochemical performance is attributed to the synergistic effects of LLZO fibers and graphite coating modification for the composite SE, fibrous fast ion-conductors provide continuous ion transport channels, and graphite modification on the electrolyte surface improves the interface contact with lithium anode and restrains lithium dendrites. This design method for composite polymer solid electrolyte is expected to be popular in solid-state battery with high ambient-temperature performance.

Neurokinin1 (NK1) receptor has played a vital role in the development of tumor. However, NKP608 as a NK1 receptor antagonist whether has the effect of the resistance of colorectal cancer is still unclear. Thereby, in this study, we investigated the role of NKP608 on human colorectal cancer and explored the underlying mechanism. The cell proliferation of colorectal cancer cells was detected by cell counting kit-8 (CCK8) assay, cell migration and invasion were assessed by transwell assay, the apoptotic ratio of cells was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide stained and flow cytometry. The involvement of molecular mechanisms was examined by western blot. In this study, we found that NKP608 inhibited the proliferation, migration/invasion of HCT116 cells. In addition, NKP608 reduced expressions of Wnt-3a, β-catenin, Cyclin D1, and (vascular endothelial growth factor) VEGF while induced expression of E-Cadherin. Furthermore, flow cytometry analyzed that NKP608 induced apoptosis of HCT116 cells, consistently, western blotting detecting of apoptosis-related proteins revealed that NKP608 downregulated Bcl-2 while upregulated Bax and Active-Caspase-3. Taken together, our results demonstrated that NKP608 inhibited colorectal cancer cell proliferation, migration and invasion via suppressing the Wnt/β-catenin signaling pathway. Therefore, NKP608 might represent a promising therapeutic agent in the treatment of colorectal cancer.

The studying of synaptic plasticity, the ability of synaptic connections between neurons to be weakened or strengthened and specifically long-term potentiation (LTP) and long-term depression (LTD), is one of the most active areas of research in neuroscience. The process of synaptic connections playing a crucial role in improving cognitive processes is important to the processing of information in brain. In general, the dysfunction of synaptic plasticity was involved in a wide spectrum of central nervous system (CNS) disorders, including some neurodegenerative disorders. Thus, synaptic plasticity which is a dysfunction reported in neurodegenerative disorders may also be involved in posttraumatic stress disorder (PTSD), an anxiety and/or memory disorder developed after experiencing natural disasters, domestic violence or combat-related trauma. In this review, we mainly focus on discussing the biological function and mechanism for diagnostics and therapy of synaptic plasticity in PTSD and associated comorbidities, such as schizophrenia, depression, sleep disturbances and alcohol dependence, and further studying the molecular mechanisms of PTSD with a particular focus on the LTP/LTD, glutamatergic ligand-receptor systems, voltage-gated calcium channels (VGCCs) and brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB). The summarized function and mechanism of synaptic plasticity in PTSD and its comorbidities may help us further understand PTSD and provide insight into novel neuroplasticity modifying for diagnostics and treatment for PTSD.

Mechanosensitive ion channels convert mechanical stimuli into a flow of ions. These channels are widely distributed from bacteria to higher plants and humans, and are involved in many crucial physiological processes. Here we show that two members of the OSCA protein family in Arabidopsis thaliana, namely AtOSCA1.1 and AtOSCA3.1, belong to a new class of mechanosensitive ion channels. We solve the structure of the AtOSCA1.1 channel at 3.5-Å resolution and AtOSCA3.1 at 4.8-Å resolution by cryo-electron microscopy. OSCA channels are symmetric dimers that are mediated by cytosolic inter-subunit interactions. Strikingly, they have structural similarity to the mammalian TMEM16 family proteins. Our structural analysis accompanied with electrophysiological studies identifies the ion permeation pathway within each subunit and suggests a conformational change model for activation. Cryo-EM and electrophysiological studies of two mechanosensitive OSCA channels from Arabidopsis thalianareveal their structural similarity to osmosensitive TMEM16 channels and suggest they are gated by force from lipid in response to osmotic stress.

TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution. We also present the structure of human TRPC3 at 4.4 Å resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels.

ATP-sensitive potassium channels (KATP) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATPchannels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic KATPchannels solved by cryo-electron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 (inward-rectifying potassium channel 6.2) N-terminus participates in the coupling between the peripheral SUR1 (sulfonylurea receptor 1) subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.

High electronic conductivity and ionic conductivity are important for Na3V2(PO4)3 (NVP) to be used in Na-ion and Na-Li hybrid-ion battery. In this work, a three dimentional (3D) Na3V2(PO4)3/C (NVP/C) fiber membrane with nano carbon-coated NVP particles uniformly embedded on the surface of carbon fibers was successfully prepared by a modified electrospinning technique. The combined use of polyacrylonitrile (PAN) and polyvinylpyrrolidone (PVP) in the fiber precursor promotes the distribution of NVP particles and maintains the stability of 3D long-range conductive networks. The NVP/C fiber membrane can be used as self-standing cathodes for Na-ion battery. The discharge capacity of the NVP/C-Na battery is 110.9, 108.1, 104.6, 104.3, 95.6 and 72.4 mAh/g at the current densities of 0.1C, 0.2C, 0.5C, 1C, 5C and 10C, respectively. After the rate tests, the Na3V2(PO4)3/C fiber membrane cathode still exhibits excellent cycle stability at 0.5C, 5C and 10C with a retention discharge capacity of 102, 87.9 and 57.1mAh/g after 100 cycles. Simultaneously, this NVP/C fiber membrane can also be used as cathodes for Na-Li hybrid-ion battery, and shows good electrochemical performance in the voltage range of 2.5-4.8 V. This 3D fiber membrane electrode shows a great potential in the use of flexible Na-ion and Na-Li hybrid ion batteries.

ABSTRACTPtdIns3P signaling is critical for dynamic membrane remodeling during autophagosome formation. Proteins in the Atg18/WIPI family are PtdIns3P-binding effectors which can form complexes with proteins in the Atg2 family, and both families are essential for macroautophagy/autophagy. However, little is known about the biophysical properties and biological functions of the Atg2-Atg18/WIPI complex as a whole. Here, we demonstrate that an ortholog of yeast Atg18, mammalian WDR45/WIPI4 has a stronger binding capacity for mammalian ATG2A or ATG2B than the other 3 WIPIs. We purified the full-length Rattus norvegicusATG2B and found that it could bind to liposomes independently of PtdIns3P or WDR45. We also purified the ATG2B-WDR45 complex and then performed 3-dimensional reconstruction of the complex by single-particle electron microscopy, which revealed a club-shaped heterodimer with an approximate length of 22 nm. Furthermore, we performed cross-linking mass spectrometry and identified a set of highly cross-linked intermolecular and intramolecular lysine pairs. Finally, based on the cross-linking data followed by bioinformatics and mutagenesis analysis, we determined the conserved aromatic H/YF motif in the C terminus of ATG2A and ATG2B that is crucial for complex formation.

The motion axis of a computer numerical control (CNC) machine tool is mainly composed of a permanent-magnet synchronous motor (PMSM), ball screw, and moving table so that the motion axis can be practically modeled as a two-mass mechanical system. However, the proportional (P)–proportional integral (PI) (P–PI) control design, which is extensively used in commercial PMSM drivers, generally considers the motion axis as a single-mass mechanical system, thereby limiting the cornering motion performance of the CNC machine tool. In this study, the motion axis is modeled as a two-mass mechanical system, and the P–PI control parameters are designed and adjusted to reduce cornering errors during linear cornering motions. The two-mass equivalent system is first derived from the motion axis model, and the pole assignment method is used to design the proportional and integral control parameters such that the PMSM velocity responses have short rise times and small overshoots. Thereafter, particle swarm optimization is applied to adjust the proportional control parameter to further reduce the cornering errors using an objective function with weighted errors. The results of experiments performed with a CNC lathe show that the cornering errors of the test path could be reduced by 30%, thus validating the feasibility and performance of the P–PI control parameter design and adjustment method developed herein.

This paper proposes a novel high capacity servo press system with two servo motor inputs and high ratio force amplifier mechanism for metal forming. First, the press structure was expressed. The force amplifier was made of seven-bar mechanism which possesses quick-return character and high ratio force amplifier. The symmetric structure balanced the force in horizontal direction, and dispersed the forces on two transmission routes. In theoretical study of the new structure, kinematic and dynamic analyses were obtained by examining the geometry of the structure. The performance of press was discussed by example demonstration. Finally, the kinematic experiments and metal forming experiments were carried out on the prototype machine by using grating scale system. The measured data match the theoretical calculation well, which validates the feasibility of this new press mechanism.

Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h. MaR1 markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema and lung injury. In addition, rat lung tissue protein was isolated after intervention, and we found MaR1 improved epithelial sodium channel (ENaC), Na,K-adenosine triphosphatase (ATPase) protein expression and Na,K-ATPase activity. MaR1 down-regulated Nedd4-2 protein expression though PI3k/Akt but not though PI3k/SGK1 pathway in vivo. In primary rat alveolar type II epithelial cells stimulated with LPS, MaR1-upregulated ENaC and Na,K-ATPase protein abundance in the plasma membrane. Finally, the lipoxin A4 Receptor inhibitor (BOC-2) and PI3K inhibitor (LY294002) not only blocked MaR1’s effects on cAMP/cGMP, the expression of phosphorylated Akt and Nedd4-2, but also inhibited the effect of MaR1 on AFC in vivo. In conclusion, MaR1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. Our findings reveal a novel mechanism for pulmonary edema fluid reabsorption and MaR1 may provide a new therapy for the resolution of ALI/ARDS.

Supplemental Digital Content is available in the text.The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4Asingle nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1.68, P=0.042). In the current study, we investigated the association between the same polymorphism with OS in our Asian NSCLC-adenocarcinoma patients comprising Chinese (N=572), Malays (N=50), and Indians (N=22). KDM4ASNP-A482 genotype status was determined by Sanger sequencing. OS was calculated from the date of diagnosis to date of death or censored at the date of last follow-up. Kaplan–Meier analysis, log-rank test, and Cox regression methods were utilized to evaluate OS outcomes. KDM4ASNP-A482 had a minor allele (C) frequency of 18.8% and a major allele (A) frequency of 81.2% in our Asian NSCLC (adenocarcinoma) patients. However, the OS in our Asian NSCLC patients homozygous for KDM4ASNP-A482 was not significantly different from those who were wild type or heterozygous at this locus [CC vs. AA/AC: median OS (95% confidence interval): 40.2 (18.7–61.6) vs. 29.6 (26.9–32.3) months; P=0.858]. The results remained statistically nonsignificant even after adjustment for epidermal growth factor receptor mutational status, suggesting that KDM4ASNP-A482 does not significantly influence OS in Asian NSCLC patients.

Metal ions play critical roles in RNA structure and function. However, web servers and software packages for predicting ion effects in RNA structures are notably scarce. Furthermore, the existing web servers and software packages mainly neglect ion correlation and fluctuation effects, which are potentially important for RNAs. We here report a new web server, the MCTBI server (http://rna.physics.missouri.edu/MCTBI), for the prediction of ion effects for RNA structures. This server is based on the recently developed MCTBI, a model that can account for ion correlation and fluctuation effects for nucleic acid structures and can provide improved predictions for the effects of metal ions, especially for multivalent ions such as Mg2+effects, as shown by extensive theory-experiment test results. The MCTBI web server predicts metal ion binding fractions, the most probable bound ion distribution, the electrostatic free energy of the system, and the free energy components. The results provide mechanistic insights into the role of metal ions in RNA structure formation and folding stability, which is important for understanding RNA functions and the rational design of RNA structures.

Smith–Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by an interstitial deletion involving chromosome 17p11.2 containing the retinoic acid-induced 1 (RAI1) gene or due to mutation of RAI1. Few cases have been reported in the medical literature regarding prenatal diagnosis of SMS. We report on the prenatal diagnosis of SMS in two fetuses with increased nuchal translucency (NT), mild lateral ventriculomegaly, and congenital heart defects by whole-genome and high-resolution chromosome microarray analysis (CMA).

The body of research on acupuncture as a treatment strategy for fibromyalgia (FM) is steadily growing. This evidence map identifies, describes, and summarizes the current status of studies conducted to evaluate the efficacy of acupuncture for FM, identify research gaps, and provide information that could guide the design of future studies.