Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration...Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.展开更多
BACKGROUND Managing critical care emergencies in children with autism spectrum disorder(ASD)presents unique challenges due to their distinct sensory sensitivities,communication difficulties,and behavioral issues.Effec...BACKGROUND Managing critical care emergencies in children with autism spectrum disorder(ASD)presents unique challenges due to their distinct sensory sensitivities,communication difficulties,and behavioral issues.Effective strategies and protocols are essential for optimal care in these high-stress situations.AIM To systematically evaluate and synthesize current evidence on best practices for managing critical care emergencies in children with ASD.The review focuses on key areas,including sensory-friendly environments,communication strategies,behavioral management,and the role of multidisciplinary approaches.METHODS A comprehensive search was conducted across major medical databases,including PubMed,Embase,and Cochrane Library,for studies published between 2000 and 2023.Studies were selected based on their relevance to critical care management in children with ASD,encompassing randomized controlled trials,observational studies,qualitative research,and case studies.Data were extracted and analyzed to identify common themes,successful strategies,and areas for improvement.RESULTS The review identified 50 studies that met the inclusion criteria.Findings highlighted the importance of creating sensory-friendly environments,utilizing effective communication strategies,and implementing individualized behavioral management plans.These findings,derived from a comprehensive review of current evidence,provide valuable insights into the best practices for managing critical care emergencies in children with ASD.Sensory modifications,such as reduced lighting and noise,visual aids,and augmentative and alternative communication tools,enhanced patient comfort and cooperation.The involvement of multidisciplinary teams was crucial in delivering holistic care.Case studies provided practical insights and underscored the need for continuous refi-nement of protocols.CONCLUSION The review emphasizes the need for a tailored approach to managing critical care emergencies for children with ASD.Sensory-friendly adjustments,effective communication,and behavioral strategies supported by a mul-tidisciplinary team are integral to improving outcomes.Despite progress,ongoing refinement of care practices and protocols is necessary.This ongoing process addresses remaining challenges and engages healthcare professionals in continuous improvement of care for children with ASD in critical settings.展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The ...Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The discovery and introduction of novel antibiotics are time-consuming and expensive.According to WHO’s report of antibacterial agents in clinical development,only 18 novel antibiotics have been approved since 2014.Therefore,novel antibiotics are critically needed.Artificial intelligence(AI)has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics.Here,we first summarized recently marketed novel antibiotics,and antibiotic candidates in clinical development.In addition,we systematically reviewed the involvement of AI in antibacterial drug development and utilization,including small molecules,antimicrobial peptides,phage therapy,essential oils,as well as resistance mechanism prediction,and antibiotic stewardship.展开更多
Objectives This study aimed to investigate the impact of foam macrophages(FMs) on the intracellular survival of Mycobacterium tuberculosis(MTB) and identify the molecular mechanisms influencing MTB survival.Methods An...Objectives This study aimed to investigate the impact of foam macrophages(FMs) on the intracellular survival of Mycobacterium tuberculosis(MTB) and identify the molecular mechanisms influencing MTB survival.Methods An in vitro FM model was established using oleic acid induction. Transcriptomic and metabolomic analyses were conducted to identify the key molecular pathways involved in FM-mediated MTB survival.Results Induced FMs effectively restricted MTB survival. Transcriptomic and metabolomic profiling revealed distinct changes in gene and metabolite expression in FMs during MTB infection compared with normal macrophages. Integrated analyses identified significant alterations in the cyclic adenosine monophosphate(cAMP) signaling pathway, indicating that its activation contributes to the FM-mediated restriction of MTB survival.Conclusions FMs inhibit MTB survival. The cAMP signaling pathway is a key contributor. These findings enhance the understanding of the role of FMs in tuberculosis progression, suggest potential targets for host-directed therapies, and offer new directions for developing diagnostic and therapeutic strategies against tuberculosis.展开更多
BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secret...BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secretion through paracrine effects but are more susceptible to hypoxic injury post-transplant,while small islets offer better viability and insulin independence.In vivo studies suggest large islets are essential for maintaining euglycemia,though smaller islets are typically preferred in transplantation for better outcomes.AIM To document the impact of islet dimension on clinical and preclinical transplant outcomes to optimize procedures.METHODS PubMed,Scopus and EMBASE platforms were searched for relevant literature up to 9 April 2024.Articles reported on either glucose-stimulated insulin-secreting(GSIS)capacity,islet viability and engraftment,or insulin independence based on the islet dimension were included.The risk of bias was measured using the Appraisal Tool for Cross-Sectional Studies.Extracted data was analyzed via a narrative synthesis.RESULTS Nineteen studies were included in the review.A total of sixteen studies reported the GSIS,of which nine documented the increased insulin secretion in the small islet,where the majority reported insulin secretion per islet equivalent(IEQ).Seven studies documented increased GSIS in large-sized islets that measure insulin secretion per cell or islet.All the articles that compared small and large islets reported poor viability and engraftment of large islets.CONCLUSION Small islets with a diameter<125μm have desired transplantation outcomes due to their better survival following isolation.Large-sized islets receive blood supply directly from arterioles in vivo to meet their higher metabolic demands.The large islet undergoes central necrosis soon after the isolation(devascularization);failing to maintain the viability and glucose stimuli leads to a decline in GSIS and the overall function of the islet.Improved preservation of large islets after islet isolation,enhances the islet yield(IEQ),thereby reducing the likelihood of failed islet isolation and potentially improves transplant outcome.展开更多
Nonalcoholic fatty liver disease(NAFLD)has emerged as the prevailing chronic liver disease in the pediatric population due to the global obesity pandemic.Evidence shows that prenatal and postnatal exposure to maternal...Nonalcoholic fatty liver disease(NAFLD)has emerged as the prevailing chronic liver disease in the pediatric population due to the global obesity pandemic.Evidence shows that prenatal and postnatal exposure to maternal abnormalities leads to a higher risk of pediatric NAFLD through persistent alterations in developmental programming.Gestational diabetes mellitus(GDM)is a hyperglycemic syndrome which has become the most prevalent complication in pregnant women.An increasing number of both epidemiologic investigations and animal model studies have validated adverse and long-term outcomes in offspring following GDM exposure in utero.Similarly,GDM is considered a crucial risk factor for pediatric NAFLD.This review aimed to summarize currently published studies concerning the inductive roles of GDM in offspring NAFLD de velopment during childhood and adolescence.Dysregulations in hepatic lipid metabolism and gut microbiota in offspring,as well as dysfunctions in the placenta are potential factors in the pathogenesis of GDM-associated pediatric NAFLD.In addition,potentially effective interventions for GDM-associated offspring NAFLD are also discussed in this review.However,most of these therapeutic approaches still require further clinical research for validation.展开更多
Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibi...Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.展开更多
Respiratory syncytial virus(RSV)is one of the most common viruses leading to lower respiratory tract infections(LRTIs)in children and elderly individuals worldwide.Although significant progress in the prevention and t...Respiratory syncytial virus(RSV)is one of the most common viruses leading to lower respiratory tract infections(LRTIs)in children and elderly individuals worldwide.Although significant progress in the prevention and treatment of RSV infection was made in 2023,with two anti-RSV vaccines and one monoclonal antibody approved by the FDA,there is still a lack of postinfection therapeutic drugs in clinical practice,especially for the pediatric population.In recent years,with an increasing understanding of the pathogenic mechanisms of RSV,drugs and drug candidates,have shown great potential for clinical application.In this review,we categorize and discuss promising anti-RSV drug candidates that have been in preclinical or clinical development over the last five years.展开更多
Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investig...Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.展开更多
This article summarizes the epidemiological characteristics and clinical manifest-ations of nonalcoholic fatty liver disease(NAFLD).The incidence of NAFLD has been increased dramatically and become the leading cause o...This article summarizes the epidemiological characteristics and clinical manifest-ations of nonalcoholic fatty liver disease(NAFLD).The incidence of NAFLD has been increased dramatically and become the leading cause of chronic liver disease worldwide.In addition to its adverse outcomes of liver fibrosis,cirrhosis,and hepatocellular carcinoma,and related complications,NAFLD has recently been found to be associated with the high-risk extrahepatic carcinomas,such as various types of lung cancer(i.e.,lung adenocarcinoma,squamous cell carcinoma,and small cell lung cancer).The presence of hepatic steatosis also predisposes lung cancer to liver metastasis,but has better response to immune checkpoint inhibi-tors.Whether other factors(i.e.,gender,smoking,etc.)are associated with NAFLD and lung cancer remains controversial.We also comment on the reciprocal rela-tionships between NAFLD and components of metabolic syndrome.Most meta-bolic syndrome components are suggested to facilitate lung cancer development via activating insulin/insulin-like growth factor axis.In addition,suppressed anti-tumor immunity and accelerated tumor progression could be attributed to the cell-specific metabolic reprogramming in condition of high-fat diet and related obesity.These findings may reveal the role of NAFLD in pulmonary carcinoma and help develop new treatment strategies for this disease.展开更多
Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabo...Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabolism.In the context of galactose metabolism,intracellular glucose levels are heightened.Galactose mutarotase(GALM)plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion ofβ-D-galactose intoα-D-galactose(α-D-G).The latter is then converted into glucose-6-phosphate,improving glucose metabolism levels.However,the involvement of GALM in AD progression is still unclear.In the present study,we found that the expression of GALM was significantly increased in AD patients and model mice.Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein(APP)and APP-cleaving enzymes including a disintegrin and metalloprotease 10(ADAM10),β-site APP-cleaving enzyme 1(BACE1),and presenilin-1(PS1).Interestingly,genetic overexpression of GALM reduced APP and Aβdeposition by increasing the maturation of ADAM10,although it did not alter the expression of BACE1 and PS1.Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation(LTP)and spatial learning and memory in AD model mice.Importantly,directα-D-G(20 mg/kg,i.p.)also inhibited Aβdeposition by increasing the maturation of ADAM10,thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice.Taken together,our results indicate that GALM shifts APP processing towardsα-cleavage,preventing Aβgeneration by increasing the level of mature ADAM10.These findings indicate that GALM may be a potential therapeutic target for AD,andα-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.展开更多
Objective This study aimed to evaluate the association between susceptibility genes and non-alcoholic fatty liver disease(NAFLD)in children with obesity.Methods We conducted a two-step case-control study.Ninety-three ...Objective This study aimed to evaluate the association between susceptibility genes and non-alcoholic fatty liver disease(NAFLD)in children with obesity.Methods We conducted a two-step case-control study.Ninety-three participants were subjected to whole-exome sequencing(exploratory set).Differential genes identified in the small sample were validated in 1,022 participants using multiplex polymerase chain reaction and high-throughput sequencing(validation set).Results In the exploratory set,14 genes from the NAFLD-associated pathways were identified.In the validation set,after adjusting for sex,age,and body mass index,ECI2 rs2326408(dominant model:OR=1.33,95%CI:1.02–1.72;additive model:OR=1.22,95%CI:1.01–1.47),C6orf201 rs659305(dominant model:OR=1.30,95%CI:1.01–1.69;additive model:OR=1.21,95%CI:1.00–1.45),CALML5rs10904516(pre-ad dominant model:OR=1.36,95%CI:1.01–1.83;adjusted dominant model:OR=1.40,95%CI:1.03–1.91;and pre-ad additive model:OR=1.26,95%CI:1.04–1.66)polymorphisms were significantly associated with NAFLD in children with obesity(P<0.05).Interaction analysis revealed that the gene-gene interaction model of CALML5 rs10904516,COX11 rs17209882,and SCD5 rs3733228 was optional(P<0.05),demonstrating a negative interaction between the three genes.Conclusion In the Chinese population,the CALML5 rs10904516,C6orf201 rs659305,and ECI2rs2326408 variants could be genetic markers for NAFLD susceptibility.展开更多
Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s hea...Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s health.The oral and gut microbiota,constituting the largest ecosystem within the human body,are important for maintaining human health and notably contribute to the healthy aging of menopausal women.Therefore,a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance.This paper presents the current understanding of the microbiome during menopause,with a particular focus on alterations in the oral and gut microbiota.Our study elucidates the complex interplay between the microbiome and sex hormone levels,explores microbial crosstalk dynamics,and investigates the associations between the microbiome and diseases linked to menopause.Additionally,this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases.Given that menopause can last for approximately 30 years,gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions,which may result in symptomatic relief from menopause and an increase in quality of life in women.展开更多
BACKGROUND Mycoplasma pneumoniae(M.pneumoniae)is considered to be one of the causative agents of community acquired pneumonia in children with general or severe course of disease.Severe M.pneumoniae pneumonia(SMPP)has...BACKGROUND Mycoplasma pneumoniae(M.pneumoniae)is considered to be one of the causative agents of community acquired pneumonia in children with general or severe course of disease.Severe M.pneumoniae pneumonia(SMPP)has emerged as a crucial global health concern due to high mortality rate in children under 5 years,potentially life-threatening complications,and growing challenges in pediatric treatment associated with rising macrolide resistance.Additionally,MPP can be complicated by other bacterial and/or viral pathogens,which may exacerbate disease severity.After the lifting of strict non-pharmaceutical interventions(NPIs)worldwide,the dramatic rise of incidence of MPP in Asia and Europe was observed.AIM To perform the comprehensive study of community acquired MPP cases registered in 2023 in Baoding Hospital,China.METHODS A total of 1160 children from 1 month to 15 years old with confirmed MPP diagnosis were enrolled in the study.The blood and respiratory samples were collected within the 24 hours after admission.The hematological parameters,biochemical markers,cytokine profiles were assessed.The respiratory samples were tested for the presence of M.pneumoniae and other 23 bacterial/viral pathogens by multiplex polymerase chain reaction(PCR).The macrolide resistance mutations(A2063G,A2064G in the 23S rRNA gene of M.pneumoniae)were determined by PCR.RESULTS Number of MPP cases has dramatically increased starting August with peak in November.SMPP and general MPP(GMPP)were identified in 264 and 896 of 1160 hospitalized children.The binary logistic regression analysis identified six[C-reactive protein(CRP),lactate dehydrogenase,procalcitonin,erythrocyte sedimentation rate,fibrin and fibrinogen degradation products(FDPs),D-dimer]and four(neutrophils,CRP,FDPs,prothrombin time)predictors of SMPP in age groups 2-5 years and 6-15 years,respectively.Children with SMPP showed significantly higher levels of cytokine interleukin(IL)-17F(2-5 years),and cytokines interferon-gamma,tumor necrosis factoralpha,IL-10(6-13 years).Concomitant viral/bacterial pathogens were determined in 24.3%and 28.0%cases of SMPP and GMPP.Among them,Streptococcus pneumoniae(S.pneumoniae)and Haemophilus influenzae(H.influenzae)were predominant.93.2%cases of MPP were associated with macrolide resistant M.pneumoniae.CONCLUSION Specific MPP epidemiological pattern associated with lifting NPIs was revealed:Increase of hospitalized cases,prevalence of S.pneumoniae and H.influenzae among concomitant pathogens,93.2%of macrolide resistant M.pneumonia.展开更多
Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear....Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.展开更多
Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained...Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.展开更多
Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription...Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.展开更多
Identification of the cell origin of human neoplasms remains a challenging but important task in cancer research.The outcomes in this area of study may allow us to design novel strategies for early cancer detection an...Identification of the cell origin of human neoplasms remains a challenging but important task in cancer research.The outcomes in this area of study may allow us to design novel strategies for early cancer detection and targeted cancer therapeutics.Skin is a great organ to study cancer stem cells because stem cells in skin have been well investigated and approaches of genetic manipulation in specific cell compartments are available to mimic clinical skin cancer in a mouse model.Recently,by using different genetic engineered mouse models,several groups have tried to discover which cell type in skin was responsible for the initiation of basal cell carcinoma,the most common type of skin cancer.These studies raised more questions but also showed more ways for future investigation.展开更多
Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial q...Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.展开更多
基金supported in part by NIH R01 NS100531,R01 NS103481NIH R21NS130241(to LD)+3 种基金Merit Review Award I01 BX002356,I01 BX003705 from the U.S.Department of Veterans AffairsIndiana Spinal Cord and Brain Injury Research Foundation(No.19919)Mari Hulman George Endowment Funds(to XMX)Indiana Spinal Cord&Brain Injury Research Fund from ISDH(to NKL and LD)。
文摘Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.
文摘BACKGROUND Managing critical care emergencies in children with autism spectrum disorder(ASD)presents unique challenges due to their distinct sensory sensitivities,communication difficulties,and behavioral issues.Effective strategies and protocols are essential for optimal care in these high-stress situations.AIM To systematically evaluate and synthesize current evidence on best practices for managing critical care emergencies in children with ASD.The review focuses on key areas,including sensory-friendly environments,communication strategies,behavioral management,and the role of multidisciplinary approaches.METHODS A comprehensive search was conducted across major medical databases,including PubMed,Embase,and Cochrane Library,for studies published between 2000 and 2023.Studies were selected based on their relevance to critical care management in children with ASD,encompassing randomized controlled trials,observational studies,qualitative research,and case studies.Data were extracted and analyzed to identify common themes,successful strategies,and areas for improvement.RESULTS The review identified 50 studies that met the inclusion criteria.Findings highlighted the importance of creating sensory-friendly environments,utilizing effective communication strategies,and implementing individualized behavioral management plans.These findings,derived from a comprehensive review of current evidence,provide valuable insights into the best practices for managing critical care emergencies in children with ASD.Sensory modifications,such as reduced lighting and noise,visual aids,and augmentative and alternative communication tools,enhanced patient comfort and cooperation.The involvement of multidisciplinary teams was crucial in delivering holistic care.Case studies provided practical insights and underscored the need for continuous refi-nement of protocols.CONCLUSION The review emphasizes the need for a tailored approach to managing critical care emergencies for children with ASD.Sensory-friendly adjustments,effective communication,and behavioral strategies supported by a mul-tidisciplinary team are integral to improving outcomes.Despite progress,ongoing refinement of care practices and protocols is necessary.This ongoing process addresses remaining challenges and engages healthcare professionals in continuous improvement of care for children with ASD in critical settings.
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金supported by the National Natural Science Foundation of China(32300157)the Shanghai Municipal Science and Technology Commission(19411964900)+1 种基金the Major Research and Development Project of Innovative Drugs,Ministry of Science and Technology of China(2017ZX09304005)the Wellcome Trust.
文摘Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The discovery and introduction of novel antibiotics are time-consuming and expensive.According to WHO’s report of antibacterial agents in clinical development,only 18 novel antibiotics have been approved since 2014.Therefore,novel antibiotics are critically needed.Artificial intelligence(AI)has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics.Here,we first summarized recently marketed novel antibiotics,and antibiotic candidates in clinical development.In addition,we systematically reviewed the involvement of AI in antibacterial drug development and utilization,including small molecules,antimicrobial peptides,phage therapy,essential oils,as well as resistance mechanism prediction,and antibiotic stewardship.
基金supported by the Beijing Natural Science Foundation (grant number: 7232060)National Key Research and Development Program of China (grant number: 2023YFC2307301)Top Level Public Health Technical Personnel Training Plan (grant number: LJRC-03-09)。
文摘Objectives This study aimed to investigate the impact of foam macrophages(FMs) on the intracellular survival of Mycobacterium tuberculosis(MTB) and identify the molecular mechanisms influencing MTB survival.Methods An in vitro FM model was established using oleic acid induction. Transcriptomic and metabolomic analyses were conducted to identify the key molecular pathways involved in FM-mediated MTB survival.Results Induced FMs effectively restricted MTB survival. Transcriptomic and metabolomic profiling revealed distinct changes in gene and metabolite expression in FMs during MTB infection compared with normal macrophages. Integrated analyses identified significant alterations in the cyclic adenosine monophosphate(cAMP) signaling pathway, indicating that its activation contributes to the FM-mediated restriction of MTB survival.Conclusions FMs inhibit MTB survival. The cAMP signaling pathway is a key contributor. These findings enhance the understanding of the role of FMs in tuberculosis progression, suggest potential targets for host-directed therapies, and offer new directions for developing diagnostic and therapeutic strategies against tuberculosis.
文摘BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secretion through paracrine effects but are more susceptible to hypoxic injury post-transplant,while small islets offer better viability and insulin independence.In vivo studies suggest large islets are essential for maintaining euglycemia,though smaller islets are typically preferred in transplantation for better outcomes.AIM To document the impact of islet dimension on clinical and preclinical transplant outcomes to optimize procedures.METHODS PubMed,Scopus and EMBASE platforms were searched for relevant literature up to 9 April 2024.Articles reported on either glucose-stimulated insulin-secreting(GSIS)capacity,islet viability and engraftment,or insulin independence based on the islet dimension were included.The risk of bias was measured using the Appraisal Tool for Cross-Sectional Studies.Extracted data was analyzed via a narrative synthesis.RESULTS Nineteen studies were included in the review.A total of sixteen studies reported the GSIS,of which nine documented the increased insulin secretion in the small islet,where the majority reported insulin secretion per islet equivalent(IEQ).Seven studies documented increased GSIS in large-sized islets that measure insulin secretion per cell or islet.All the articles that compared small and large islets reported poor viability and engraftment of large islets.CONCLUSION Small islets with a diameter<125μm have desired transplantation outcomes due to their better survival following isolation.Large-sized islets receive blood supply directly from arterioles in vivo to meet their higher metabolic demands.The large islet undergoes central necrosis soon after the isolation(devascularization);failing to maintain the viability and glucose stimuli leads to a decline in GSIS and the overall function of the islet.Improved preservation of large islets after islet isolation,enhances the islet yield(IEQ),thereby reducing the likelihood of failed islet isolation and potentially improves transplant outcome.
基金supported by grants from the National Nat-ural Science Foundation of China(82170593)National Key R&D Program of China(2021YFC2700802)Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)。
文摘Nonalcoholic fatty liver disease(NAFLD)has emerged as the prevailing chronic liver disease in the pediatric population due to the global obesity pandemic.Evidence shows that prenatal and postnatal exposure to maternal abnormalities leads to a higher risk of pediatric NAFLD through persistent alterations in developmental programming.Gestational diabetes mellitus(GDM)is a hyperglycemic syndrome which has become the most prevalent complication in pregnant women.An increasing number of both epidemiologic investigations and animal model studies have validated adverse and long-term outcomes in offspring following GDM exposure in utero.Similarly,GDM is considered a crucial risk factor for pediatric NAFLD.This review aimed to summarize currently published studies concerning the inductive roles of GDM in offspring NAFLD de velopment during childhood and adolescence.Dysregulations in hepatic lipid metabolism and gut microbiota in offspring,as well as dysfunctions in the placenta are potential factors in the pathogenesis of GDM-associated pediatric NAFLD.In addition,potentially effective interventions for GDM-associated offspring NAFLD are also discussed in this review.However,most of these therapeutic approaches still require further clinical research for validation.
基金supported by grants from the National Key R&D Program of China(2019YFA0801603)the Guangdong High Level Innovation Research Institute(2021B0909050004)+2 种基金the National Natural Science Foundation of China(32330044,32170951,82201615,and 82101393)the Natural Science Foundation of Jiangsu Province(BK20201255 and BK20210008)the Fundamental Research Funds for the Central Universities(021414380533).
文摘Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
基金funded by the Beijing Natural Science Foundation(5242007,L222076,L246011)the High-level Public Health Technical Talents Project by the Beijing Municipal Commission of Health(Key discipline personnel-02-05)+1 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-12M-5-026,2022-I2M-CoV19-006)the Reform and Development of the Beijing Municipal Health Commission,and the Respiratory Research Project of the National Clinical Research Center for Respiratory Diseases(HXZX-202106).
文摘Respiratory syncytial virus(RSV)is one of the most common viruses leading to lower respiratory tract infections(LRTIs)in children and elderly individuals worldwide.Although significant progress in the prevention and treatment of RSV infection was made in 2023,with two anti-RSV vaccines and one monoclonal antibody approved by the FDA,there is still a lack of postinfection therapeutic drugs in clinical practice,especially for the pediatric population.In recent years,with an increasing understanding of the pathogenic mechanisms of RSV,drugs and drug candidates,have shown great potential for clinical application.In this review,we categorize and discuss promising anti-RSV drug candidates that have been in preclinical or clinical development over the last five years.
基金supported by grants from the National Key R&D Program of China(2022YFA1305600)National Natural Science Foundation of China(82100950,82470602,and 82470600)Natural Science Foundation of Shanghai(23ZR1452600)。
文摘Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.
基金Supported by National Science and Technology Major Project of China,No.2023ZD0508700National Natural Science Foundation of China,No.81470859and Program of Taizhou Science and Technology Grant,No.24ywb33.
文摘This article summarizes the epidemiological characteristics and clinical manifest-ations of nonalcoholic fatty liver disease(NAFLD).The incidence of NAFLD has been increased dramatically and become the leading cause of chronic liver disease worldwide.In addition to its adverse outcomes of liver fibrosis,cirrhosis,and hepatocellular carcinoma,and related complications,NAFLD has recently been found to be associated with the high-risk extrahepatic carcinomas,such as various types of lung cancer(i.e.,lung adenocarcinoma,squamous cell carcinoma,and small cell lung cancer).The presence of hepatic steatosis also predisposes lung cancer to liver metastasis,but has better response to immune checkpoint inhibi-tors.Whether other factors(i.e.,gender,smoking,etc.)are associated with NAFLD and lung cancer remains controversial.We also comment on the reciprocal rela-tionships between NAFLD and components of metabolic syndrome.Most meta-bolic syndrome components are suggested to facilitate lung cancer development via activating insulin/insulin-like growth factor axis.In addition,suppressed anti-tumor immunity and accelerated tumor progression could be attributed to the cell-specific metabolic reprogramming in condition of high-fat diet and related obesity.These findings may reveal the role of NAFLD in pulmonary carcinoma and help develop new treatment strategies for this disease.
基金supported by grants from the National Natural Science Foundation of China(32371030,82371194,and 82071395)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-LZX0010 and CSTB2024NSCQ-MSX0269)the CQMU Program for Youth Innovation in Future Medicine(W0044).
文摘Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabolism.In the context of galactose metabolism,intracellular glucose levels are heightened.Galactose mutarotase(GALM)plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion ofβ-D-galactose intoα-D-galactose(α-D-G).The latter is then converted into glucose-6-phosphate,improving glucose metabolism levels.However,the involvement of GALM in AD progression is still unclear.In the present study,we found that the expression of GALM was significantly increased in AD patients and model mice.Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein(APP)and APP-cleaving enzymes including a disintegrin and metalloprotease 10(ADAM10),β-site APP-cleaving enzyme 1(BACE1),and presenilin-1(PS1).Interestingly,genetic overexpression of GALM reduced APP and Aβdeposition by increasing the maturation of ADAM10,although it did not alter the expression of BACE1 and PS1.Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation(LTP)and spatial learning and memory in AD model mice.Importantly,directα-D-G(20 mg/kg,i.p.)also inhibited Aβdeposition by increasing the maturation of ADAM10,thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice.Taken together,our results indicate that GALM shifts APP processing towardsα-cleavage,preventing Aβgeneration by increasing the level of mature ADAM10.These findings indicate that GALM may be a potential therapeutic target for AD,andα-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
基金supported by the Hunan Provincial Natural Science Foundation of China(2024JJ6257)Hunan Children’s Hospital Cultivation Project Fund(2024GZPY04)+2 种基金Opening fundings of Hunan Provincial Key Laboratory of Pediatric Orthopedics(2023TP1019)Science and Technology Project of Furong Laboratory(2023SK2111)Hunan Provincial Clinical Medical Research Center for pediatric Limb Deformities(2019SK4006)。
文摘Objective This study aimed to evaluate the association between susceptibility genes and non-alcoholic fatty liver disease(NAFLD)in children with obesity.Methods We conducted a two-step case-control study.Ninety-three participants were subjected to whole-exome sequencing(exploratory set).Differential genes identified in the small sample were validated in 1,022 participants using multiplex polymerase chain reaction and high-throughput sequencing(validation set).Results In the exploratory set,14 genes from the NAFLD-associated pathways were identified.In the validation set,after adjusting for sex,age,and body mass index,ECI2 rs2326408(dominant model:OR=1.33,95%CI:1.02–1.72;additive model:OR=1.22,95%CI:1.01–1.47),C6orf201 rs659305(dominant model:OR=1.30,95%CI:1.01–1.69;additive model:OR=1.21,95%CI:1.00–1.45),CALML5rs10904516(pre-ad dominant model:OR=1.36,95%CI:1.01–1.83;adjusted dominant model:OR=1.40,95%CI:1.03–1.91;and pre-ad additive model:OR=1.26,95%CI:1.04–1.66)polymorphisms were significantly associated with NAFLD in children with obesity(P<0.05).Interaction analysis revealed that the gene-gene interaction model of CALML5 rs10904516,COX11 rs17209882,and SCD5 rs3733228 was optional(P<0.05),demonstrating a negative interaction between the three genes.Conclusion In the Chinese population,the CALML5 rs10904516,C6orf201 rs659305,and ECI2rs2326408 variants could be genetic markers for NAFLD susceptibility.
基金supported by Science&Technology Fundamental Resources Investigation Program(2022FY100800)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-12M-1-023/2023-12M-C&T-B-005)+1 种基金Funding for Reform and Development of Beijing Municipal Health Commissionthe National High Level Hospital Clinical Research Funding(2022-PUMCH-B-094).
文摘Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s health.The oral and gut microbiota,constituting the largest ecosystem within the human body,are important for maintaining human health and notably contribute to the healthy aging of menopausal women.Therefore,a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance.This paper presents the current understanding of the microbiome during menopause,with a particular focus on alterations in the oral and gut microbiota.Our study elucidates the complex interplay between the microbiome and sex hormone levels,explores microbial crosstalk dynamics,and investigates the associations between the microbiome and diseases linked to menopause.Additionally,this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases.Given that menopause can last for approximately 30 years,gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions,which may result in symptomatic relief from menopause and an increase in quality of life in women.
基金Supported by Baoding Science and Technology Plan Project,No.2272P011Hebei Province Scientific Research Project,No.20241734Hebei Natural Science Foundation Project,No.H2024104011.
文摘BACKGROUND Mycoplasma pneumoniae(M.pneumoniae)is considered to be one of the causative agents of community acquired pneumonia in children with general or severe course of disease.Severe M.pneumoniae pneumonia(SMPP)has emerged as a crucial global health concern due to high mortality rate in children under 5 years,potentially life-threatening complications,and growing challenges in pediatric treatment associated with rising macrolide resistance.Additionally,MPP can be complicated by other bacterial and/or viral pathogens,which may exacerbate disease severity.After the lifting of strict non-pharmaceutical interventions(NPIs)worldwide,the dramatic rise of incidence of MPP in Asia and Europe was observed.AIM To perform the comprehensive study of community acquired MPP cases registered in 2023 in Baoding Hospital,China.METHODS A total of 1160 children from 1 month to 15 years old with confirmed MPP diagnosis were enrolled in the study.The blood and respiratory samples were collected within the 24 hours after admission.The hematological parameters,biochemical markers,cytokine profiles were assessed.The respiratory samples were tested for the presence of M.pneumoniae and other 23 bacterial/viral pathogens by multiplex polymerase chain reaction(PCR).The macrolide resistance mutations(A2063G,A2064G in the 23S rRNA gene of M.pneumoniae)were determined by PCR.RESULTS Number of MPP cases has dramatically increased starting August with peak in November.SMPP and general MPP(GMPP)were identified in 264 and 896 of 1160 hospitalized children.The binary logistic regression analysis identified six[C-reactive protein(CRP),lactate dehydrogenase,procalcitonin,erythrocyte sedimentation rate,fibrin and fibrinogen degradation products(FDPs),D-dimer]and four(neutrophils,CRP,FDPs,prothrombin time)predictors of SMPP in age groups 2-5 years and 6-15 years,respectively.Children with SMPP showed significantly higher levels of cytokine interleukin(IL)-17F(2-5 years),and cytokines interferon-gamma,tumor necrosis factoralpha,IL-10(6-13 years).Concomitant viral/bacterial pathogens were determined in 24.3%and 28.0%cases of SMPP and GMPP.Among them,Streptococcus pneumoniae(S.pneumoniae)and Haemophilus influenzae(H.influenzae)were predominant.93.2%cases of MPP were associated with macrolide resistant M.pneumoniae.CONCLUSION Specific MPP epidemiological pattern associated with lifting NPIs was revealed:Increase of hospitalized cases,prevalence of S.pneumoniae and H.influenzae among concomitant pathogens,93.2%of macrolide resistant M.pneumonia.
基金supported by the National Natural Science Foundation of China(82002432 to J.W.,82302068 to M.Z.,and 32300568 to T.W.)the Natural Science Foundation of Shandong Province(ZR2024MH159 to Y.Z.,ZR2020QH179 to J.W.,ZR2022QH057 to M.Z.,and ZR2021QH005 to T.W.)the China Postdoctoral Science Foundation(2024M752006 to S.M.)。
文摘Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.
基金funded by the following grants and contracts:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38020400 to S.W.)the National Natural Science Foundation of China(32325013 to S.W.,32271186 to J.T.,31900408 to M.Z.)+5 种基金the CAS Project for Young Scientists in Basic Research(YSBR-077 to S.W.)Shanghai Science and Technology Commission Excellent Academic Leaders Program(22XD1424700 to S.W.)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066 to L.J.and J.W.)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to L.J.and S.W.)the National Science and Technology Basic Research Project(2015FY111700 to L.J.)the 111 Project(B13016 to L.J.).
文摘Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.
基金supported by the Zhejiang Provincial Nat ural Science Foundation of China(Nos.LZ23C060002 and LZ24H160004)the National Natural Science Foundation of China(Nos.32270746,82203247,82203415,82272637,82204429,and 82073332)+2 种基金the National Key Research and Development Program of China(No.2022YFE0107800)the Medical Interdisciplinary Innovation Program 2024,Zhejiang University School of Medicine,and the Fundamental Research Funds for the Central Universities(No.K20220228)It is add-itionally supported by the National Institute of Health(No.R01-CA200992-03).
文摘Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
文摘Identification of the cell origin of human neoplasms remains a challenging but important task in cancer research.The outcomes in this area of study may allow us to design novel strategies for early cancer detection and targeted cancer therapeutics.Skin is a great organ to study cancer stem cells because stem cells in skin have been well investigated and approaches of genetic manipulation in specific cell compartments are available to mimic clinical skin cancer in a mouse model.Recently,by using different genetic engineered mouse models,several groups have tried to discover which cell type in skin was responsible for the initiation of basal cell carcinoma,the most common type of skin cancer.These studies raised more questions but also showed more ways for future investigation.
基金supported by the National Natural Science Foundation of China,Nos.82001211(to KY),82101241(to SW),and 82125032(to FL).
文摘Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.
