GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was primarily expressed in the muscular and skeletal systems. With the deepening of research, it was found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interactions. Compared with other aGPCRs proteins, GPR126 has a longer N-terminal domain, which can bind to ligands one-to-one and one-to-many. Its N-terminus contains five domains, a CUB (complement C1r/C1s, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a SEA (Sperm protein, Enterokinase, and Agrin) domain, a hormone binding (HormR) domain, and a conserved GAIN domain. The GAIN domain has a self-shearing function, which is essential for the maturation, stability, transport and function of aGPCRs. Different SEA domains constitute different GPR126 isomers, which can regulate the activation and closure of downstream signaling pathways through conformational changes. GPR126 has a typical aGPCRs seven-transmembrane helical structure, which can be coupled to Gs and Gi, causing cAMP to up- or down-regulation, mediating transmembrane signaling and participating in the regulation of cell proliferation, differentiation and migration. GPR126 is activated in a tethered-stalk peptide agonism or orthosteric agonism, which is mainly manifested by self-proteolysis or conformational changes in the GAIN domain, which mediates the rapid activation or closure of downstream pathways by tethered agonists. In addition to the tethered short stem peptide activation mode, GPR126 also has another allosteric agonism or tunable agonism mode, which is specifically expressed as the GAIN domain does not have self-shearing function in the physiological state, NTF and CTF always maintain the binding state, and the NTF binds to the ligand to cause conformational changes of the receptor, which somehow transmits signals to the GAIN domain in a spatial structure. The GAIN domain can cause the 7TM domain to produce an activated or inhibited signal for signal transduction, For example, type IV collagen interacts with the CUB and PTX domains of GPR126 to activate GPR126 downstream signal transduction. GPR126 has homology of 51.6%-86.9% among different species, with 10 conserved regions between different species, which can be traced back to the oldest metazoans as well as unicellular animals.In terms of diseases, GPR126 dysfunction involves the pathological process of bone, myelin, embryo and other related diseases, and is also closely related to the occurrence and development of malignant tumors such as breast cancer and colon cancer. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still needs further research. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126, which provides ideas and references for future research on GPR126.

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

Objective To investigate the risk factors for re-fracture after percutaneous kyphoplasty (PKP) in elderly patients with osteoporotic thoracolumbar compression fractures and to construct a line graph prediction model. Methods One hundred and eighty-two elderly patients with osteoporotic thoracolumbar compression fractures treated with PKP from January 2016 to November 2019 were selected for the study‚ and the patients were continuously followed up for 3 years after surgery. Clinical data were collected from both groups; Receiver operating characteristic (ROC) curve analysis was performed on the measures; Logistic regression analysis was performed to determine the independent risk factors affecting postoperative re-fracture in PKP; the R language software 4. 0 “rms” package was used to construct a predictive model for the line graph‚ and the calibration and decision curves were used to internally validate the predictive model for the line graph and for clinical evaluation of predictive performance. Results The differences between the two groups were statistically significant (P<0. 05) in terms of bone mineral density (BMD)‚ number of injured vertebrae‚ single-segment cement injection‚ type of cement distribution‚ cement leakage‚ difference in vertebral body height before and after PKP‚ and change in posterior convexity angle. The area under the curve (AUC) for BMD‚ number of injured vertebrae‚ single-segment cement injection volume‚ cement leakage‚ pre-and post-PKP vertebral height difference‚ and posterior convexity change were 0. 772‚ 0. 732‚ 0. 722‚ 0. 801‚ and 0. 813‚ respectively‚ and the best cutoff values were -3. 1‚ 2‚ 3. 9 ml‚ 0. 4 mm‚ and 8. 7°‚ respectively. BMD‚ number of injured vertebrae‚ single-segment cement injection volume‚ cement leakage‚ pre-and post-PKP vertebral height difference‚ and posterior convexity change were independent risk factors for re-fracture after PKP in elderly patients with osteoporotic thoracolumbar compression fractures. The calibration curve of the column line graph prediction model was close to the original curve and the ideal curve with a C-index of 0. 818 (95% CI: 0. 762-0. 883)‚ and the model fit was good; the threshold value of the column line graph prediction model was >0. 22‚ which could provide a net clinical benefit‚ and the net clinical benefit was higher than the independent predictors. Conclusion BMD‚ number of injured vertebrae‚ single-segment cement injection‚ cement leakage‚ pre-and post-PKP vertebral height difference‚ and posterior convexity angle change are independent risk factors affecting the recurrent fracture after PKP in elderly patients with osteoporotic thoracolumbar compression fracture‚ and this study constructs a column line graph model to predict the recurrent fracture after PKP in elderly patients with osteoporotic thoracolumbar compression fracture as a predictor for clinical. This study provides an important reference for clinical prevention and treatment‚ and has clinical application value.

AIM:To investigate the effects of the γ-aminobutyric acid(GABAergic)neural pathway from the anterior cingulate cortex(ACC)to the nucleus accumbens(NAc)on the regulation of irritable bowel syndrome(IBS)and its underlying mechanisms in mice.METHODS:(1)A C57BL/6J mice model of IBS was established by using chronic acute combing stress(CACS).The mice were divided into a normal group and an IBS group(n=8).The presence of IBS-like symptoms was determined through behavioural tests,an intestinal motility test and abdominal withdrawal reflex scores.(2)Fluorescence gold(FG)retrograde tracing and immunohistochemistry were used to investigate the ACC-NAc GABAergic neural pathway and to examine the activation of GABA in the ACC in IBS mice(n=8).(3)A total of 1.5 μL of normal saline(NS),GABAA receptor antagonist bicuculline(BIC)or agonist isoguvacine hydrochloride(Isog)was ad-ministered via a preburied catheter into the NAc of mice in IBS and normal groups.The mice were randomly divided into three groups(n=8):NS group,BIC group and Isog group.IBS-like symptoms were assessed.(4)The mice were prein-jected with AAV2/9-mDlx-iCre-WPRE-pA in the ACC and AAV2/2Retro Plus-hSyn-DIO-hM3D(Gq)-eGFP-WPRE-pA in the NAc and subsequently divided into four groups(n=8):NS(intraperitoneal injection)+NS(NAc microinjection)group,NS+BIC group,clozapine N-oxide(CNO)+NS group and CNO+BIC group.The mice who received AAV2/2Retro-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-pA in the NAc were randomly divided into three groups(n=8):NS+NS group,NS+BIC group and CNO+NS group.Enzyme-linked immunosorbent assay(ELISA)was employed to estimate the expression levels of histamine and 5-hydroxytryptamine(5-HT)in colon tissue,and the effects of GABAergic neural pathways from ACC to NAc on IBS were studied.RESULTS:CACS induced IBS-like symptoms in mice.The results of FG retrograde tracing combined with fluorescence immunohistochemistry showed that GABA neurons of ACC could project to NAc.The injection of BIC in the NAc was found to significantly reduce anxiety-like behaviours,diarrheal symptoms and visceral hy-persensitivity in the IBS mice(P<0.05).Chemogenetic inhibition of the ACC-NAc GABAergic neurons ameliorated IBS-like symptoms in mice(P<0.05).CONCLUSION:The GABAergic pathway of ACC-NAc might be involved in the regu-lation of IBS in mice,which may be related to the release of histamine and 5-HT in colon tissue.

In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Based on the traditional Chinese medicine theories and modern medical theories,Professor XU Fu-song,a famous veteran Chinese medicine physician in China,established the theory of"inner kidney and outer kidney",emphasizing concomitant treatment of inner kidney and outer kidney,which plays an important guiding role in deepening the understanding of the pathogenesis and clinical diagnosis and treatment of male infertility.This article summarizes the relevant academic thoughts and experiences of Pro-fessor XU,with an analysis of his advanced ideas in the field of male reproduction.

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As_2S_2 or As_4S_4), orpiment(As_2S_3), and white arsenic(As_2O_3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.
Arsenic/analysis* ; Arsenicals/analysis* ; Sulfides ; Arsenic Trioxide ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/analysis* ; Biological Products