G-protein coupled receptors (GPCRs) are an essential family of proteins on the cell membrane, widely distributed in various types of tissues and cells. Typical GPCRs are composed of characteristic 7 transmembraneα-helix domains, extracellular domain and intracellular domain. They play a key role in transmitting information inside and outside cells. These receptors can sense and respond to a variety of external signals, including odor molecules, hormones, neurotransmitters, chemokines, and so on, thereby regulating the physiological functions and metabolic activities of cells. When external signal molecules bind, these receptors undergo conformational changes, thereby activating signal transduction pathways inside cells. The most common downstream signal pathway is the activation of G proteins, but it may also activate the β-arrestin signaling pathway. This series of signal transduction processes ultimately regulates physiological processes such as cell metabolism, proliferation, and differentiation, and also plays an important role in the occurrence and development of diseases. Due to its importance in regulating cell functions and participating in the development of diseases, GPCRs have become important targets in the field of drug research and development. The mechanism of action of many drugs is achieved by intervening in the GPCR signaling pathway. As important form of function regulating, dimerization has attracted widespread attention in the research of GPCR field. In the early days, the formation of GPCR dimerization and its effect on receptor function were mainly studied by immunoprecipitation, immunofluorescence and radioligand binding experiments in overexpression systems. Nowadays, with the continuous development of biochemical and biophysical methods, more and more GPCR dimers have been identified. GPCR dimer refers to the process in which two GPCR subunits bind to each other to form a complex. The same GPCR subunits form homodimers, and different GPCR subunits form heterodimers through direct interaction. Dimerization changes the activity, affinity, internalization, localization and transport, and signal transduction characteristics of GPCR, thereby producing more complex and delicate regulation of cellular physiological processes. In recent years, the research on GPCR dimers has been continuously deepened, revealing its important role in a variety of physiological and pathological processes. In general, the structure of GPCR dimers is complex and diverse, and its formation and stability are affected by many factors, including the specificity of receptor interaction interface, the conformational changes of receptor, and the regulation of intracellular and extracellular environment. By understanding the mechanism of GPCR dimerization, we can better understand the behavior of these receptors in signal transduction and provide new ideas and opportunities for the development of novel drug targets. More and more studies have reported the dimerization of GPCR and its structure and function regulation mechanism. This article reviews the research progress on the structure and function of GPCR dimers, and summarizes some research methods and technologies, which provide a basis for understanding the discovery of GPCR dimers, dimerization methods, structure and function regulation mechanisms, and further targeting GPCR dimers. It provides a research basis for the development of polymer drugs.

Pharmacokinetics of traditional Chinese medicine(TCM)is a discipline that adopts pharmacokinetic research methods and techniques under the guidance of TCM theories to elucidate the dynamic changes in the absorption,distribution,metabolism and excretion of active ingredients,active sites,single-flavour Chinese medicinal and compounded formulas of TCM in vivo.However,the sources and components of TCM are complex,and the pharmacodynamic substances and mechanisms of action of the majority of TCM are not yet clear,so the pharmacokinetic study of TCM is later than that of chemical medicines,and is far more complex than that of chemical medicines,and its development also confronts with challenges.The pharmacokinetic study of TCM originated in the 1950s and has experienced more than 70 years of development from the initial in vivo study of a single active ingredient,to the pharmacokinetic and pharmacodynamic study of active ingredients,to the pharmacokinetic study of compound and multi-component of Chinese medicine.In recent years,with the help of advanced extraction,separation and analysis technologies,gene-editing animals and cell models,multi-omics technologies,protein purification and structure analysis technologies,and artificial intelligence,etc.,the pharmacokinetics of TCM has been substantially applied in revealing and elucidating the pharmacodynamic substances and mechanisms of action of Chinese medicines,research and development of new drugs of TCM,scientific and technological upgrading of large varieties of Chinese patent medicines,as well as guiding the rational use of medicines in clinics.Pharmacokinetic studies of TCM have made remarkable breakthroughs and significant development in theory,methodology,technology and application.In this paper,the history of the development of pharmacokinetics of TCM and the progress of cutting-edge research was reviewed,with the aim of providing ideas and references for the pharmacokinetics of TCM and related research.

Objective To investigate the independent risk factors of comprehensive complication index(CCI)≥26.2 after radical resection of colon cancer,and use these factors to establish and verify a dynamic web-based nomogram model.Methods The clinical data of colon cancer patients who underwent radical resection in the Affiliated Hospital of Jiangnan University from November 2020 to April 2022 were retrospectively collected,and divided into main cohort(November 2020 to October 2021,n=438)and validation cohort(November 2021 to April 2022,n=196).CCI scores of all patients were obtained based on CCI calculator(http://www.assessurgery.com).Univariate and multivariate logistic regression analysis were performed to identify the risk factors for CCI≥26.2,and a nomogram model was constructed.Receiver operator characteristic curve(ROC),C index and calibration curve were used to evaluate the differentiation and consistency of predictive nomogram model,and the decision curve analysis was conducted to assess the clinical benefits of the model.Internal validation of the model is performed in the validation cohort.Results A total of 438 patients were identified in present study,of which 63 cases(14.4%)had CCI≥26.2.Multivariate logistic regression analysis revealed that age≥60 years(OR=2.662,95%CI 1.341-5.285,P=0.005),low third lumbar spine skeletal muscle mass index(L3MI;OR=4.572,95%CI 2.435-8.583,P<0.001),NRS2002≥3(OR=4.281,95%CI 2.304-7.952,P<0.001),and preoperative bowel obstruction(OR=3.785,95%CI 1.971-7.268,P<0.001)were significant independent risk factors for postoperative CCI≥26.2.Based on these results,a static and web-based dynamic nomogram was established(https://jndxfsyywcwksyf.shinyapps.io/DynNomCCI/).The C-index and area under the curve(AUC)of the nomogram were 0.742 and 0.787,respectively.The calibration curve indicated a good consistency between the predicted probability and the actual probability.In the validation cohort,the nomogram also presented good discrimination(C-index=0.722,AUC=0.795)and predictive consistency.The decision curve analysis indicated the clinical benefit and application value of the nomogram prediction model.Conclusion This easy-to-use dynamic nomogram based on 4 independent risk factors can conveniently and reliably predict the probability of CCI≥26.2 after radical resection of colon cancer,which helps optimize the preoperative evaluation system,formulate precise individualized treatment strategies,and enhance recovery after surgery.

The transmission cycle of echinococcosis was established in 1853.More than 160 years have elapsed since Iceland initiated control measures to break the transmission cycle of echinococcosis in 1863.Control plans have been implemented in more than a dozen countries/territories,and lessons have been learned from failures as well as successes.In this review,we fo-cus on the failure experiences,which have also promoted successes in the control of cystic echinococcosis(caused by the para-site Echinococcus granulosus)in regions including Iceland,New Zealand,Uruguay,Wales(England),Turkana(Kenya),and Sardinia(Italy).The causes of the failures were analyzed,and the effects of health education,dog deworming,and con-trol measures for infected animal slaughter on echinococcosis control are comprehensively summarized.However,no suc-cessful experience has been reported in the control of alveolar echinococcosis(caused by the parasite Echinococcus multilocu-laris).On the basis of the biological characteristics of E.mul-tilocularis parasitization in dogs for a duration of 30 days and larvae parasitization in rodents,the fundamental measure for controlling alveolar echinococcosis is administration of monthly deworming treatments to dogs in high prevalence areas.

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

Objective: To investigate the clinical efficacy of liver transplantation in the treatment of acute liver in children with NBAS gene deficiency disease and their outcome. Methods: This retrospective study enrolled children with NBAS gene deficiency who were admitted to the Children's Hospital of Fudan University for liver transplantation from January 2013 to June 2022. The clinical data were collected and analyzed. Medical literature published before June 2022 was searched with the keywords of "NBAS" "neuroblastoma amplified sequence recurrent" "acute liver failure" "SOPH syndrome" "short stature with optic nerve atrophy" "Pelger-Huët anomaly" in PubMed, China National Knowledge Infrastructure and Wanfang database. Results: Liver transplantation was performed in 3 patients (2 males and 1 female) with NBAS deficiency. All patients presented with fever-triggered recurrent acute liver failure. The genetic detection found compound heterozygous NBAS gene pathogenic variants in them. The total episodes of acute liver failure before liver transplantation were 11, 2, and 4 respectively, and the age at liver transplantation was 3.5, 2.3, and 2.0 years respectively. During liver transplantation, patient 1 was in the convalescent phase of acute liver failure, patient 2 was in the acute phase, presenting with hepatic encephalopathy (grade V) and respiratory failure, and patient 3 was considered to be in the acute phase. After liver transplantation, patient 1 recovered normal liver function within 1 month and had no liver transplantation-related complications. Patient 2 had secondary epilepsy, intellectual disability, movement disorder, and transiently elevated transaminases. Patient 3 died of severe infection within 1 month. There was no literature in Chinese, 6 in English, 8 NBAS-deficient patients who were treated with liver transplantation. Total 11 patients presented with fever-triggered recurrent acute liver failure. Their age at liver transplantation ranged from 0.9 to 5.0 years. Postoperative complications occurred in 3 patients. Until the last visit, they were followed up for 0.7 to 14.0 years. Total 2 patients died and the 9 surviving patients did not develop acute liver failure. Conclusions: Liver transplantation is effective for the treatment of acute liver failure associated with NBAS gene disease. However, postoperative complications of liver transplantation may occur. The timing of liver transplantation still needs further research.
Child ; Male ; Humans ; Female ; Infant ; Child, Preschool ; Retrospective Studies ; Neoplasm Proteins/genetics* ; Optic Atrophy/genetics* ; Pelger-Huet Anomaly/genetics* ; Liver Failure, Acute/complications*

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
Humans ; Brain Neoplasms/pathology* ; Neoplasm Recurrence, Local/metabolism* ; Glioma/pathology* ; Neural Stem Cells/pathology* ; Oligodendrocyte Precursor Cells/pathology* ; Tumor Microenvironment

Femoral neck fracture (FNF) in the elderly patients is currently a major health challenge worldwide, with excessive consumption of medical resources, high incidence of complications as well as suboptimal outcome and prognosis. Hip joint arthroplasty (HJA) has been the mainstream treatment for FNF in the elderly, but the conventional surgical approaches and techniques are still confronted with a series of bottlenecks such as dislocation, limp and limb length discrepancy. In recent years, direct anterior approach (DAA) for HJA (DAA-HJA) has been a major new choice in the field of joint replacement, which achieves improved clinical effectiveness of HJA in the treatment of elderly FNF, due to the fact that DAA approach involves the neuromuscular interface and accords with the idea of soft tissue retention and enhanced recovery after surgery. However, there is still a lack of unified understanding of standard technique and procedure of DAA-HJA in the treatment of elderly FNF. Therefore, relevant experts from the Hip Joint Group of Chinese Orthopedics Association of Chinese Medical Association, Youth Arthrology Group of Orthopedic Committee of PLA, Orthopedic Committee of Chongqing Medical Association, Branch of Orthopedic Surgeons of Chongqing Medical Doctor Association and Sport Medicine Committee of Chongqing Medical Association were organized to formulate the " Chinese expert consensus on the technical standard of direct anterior hip arthroplasty for elderly femoral neck fracture ( version 2023)" based on evidence-based medicine. This consensus mainly proposed 13 recommendations covering indications, surgical plans, prosthesis selections, surgical techniques and processes, and postoperative management of DAA-HJA in elderly patients with FNF, aiming to promote standardized, systematic and patient-specific diagnosis and treatment to improve the functional prognosis of the patients.

Objective: To summarize the management and short-term outcomes of neonates delivered by mothers infected with SARS-CoV-2 Omicron variant. Methods: A retrospective study was performed on 158 neonates born to mothers infected with SARS-CoV-2 Omicron variant admitted to the isolation ward of Children's Hospital of Fudan University from March 15^th, 2022 to May 30^th, 2022. The postnatal infection control measures for these neonates, and their clinical characteristics and short-term outcomes were analyzed. They were divided into maternal symptomatic group and maternal asymptomatic group according to whether their mothers had SARS-CoV-2 symptoms. The clinical outcomes were compared between the 2 groups using Rank sum test and Chi-square test. Results: All neonates were under strict infection control measures at birth and after birth. Of the 158 neonates, 75 (47.5%) were male. The gestational age was (38⁺³±1⁺³) weeks and the birth weight was (3 201±463)g. Of the neonates included, ten were preterm (6.3%) and the minimum gestational age was 30⁺¹ weeks. Six neonates (3.8%) had respiratory difficulty and 4 of them were premature and required mechanical ventilation. All 158 neonates were tested negative for SARS-COV-2 nucleic acid by daily nasal swabs for the first 7 days. A total of 156 mothers (2 cases of twin pregnancy) infected with SARS-CoV-2 Omicron variant, the time from confirmed SARS-CoV-2 infection to delivery was 7 (3, 12) days. Among them, 88 cases (56.4%) showed clinical symptoms, but none needed intensive care treatment. The peripheral white blood cell count of the neonates in maternal symptomatic group was significantly higher than that in maternal symptomatic group (23.0 (18.7, 28.0) × 10⁹ vs. 19.6 (15.4, 36.6) × 10⁹/L, Z=2.44, P<0.05). Conclusions: Neonates of mothers infected with SARS-CoV-2 Omicron variant during third trimester have benign short-term outcomes, without intrauterine infection through vertical transmission. Strict infection control measures at birth and after birth can effectively protect these neonates from SARS-CoV-2 infection.
Female ; Humans ; Infant ; Infant, Newborn ; Male ; Pregnancy ; COVID-19 ; Mothers ; Pregnancy Complications, Infectious/prevention & control* ; Retrospective Studies ; SARS-CoV-2

BACKGROUND: The new emerging avian influenza A H7N9 virus, causing severe human infection with a mortality rate of around 41%. This study aims to provide a novel treatment option for the prevention and control of H7N9. METHODS: H7 hemagglutinin (HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province, China. The human monoclonal antibodies (mAbs) were generated by amplification and cloning of these HA-specific B cells. First, all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay. Then, those mAbs, exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting (HAI) and microneutralization in vitro assays. Finally, the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models. RESULTS: The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes, including H1N1 and H3N2. The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50 (TCID50) of H7N9 virus (influenza A/Nanjing/1/2013) in vitro, with neutralizing activity as low as 78 ng/mL. In addition, the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically. CONCLUSION The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.
Animals ; Antibodies, Monoclonal/therapeutic use* ; Antibodies, Neutralizing/therapeutic use* ; Antibodies, Viral ; Hemagglutinins ; Humans ; Influenza A Virus, H1N1 Subtype ; Influenza A Virus, H3N2 Subtype ; Influenza A Virus, H7N9 Subtype ; Influenza Vaccines ; Influenza in Birds ; Influenza, Human/prevention & control* ; Mice