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
BACKGROUND In multisystem inflammatory syndrome in children(MIS-C)with coronavirus disease 2019,there was paucity of data from low-income and middle-income countries on cardiovascular involvement and its longitudinal ...BACKGROUND In multisystem inflammatory syndrome in children(MIS-C)with coronavirus disease 2019,there was paucity of data from low-income and middle-income countries on cardiovascular involvement and its longitudinal outcomes.We planned to estimate the pattern of cardiovascular involvement among children with MIS-C and its mid-term outcomes.AIM To determine association between cardiovascular abnormalities and clinical and laboratory parameters.To study the time-line for resolution of various abnormalities.METHODS In this prospective study done in a tertiary care hospital,270 were recruited from June 2020 to January 2022.Baseline demographic data and clinical presentation were recorded.Laboratory parameters and echocardiography were done at admission.Follow-up was done at 2 weeks,3 months,6 months and 1 year after diagnosis.Descriptive statistics were used for parametric and non-parametric data.Risk factors were identified by multivariate regression analysis.RESULTS The 211(78.2%)had cardiac involvement and 102 needed intensive care unit(ICU)admission.Cardiovascular abnormalities observed were shock 123(45.6%),coronary dilatation 28(10.4%),coronary aneurysm 77(28.5%),left ventricular(LV)dysfunction 78(29.3%),mitral regurgitation(MR)77(28.5%)and pericardial effusion 98(36.3%).Coronary artery aneurysm/dilatation during follow-up at 2 weeks and 1 year were 25.7%and 0.9%respectively.Multivariate regression analysis revealed breathlessness[odds ratio(OR)=3.91,95%CI:1.25-12.21,P=0.019]and hi-flow nasal cannula(HFNC)support(OR=8.5,95%CI:1.06-68.38,P=0.044)as predictors of cardiovascular involvement.Higher mean age(OR=1.16,95%CI:1.02-1.32,P=0.026),breathlessness(OR=4.99,95%CI:2.05-12.20,P<0.001),gallop(OR=4.45,95%CI:0.41-2.52,P=0.016),MR(OR=3.61,95%CI:1.53-8.53,P=0.004)and invasive ventilation(OR=4.01,95%CI:1.28-12.58,P=0.017)were predictive of LV dysfunction.Altered sensorium(OR=4.96,95%CI:2.23-11.02,P<0.001),headache(OR=6.61,95%CI:1.46-29.92,P=0.014),HFNC(OR=7.03,95%CI:2.04-24.29,P=0.002),non-rebreathing mask usage(OR=21.13,95%CI:9.00-49.61,P<0.001)and invasive ventilation(OR=5.64,95%CI:1.42-22.45,P=0.014)were risk factors for shock.Anemia was a risk factor for coronary involvement(OR=3.09,95%CI:1.79-5.34,P<0.001).CONCLUSION Significant number of children with MIS-C had cardiovascular involvement contributing to higher ICU management.Although shock resolved quickly,resolution of ventricular function and coronary abnormalities were slower,and hence warrants a structured long-term follow-up protocol.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
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
BACKGROUND Thiocolchicoside(TCC),a muscle relaxant with anti-inflammatory properties,is often used alongside nonsteroidal anti-inflammatory drugs(NSAIDs)to treat musculoskeletal pain.This synergistic approach leverage...BACKGROUND Thiocolchicoside(TCC),a muscle relaxant with anti-inflammatory properties,is often used alongside nonsteroidal anti-inflammatory drugs(NSAIDs)to treat musculoskeletal pain.This synergistic approach leverages the complementary mechanisms of action,providing more effective relief for conditions such as arthritis,muscle spasms,and soft tissue injuries.AIM To evaluate the comparative efficacy of the combination therapy of TCC and NSAIDs vs NSAID monotherapy in pain management.METHODS A systematic search of PubMed and Google Scholar databases through October 2024 was performed to evaluate the effectiveness of combined TCC and NSAID therapy vs NSAIDs alone.A retrospective analysis of electronic medical records from India spanning 3 years(2020-2023)examined treatment patterns and focused on clinical outcomes including pain relief,functional improvement,and adverse effects.Key metrics for assessment included visual analog scale scores and hand-to-floor distance,with secondary outcomes assessing patient satisfaction and adverse event(AE)incidence.RESULTS A systematic literature search revealed seven studies,involving 1137 subjects,aligning with the eligibility criteria from a total of 833 hits.Combination therapy using parenteral TCC with NSAIDs significantly reduced pain intensity[standardised mean difference(SMD):-1.33,P<0.001]and enhanced functional improvement(SMD:-1.08,P<0.001)compared to NSAIDs alone.Patients on combination therapy are 6.7 times more likely to experience over 30%pain relief and 5.2 times more likely to achieve over 50%pain relief.Post surgery pain reduction and patient satisfaction were notably higher in the combination group[odds ratio(OR)=10.14,P<0.001].There were no significant differences in mild/moderate AE rates between the groups(OR=1.30,P=0.378).CONCLUSION Evidence indicates that multimodal therapy,including parenteral TCC with NSAIDs,provides quicker and effective pain relief,reduces muscle spasms,and improves hand-to-floor distance compared to using NSAIDs or TCC alone.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
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
BACKGROUND Diabetes has become a widespread metabolic disease affecting multiple organs.Among diabetic complications,cardiovascular complications are the main cause of patient morbidity and mortality.Diabetic cardiomy...BACKGROUND Diabetes has become a widespread metabolic disease affecting multiple organs.Among diabetic complications,cardiovascular complications are the main cause of patient morbidity and mortality.Diabetic cardiomyopathy is a diabetes-specific cardiomyopathy in the absence of other cardiovascular disease and occurs more frequently in type 1 diabetes(T1D)than in type 2 diabetes.Previous studies on diabetic cardiomyopathy have predominantly focused on the effects of diabetes on left ventricular(LV)dysfunction,while studies of right ventricular(RV)dysfunction have been sparse but are gaining attention.Although T1D accounts for only 5%-10%of the total diabetic population,diabetic cardiomyopathy is a major cause of morbidity and mortality in children with life-long,long-term complications.AIM To evaluate longitudinal RV and LV functional changes in female transgenic OVE26,T1D mice and wild-type FVB mice over a 30-week period.METHODS RV and LV structure and function were evaluated by transthoracic echocardiography.RV systolic pressure was measured by a transducer-tipped pressure catheter.Sirius-red staining was used to quantify collagen and fibrosis,wheat germ agglutinin staining was utilized to measure cardiomyocyte size,and quantitative real-time polymerase chain reaction and Western blotting were used to quantify miRNA expression and protein abundance,respectively.RESULTS RV systolic function,measured by tricuspid valve annular plane systolic excursion and RV systolic velocity,was similar between control and T1D mice,but LV systolic function decreased in T1D mice at 30 weeks of age.RV diastolic dysfunction in T1D mice significantly increased by 18 weeks and progressed until 30 weeks,while LV diastolic dysfunction trended towards abnormal at 12 weeks,significantly increased by 18 weeks,and continued to progress by 30 weeks.Furthermore,RV diastolic dysfunction was accompanied by RV cardiac fibrosis and hypertrophy in T1D mice,occurring later than that in the LV.Pulmonary arterial hypertension developed in T1D mice,evidenced by increased pulmonary acceleration time to pulmonary ejection time ratio and increased RV peak systolic pressure at 30 weeks.These results suggest the development of early LV diastolic dysfunction followed by LV systolic dysfunction and RV diastolic dysfunction at 30 weeks in T1D mice.CONCLUSION RV diastolic dysfunction develops later than LV dysfunction in OVE26 T1D mice.Mild pulmonary arterial hypertension appear at later stages of T1D and could contribute to RV systolic impairment and remodeling.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
Human adenovirus type 108(HAdV-108)has been detected in multiple countries,including China,and is associated with severe acute respiratory infection(ARI)in children,with reported fatalities.However,studies on HAdV-108...Human adenovirus type 108(HAdV-108)has been detected in multiple countries,including China,and is associated with severe acute respiratory infection(ARI)in children,with reported fatalities.However,studies on HAdV-108 remain limited.This study aimed to investigate the clinical and genetic characteristics of HAdV-108 in ARI children in China.From 2014 to 2024,6720 respiratory samples were collected from hospitalized children with ARI at ten hospitals across northern and southern China,of which 505(7.51%)tested positive for HAdV.The whole-genome and three major capsid protein genes were amplified and sequenced for bioinformatics analysis,which revealed that among 317 HAdV-isolated samples,21(6.62%)were identified as HAdV-108,ranking third after HAdV-114 and HAdV-7.Clinical analysis of HAdV-108-positive cases showed that the main manifestations were cough and fever.Seven children had gastrointestinal symptoms,and two children without underlying diseases were diagnosed with severe pneumonia.Phylogenetic analysis of wholegenome sequences revealed distinct predominant epidemic branches between domestic and international strains,with one strain obtained in this study forming an independent branch.Hexon protein exhibited the fastest evolution rate,lowest identity,and greatest amino acid variability,while fiber protein displayed the slowest evolution rate,highest identity,and greatest conservation and stability.Compared with the earliest reported HAdV-108 strain,three amino acid deletions were identified in the RGD loop region of penton base protein,resulting in potential structural change.Recombination analysis identified five distinct recombination patterns.In vitro experiments demonstrated that HAdV-108 had proliferation capacity comparable to other species C adenoviruses.In summary,HAdV-108 has persistently circulated in China,causing severe ARIs and concurrent gastrointestinal manifestations.Cluster3 was the predominant epidemic branch in China.HAdV-108 exhibited significant intratype genetic variation,with random and diverse recombination events.展开更多
AIM： To examine the role of Fibrinogen-like protein 2 （fgl2）/fibroleukin in tumor development. Fgl2 has been reported to play a vital role in the pathogenesis in MHV-3 （mouse hepatitis virus） induced fulminant an...AIM： To examine the role of Fibrinogen-like protein 2 （fgl2）/fibroleukin in tumor development. Fgl2 has been reported to play a vital role in the pathogenesis in MHV-3 （mouse hepatitis virus） induced fulminant and severe hepatitis, spontaneous abortion, allo- and xenograft rejection by mediating ＂immune coagulation＂.METHODS： Tumor tissues from 133 patients with six types of distinct cancers and the animal tumor tissues from human hepatocellular carcinoma （HCC） model on nude mice （established from high metastasis HCC cell line MHCC97LM6） were obtained. RESULTS： HfgI2 was detected in tumor tissues from 127 out of 133 patients as well as tumor tissues collected from human HCC nude mice. Hfgl2 was highly expressed both in cancer cells and interstitial inflammatory cells including macrophages, NK cells, and CD8^＋ T lymphocytes and vascular endothelial cells. HfgI2 mRNA was localized in cells that expressed hfgI2 protein. Fibrin （nogen） colocalization with hfgl2 expression was determined by dual immunohistochemical staining. In vitro, IL-2 and IFN-γ, increased hfgl2 mRNA by 10-100 folds and protein expression in both THP-1 and HUVEC cell lines. One-stage clotting assays demonstrated that THP-1 and HUVEC cells expressing hfgl2 had increased procoagulant activity following cytokines stimulation. CONCLUSION： The hfgI2 contributes to the hypercoagulability in cancer and may induce tumor angiogenesis and metastasis via cytokine induction.展开更多
OBJECTIVE： To discuss the mechanism of Yiqiyang- yin recipe in rats with adriamycin （ADR）-induced ne- phropathyo METHODS： We randomly divided 30 Sprague-Daw- ley rats into 5 groups： control, model, glucocorti- co...OBJECTIVE： To discuss the mechanism of Yiqiyang- yin recipe in rats with adriamycin （ADR）-induced ne- phropathyo METHODS： We randomly divided 30 Sprague-Daw- ley rats into 5 groups： control, model, glucocorti- coid, Chinese herb, and Chinese herb plus glucocor- ticoid groups. The 24-h urine volume was collected on days 7, 14, 21, and 28 after ADR injection, and all rats were killed on day 28. We measured the 24-h levels of urinary protein, serum cholesterol, and se- rum triglycerides, and renal function of all rats by using routine biochemical methods. Pathological changes in the rat kidneys were observed under light and electron microscopes. Heparanase （HPA） mRNA expression levels were measured using re-al-time fluorescence-quantitative polymerase chain reaction. Urine levels of HPA in all groups were measured using enzyme-linked immunosor- bent assay. The expression of nephrin was detected by immunohistochemical staining and quantitative- ly analyzed using Motic image analysis 3.2 software. RESULTS： The levels of urinary protein and serum triglycerides and cholesterol in rats with ADR-in- duced nephropathy increased on day 14. The se- rum albumin levels simultaneously decreased. All the changes reached the peak on day 28. Examina- tion under the light microscope showed inflamma- tory cells and slight fibroplasia in the renal intersti- tium in the model group, but fewer inflammatory cells were observed in the intervention groups than those in the model group. Examination under the electron microscope showed extensive fusion of foot processes in ADR rats. HPA mRNA expres- sion was higher in the model group than that in the control group. The HPA mRNA levels in the in- tervention groups, especially in the Chinese herb group, and Chinese herb plus glucocorticoid group were significantly lower than the level in the model group. The HPA expression levels correlated signifi- cantly with the proteinuria level. No significant dif- ference was found in the HPA level in urine be- tween the intervention groups and the model group, whereas the model group had a higher uri- nary HPA level than the control group. Nephrin mRNA expression levels in the model group were higher than those in the control group. Nephrin mRNA expression levels were significantly lower in the intervention groups than that in the model group, especially the Chinese herb plus glucocorti- cold group. Compared with the control group, themodel group showed increased nephrin expression in the kidney. Nephrin levels in the other groups, es- pecially in the Chinese herb plus glucocorticoid group, were significantly lower than that in the model group. The nephrin levels in the kidney were negatively correlated with the proteinuria level. CONCLUSION： Yiqiyangyin recipe could attenuate foot process injury particularly in combination with a steroid reduce the development of proteinuria possibly by inhibition of HPA in the kidney, and reg- ulate the expression of nephrin in rats with ADR-in- duced nephropathy. Our study showed that treat- ment with Yiqiyangyin recipe plus glucocorticoid was better than a singular intervention, and we ex- plored the pharmacological mechanism of this combination by biochemical and molecular biologi- cal analysis to provide a basis for clinical applica- tion.展开更多
AIM:To evaluate the safety and effectiveness of intravenous ketamine-midazolam sedation during pediatric endoscopy in the Arab world.METHODS:A retrospective cohort study of all pediatric endoscopic procedures performe...AIM:To evaluate the safety and effectiveness of intravenous ketamine-midazolam sedation during pediatric endoscopy in the Arab world.METHODS:A retrospective cohort study of all pediatric endoscopic procedures performed between 2002-2008 at the shared endoscopy suite of King Abdullah University Hospital,Jordan University of Science & Technology,Jordan was conducted.All children were > 1 year old and weighed > 10 kg with American Society of Anesthesiologists class 1 or 2.Analysis was performed in terms of sedation-related complications(desaturation,respiratory distress,apnea,bradycar-dia,cardiac arrest,emergence reactions),adequacy of sedation,need for sedation reversal,or failure to complete the procedure.RESULTS:A total of 301 patients(including 160 males) with a mean age of 9.26 years(range,1-18 years) were included.All were premedicated with atropine;and 79.4%(239/301) had effective and uneventful sedation.And 248(82.4%) of the 301 patients received a mean dose of 0.16 mg/kg(range,0.07-0.39) midazolam and 1.06 mg/kg(range,0.31-2.67) ketamine,respectively within the recommended dosage guidelines.Recommended maximum midazolam dose was exceeded in 17.6% patients [34 female(F):19 male(M),P = 0.003] and ketamine in 2.7%(3 M:5 F).Maximum midazolam dose was more likely to be exceeded than ketamine(P < 0.001).Desaturation occurred in 37(12.3%) patients,and was reversible by supplemental oxygen in all except 4 who continue to have desaturation despite supplemental oxygen.Four(1.3%) patients had respiratory distress and 6(2%) were difficult to sedate and required a 3rd sedative;12(4%) required reversal and 7(2.3%) failed to complete the procedure.None developed apnea,bradycardia,arrest,or emergence reactions.CONCLUSION:Ketamine-midazolam sedation appears safe and effective for diagnostic pediatric gastrointestinal endoscopy in the Arab world for children aged > 1 year and weighing > 10 kg without co-morbidities.展开更多
Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveil...Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.展开更多
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.
文摘BACKGROUND In multisystem inflammatory syndrome in children(MIS-C)with coronavirus disease 2019,there was paucity of data from low-income and middle-income countries on cardiovascular involvement and its longitudinal outcomes.We planned to estimate the pattern of cardiovascular involvement among children with MIS-C and its mid-term outcomes.AIM To determine association between cardiovascular abnormalities and clinical and laboratory parameters.To study the time-line for resolution of various abnormalities.METHODS In this prospective study done in a tertiary care hospital,270 were recruited from June 2020 to January 2022.Baseline demographic data and clinical presentation were recorded.Laboratory parameters and echocardiography were done at admission.Follow-up was done at 2 weeks,3 months,6 months and 1 year after diagnosis.Descriptive statistics were used for parametric and non-parametric data.Risk factors were identified by multivariate regression analysis.RESULTS The 211(78.2%)had cardiac involvement and 102 needed intensive care unit(ICU)admission.Cardiovascular abnormalities observed were shock 123(45.6%),coronary dilatation 28(10.4%),coronary aneurysm 77(28.5%),left ventricular(LV)dysfunction 78(29.3%),mitral regurgitation(MR)77(28.5%)and pericardial effusion 98(36.3%).Coronary artery aneurysm/dilatation during follow-up at 2 weeks and 1 year were 25.7%and 0.9%respectively.Multivariate regression analysis revealed breathlessness[odds ratio(OR)=3.91,95%CI:1.25-12.21,P=0.019]and hi-flow nasal cannula(HFNC)support(OR=8.5,95%CI:1.06-68.38,P=0.044)as predictors of cardiovascular involvement.Higher mean age(OR=1.16,95%CI:1.02-1.32,P=0.026),breathlessness(OR=4.99,95%CI:2.05-12.20,P<0.001),gallop(OR=4.45,95%CI:0.41-2.52,P=0.016),MR(OR=3.61,95%CI:1.53-8.53,P=0.004)and invasive ventilation(OR=4.01,95%CI:1.28-12.58,P=0.017)were predictive of LV dysfunction.Altered sensorium(OR=4.96,95%CI:2.23-11.02,P<0.001),headache(OR=6.61,95%CI:1.46-29.92,P=0.014),HFNC(OR=7.03,95%CI:2.04-24.29,P=0.002),non-rebreathing mask usage(OR=21.13,95%CI:9.00-49.61,P<0.001)and invasive ventilation(OR=5.64,95%CI:1.42-22.45,P=0.014)were risk factors for shock.Anemia was a risk factor for coronary involvement(OR=3.09,95%CI:1.79-5.34,P<0.001).CONCLUSION Significant number of children with MIS-C had cardiovascular involvement contributing to higher ICU management.Although shock resolved quickly,resolution of ventricular function and coronary abnormalities were slower,and hence warrants a structured long-term follow-up protocol.
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 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.
文摘BACKGROUND Thiocolchicoside(TCC),a muscle relaxant with anti-inflammatory properties,is often used alongside nonsteroidal anti-inflammatory drugs(NSAIDs)to treat musculoskeletal pain.This synergistic approach leverages the complementary mechanisms of action,providing more effective relief for conditions such as arthritis,muscle spasms,and soft tissue injuries.AIM To evaluate the comparative efficacy of the combination therapy of TCC and NSAIDs vs NSAID monotherapy in pain management.METHODS A systematic search of PubMed and Google Scholar databases through October 2024 was performed to evaluate the effectiveness of combined TCC and NSAID therapy vs NSAIDs alone.A retrospective analysis of electronic medical records from India spanning 3 years(2020-2023)examined treatment patterns and focused on clinical outcomes including pain relief,functional improvement,and adverse effects.Key metrics for assessment included visual analog scale scores and hand-to-floor distance,with secondary outcomes assessing patient satisfaction and adverse event(AE)incidence.RESULTS A systematic literature search revealed seven studies,involving 1137 subjects,aligning with the eligibility criteria from a total of 833 hits.Combination therapy using parenteral TCC with NSAIDs significantly reduced pain intensity[standardised mean difference(SMD):-1.33,P<0.001]and enhanced functional improvement(SMD:-1.08,P<0.001)compared to NSAIDs alone.Patients on combination therapy are 6.7 times more likely to experience over 30%pain relief and 5.2 times more likely to achieve over 50%pain relief.Post surgery pain reduction and patient satisfaction were notably higher in the combination group[odds ratio(OR)=10.14,P<0.001].There were no significant differences in mild/moderate AE rates between the groups(OR=1.30,P=0.378).CONCLUSION Evidence indicates that multimodal therapy,including parenteral TCC with NSAIDs,provides quicker and effective pain relief,reduces muscle spasms,and improves hand-to-floor distance compared to using NSAIDs or TCC alone.
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 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Supported by the University of Louisville-China Pediatric Research Exchange Program(Cai L,Tan Y,Huang J,and Keller B,no salary support)University of Louisville Executive Vice President for Research and Innovation Internal Grant(Huang J and Cai L)University of Louisville School of Medicine Basic Grant(Huang J and Cai L).
文摘BACKGROUND Diabetes has become a widespread metabolic disease affecting multiple organs.Among diabetic complications,cardiovascular complications are the main cause of patient morbidity and mortality.Diabetic cardiomyopathy is a diabetes-specific cardiomyopathy in the absence of other cardiovascular disease and occurs more frequently in type 1 diabetes(T1D)than in type 2 diabetes.Previous studies on diabetic cardiomyopathy have predominantly focused on the effects of diabetes on left ventricular(LV)dysfunction,while studies of right ventricular(RV)dysfunction have been sparse but are gaining attention.Although T1D accounts for only 5%-10%of the total diabetic population,diabetic cardiomyopathy is a major cause of morbidity and mortality in children with life-long,long-term complications.AIM To evaluate longitudinal RV and LV functional changes in female transgenic OVE26,T1D mice and wild-type FVB mice over a 30-week period.METHODS RV and LV structure and function were evaluated by transthoracic echocardiography.RV systolic pressure was measured by a transducer-tipped pressure catheter.Sirius-red staining was used to quantify collagen and fibrosis,wheat germ agglutinin staining was utilized to measure cardiomyocyte size,and quantitative real-time polymerase chain reaction and Western blotting were used to quantify miRNA expression and protein abundance,respectively.RESULTS RV systolic function,measured by tricuspid valve annular plane systolic excursion and RV systolic velocity,was similar between control and T1D mice,but LV systolic function decreased in T1D mice at 30 weeks of age.RV diastolic dysfunction in T1D mice significantly increased by 18 weeks and progressed until 30 weeks,while LV diastolic dysfunction trended towards abnormal at 12 weeks,significantly increased by 18 weeks,and continued to progress by 30 weeks.Furthermore,RV diastolic dysfunction was accompanied by RV cardiac fibrosis and hypertrophy in T1D mice,occurring later than that in the LV.Pulmonary arterial hypertension developed in T1D mice,evidenced by increased pulmonary acceleration time to pulmonary ejection time ratio and increased RV peak systolic pressure at 30 weeks.These results suggest the development of early LV diastolic dysfunction followed by LV systolic dysfunction and RV diastolic dysfunction at 30 weeks in T1D mice.CONCLUSION RV diastolic dysfunction develops later than LV dysfunction in OVE26 T1D mice.Mild pulmonary arterial hypertension appear at later stages of T1D and could contribute to RV systolic impairment and remodeling.
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 National Key Research and Development Program of China(2023YFC2306001)National Natural Science Foundation of China(No.32470141)+1 种基金the Beijing Research Center for Respiratory Infectious Diseases Project(BJRID2025-008)CAMS Innovation Fund for Medical Sciences(CIFMS,NO.2019-I2M-5–026,2022-I2M-CoV19-006).
文摘Human adenovirus type 108(HAdV-108)has been detected in multiple countries,including China,and is associated with severe acute respiratory infection(ARI)in children,with reported fatalities.However,studies on HAdV-108 remain limited.This study aimed to investigate the clinical and genetic characteristics of HAdV-108 in ARI children in China.From 2014 to 2024,6720 respiratory samples were collected from hospitalized children with ARI at ten hospitals across northern and southern China,of which 505(7.51%)tested positive for HAdV.The whole-genome and three major capsid protein genes were amplified and sequenced for bioinformatics analysis,which revealed that among 317 HAdV-isolated samples,21(6.62%)were identified as HAdV-108,ranking third after HAdV-114 and HAdV-7.Clinical analysis of HAdV-108-positive cases showed that the main manifestations were cough and fever.Seven children had gastrointestinal symptoms,and two children without underlying diseases were diagnosed with severe pneumonia.Phylogenetic analysis of wholegenome sequences revealed distinct predominant epidemic branches between domestic and international strains,with one strain obtained in this study forming an independent branch.Hexon protein exhibited the fastest evolution rate,lowest identity,and greatest amino acid variability,while fiber protein displayed the slowest evolution rate,highest identity,and greatest conservation and stability.Compared with the earliest reported HAdV-108 strain,three amino acid deletions were identified in the RGD loop region of penton base protein,resulting in potential structural change.Recombination analysis identified five distinct recombination patterns.In vitro experiments demonstrated that HAdV-108 had proliferation capacity comparable to other species C adenoviruses.In summary,HAdV-108 has persistently circulated in China,causing severe ARIs and concurrent gastrointestinal manifestations.Cluster3 was the predominant epidemic branch in China.HAdV-108 exhibited significant intratype genetic variation,with random and diverse recombination events.
基金The Natural Science Foundation of China,NSFC (30672380,30571643)National Key Basic Research Program of China (2007CB512900,2005CB522901,2005CB522507)11th Five-Year Plan Key Project (2006BAI05A07)
文摘AIM： To examine the role of Fibrinogen-like protein 2 （fgl2）/fibroleukin in tumor development. Fgl2 has been reported to play a vital role in the pathogenesis in MHV-3 （mouse hepatitis virus） induced fulminant and severe hepatitis, spontaneous abortion, allo- and xenograft rejection by mediating ＂immune coagulation＂.METHODS： Tumor tissues from 133 patients with six types of distinct cancers and the animal tumor tissues from human hepatocellular carcinoma （HCC） model on nude mice （established from high metastasis HCC cell line MHCC97LM6） were obtained. RESULTS： HfgI2 was detected in tumor tissues from 127 out of 133 patients as well as tumor tissues collected from human HCC nude mice. Hfgl2 was highly expressed both in cancer cells and interstitial inflammatory cells including macrophages, NK cells, and CD8^＋ T lymphocytes and vascular endothelial cells. HfgI2 mRNA was localized in cells that expressed hfgI2 protein. Fibrin （nogen） colocalization with hfgl2 expression was determined by dual immunohistochemical staining. In vitro, IL-2 and IFN-γ, increased hfgl2 mRNA by 10-100 folds and protein expression in both THP-1 and HUVEC cell lines. One-stage clotting assays demonstrated that THP-1 and HUVEC cells expressing hfgl2 had increased procoagulant activity following cytokines stimulation. CONCLUSION： The hfgI2 contributes to the hypercoagulability in cancer and may induce tumor angiogenesis and metastasis via cytokine induction.
基金Supported by Shanghai Health Bureau Research Grant Program(Young Funding Program,No.2011QL031B)State Key Clinical Department of TCM pediatrics
文摘OBJECTIVE： To discuss the mechanism of Yiqiyang- yin recipe in rats with adriamycin （ADR）-induced ne- phropathyo METHODS： We randomly divided 30 Sprague-Daw- ley rats into 5 groups： control, model, glucocorti- coid, Chinese herb, and Chinese herb plus glucocor- ticoid groups. The 24-h urine volume was collected on days 7, 14, 21, and 28 after ADR injection, and all rats were killed on day 28. We measured the 24-h levels of urinary protein, serum cholesterol, and se- rum triglycerides, and renal function of all rats by using routine biochemical methods. Pathological changes in the rat kidneys were observed under light and electron microscopes. Heparanase （HPA） mRNA expression levels were measured using re-al-time fluorescence-quantitative polymerase chain reaction. Urine levels of HPA in all groups were measured using enzyme-linked immunosor- bent assay. The expression of nephrin was detected by immunohistochemical staining and quantitative- ly analyzed using Motic image analysis 3.2 software. RESULTS： The levels of urinary protein and serum triglycerides and cholesterol in rats with ADR-in- duced nephropathy increased on day 14. The se- rum albumin levels simultaneously decreased. All the changes reached the peak on day 28. Examina- tion under the light microscope showed inflamma- tory cells and slight fibroplasia in the renal intersti- tium in the model group, but fewer inflammatory cells were observed in the intervention groups than those in the model group. Examination under the electron microscope showed extensive fusion of foot processes in ADR rats. HPA mRNA expres- sion was higher in the model group than that in the control group. The HPA mRNA levels in the in- tervention groups, especially in the Chinese herb group, and Chinese herb plus glucocorticoid group were significantly lower than the level in the model group. The HPA expression levels correlated signifi- cantly with the proteinuria level. No significant dif- ference was found in the HPA level in urine be- tween the intervention groups and the model group, whereas the model group had a higher uri- nary HPA level than the control group. Nephrin mRNA expression levels in the model group were higher than those in the control group. Nephrin mRNA expression levels were significantly lower in the intervention groups than that in the model group, especially the Chinese herb plus glucocorti- cold group. Compared with the control group, themodel group showed increased nephrin expression in the kidney. Nephrin levels in the other groups, es- pecially in the Chinese herb plus glucocorticoid group, were significantly lower than that in the model group. The nephrin levels in the kidney were negatively correlated with the proteinuria level. CONCLUSION： Yiqiyangyin recipe could attenuate foot process injury particularly in combination with a steroid reduce the development of proteinuria possibly by inhibition of HPA in the kidney, and reg- ulate the expression of nephrin in rats with ADR-in- duced nephropathy. Our study showed that treat- ment with Yiqiyangyin recipe plus glucocorticoid was better than a singular intervention, and we ex- plored the pharmacological mechanism of this combination by biochemical and molecular biologi- cal analysis to provide a basis for clinical applica- tion.
文摘AIM:To evaluate the safety and effectiveness of intravenous ketamine-midazolam sedation during pediatric endoscopy in the Arab world.METHODS:A retrospective cohort study of all pediatric endoscopic procedures performed between 2002-2008 at the shared endoscopy suite of King Abdullah University Hospital,Jordan University of Science & Technology,Jordan was conducted.All children were > 1 year old and weighed > 10 kg with American Society of Anesthesiologists class 1 or 2.Analysis was performed in terms of sedation-related complications(desaturation,respiratory distress,apnea,bradycar-dia,cardiac arrest,emergence reactions),adequacy of sedation,need for sedation reversal,or failure to complete the procedure.RESULTS:A total of 301 patients(including 160 males) with a mean age of 9.26 years(range,1-18 years) were included.All were premedicated with atropine;and 79.4%(239/301) had effective and uneventful sedation.And 248(82.4%) of the 301 patients received a mean dose of 0.16 mg/kg(range,0.07-0.39) midazolam and 1.06 mg/kg(range,0.31-2.67) ketamine,respectively within the recommended dosage guidelines.Recommended maximum midazolam dose was exceeded in 17.6% patients [34 female(F):19 male(M),P = 0.003] and ketamine in 2.7%(3 M:5 F).Maximum midazolam dose was more likely to be exceeded than ketamine(P < 0.001).Desaturation occurred in 37(12.3%) patients,and was reversible by supplemental oxygen in all except 4 who continue to have desaturation despite supplemental oxygen.Four(1.3%) patients had respiratory distress and 6(2%) were difficult to sedate and required a 3rd sedative;12(4%) required reversal and 7(2.3%) failed to complete the procedure.None developed apnea,bradycardia,arrest,or emergence reactions.CONCLUSION:Ketamine-midazolam sedation appears safe and effective for diagnostic pediatric gastrointestinal endoscopy in the Arab world for children aged > 1 year and weighing > 10 kg without co-morbidities.
基金supported by Scientific Research Project of Beijing Children's Hospital(2012MS08)Beijing Municipal Science and Technology Project(D131100005313014)
文摘Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.
