Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

Artificial intelligence for the detection of glaucoma with SD-OCT images:a systematic review and Meta-analysis

●AIM:To quantify the performance of artificial intelligence(AI)in detecting glaucoma with spectral-domain optical coherence tomography(SD-OCT)images.●METHODS:Electronic databases including PubMed,Embase,Scopus,ScienceDirect,ProQuest and Cochrane Library were searched before May 31,2023 which adopted AI for glaucoma detection with SD-OCT images.All pieces of the literature were screened and extracted by two investigators.Meta-analysis,Meta-regression,subgroup,and publication of bias were conducted by Stata16.0.The risk of bias assessment was performed in Revman5.4 using the QUADAS-2 tool.●RESULTS:Twenty studies and 51 models were selected for systematic review and Meta-analysis.The pooled sensitivity and specificity were 0.91(95%CI:0.86–0.94,I2=94.67%),0.90(95%CI:0.87–0.92,I2=89.24%).The pooled positive likelihood ratio(PLR)and negative likelihood ratio(NLR)were 8.79(95%CI:6.93–11.15,I2=89.31%)and 0.11(95%CI:0.07–0.16,I2=95.25%).The pooled diagnostic odds ratio(DOR)and area under curve(AUC)were 83.58(95%CI:47.15–148.15,I2=100%)and 0.95(95%CI:0.93–0.97).There was no threshold effect(Spearman correlation coefficient=0.22,P>0.05).●CONCLUSION:There is a high accuracy for the detection of glaucoma with AI with SD-OCT images.The application of AI-based algorithms allows together with“doctor+artificial intelligence”to improve the diagnosis of glaucoma.

Neurosyphilis complicated by anti-γ-aminobutyric acid-B receptor encephalitis: A case report

BACKGROUND Syphilis is an infectious disease caused by Treponema pallidum that can invade the central nervous system,causing encephalitis.Few cases of anti-N-methyl-Daspartate receptor autoimmune encephalitis(AE)secondary to neurosyphilis have been reported.We report a neurosyphilis patient with anti-γ-aminobutyric acid-B receptor(GABABR)AE.CASE SUMMARY A young man in his 30s who presented with acute epileptic status was admitted to a local hospital.He was diagnosed with neurosyphilis,according to serum and cerebrospinal fluid(CSF)tests for syphilis.After 14 d of antiepileptic treatment and anti-Treponema pallidum therapy with penicillin,epilepsy was controlled but serious cognitive impairment,behavioral,and serious psychiatric symptoms were observed.He was then transferred to our hospital.The Mini-Mental State Examination(MMSE)crude test results showed only 2 points.Cranial magnetic resonance imaging revealed significant cerebral atrophy and multiple fluidattenuated inversion recovery high signals in the white matter surrounding both lateral ventricles,left amygdala and bilateral thalami.Anti-GABABR antibodies were discovered in CSF(1:3.2)and serum(1:100).The patient was diagnosed with neurosyphilis complicated by anti-GABABR AE,and received methylprednisolone and penicillin.Following treatment,his mental symptoms were alleviated.Cognitive impairment was significantly improved,with a MMSE of 8 points.Serum anti-GABABR antibody titer decreased to 1:32.The patient received methylprednisolone and penicillin after discharge.Three months later,the patient’s condition was stable,but the serum anti-GABABR antibody titer was 1:100.CONCLUSION This patient with neurosyphilis combined with anti-GABABR encephalitis benefited from immunotherapy.

sgp130对糖尿病小鼠视网膜p-STAT3及VEGF-A表达的影响

目的:观察可溶性糖蛋白130(sgp130)对糖尿病(DM)小鼠视网膜p-STAT3及VEGF-A表达的影响,探讨sgp130防治糖尿病视网膜病变(DR)炎性损害的可能性。方法:小鼠45只被随机分为正常组、DM组和sgp130组。采用链脲佐菌素对DM组和sgp130组进行DM造模。正常组、DM组不做特殊干预,sgp130组在第1、5wk被给予1.5mg/mL sgp1302μL进行玻璃体腔注射治疗。10wk后处死所有小鼠,检查视网膜组织IL-6、p-STAT3、VEGF-A等蛋白的表达。结果:在第10wk时,DM组视网膜IL-6、p-STAT3、VEGF-A表达较正常组升高(均P<0.01)。sgp130组p-STAT3、VEGF-A表达水平较DM组低(均P<0.01)。结论:sgp130可以选择性拮抗IL-6反式信号传导通路,下调下游炎性因子VEGF-A的表达,可以用于干预DM引起的IL-6相关性视网膜炎性损害。

聚维酮碘对角膜上皮细胞氧化损伤的影响

目的:观察聚维酮碘对角膜上皮细胞氧化损伤的影响。方法:观察不同浓度聚维酮碘对角膜上皮细胞氧化损伤的影响,取体外培养的生长良好的角膜上皮细胞按随机数字法分为:对照组、低浓度组、中浓度组和高浓度组。观察不同消毒时间聚维酮碘对角膜上皮细胞氧化损伤的影响,取体外培养的生长良好的角膜上皮细胞按随机数字法分为:对照组、短时间组、中等时间组和长时间组。采用ELISA检测各组丙二醛(MDA)、超氧化物歧化酶(SOD)含量,采用倒置显微镜、CCK-8法检测各组细胞活性,采用流式细胞仪检测各组细胞的凋亡率。结果:聚维酮碘浓度越高,角膜上皮细胞的MDA含量越高,SOD含量越低,细胞活性越低,凋亡率越高。聚维酮碘对角膜上皮细胞的氧化损伤呈浓度依赖性,组间有差异(均P<0.01)。聚维酮碘消毒时间越长,角膜上皮细胞的MDA含量越高,SOD含量越低,细胞活性越低,凋亡率越高。聚维酮碘对角膜上皮细胞的氧化损伤呈时间依赖性,组间有差异(均P<0.01)。结论:聚维酮碘对角膜上皮细胞有氧化损伤作用,损伤呈浓度和时间依赖性。

基于内皮细胞/周细胞构建大鼠视网膜血管新生体外三维模型

目的:构建基于视网膜微血管内皮细胞(ECs)和周细胞(RMPs)的大鼠视网膜血管新生体外三维模型。方法:分离、纯化、培养大鼠视网膜微血管内皮细胞及视网膜微血管周细胞,选用第3~7代经鉴定后的细胞用于研究,采用细胞示踪剂对细胞进行染色,混合后按表面培养法接种于Matrigel,动态观察,并检测血管新生期间血管内皮生长因子A(VEGF-A)的表达。结果:培养12h时,RMPs被ECs招募,聚集成大小不等细胞团块;24h时,ECs/RMPs共同形成复杂的三维血管样条索网;48h时,网状结构出现明显崩解,仅保持少量不完整的简单网状结构;72h时,血管样条索网完全崩解。在三维模型发生过程中,VEGF-A的表达量升高;退化时,VEGF-A的表达量下降。结论:成功基于视网膜微血管全成分细胞ECs和RMPs构建了大鼠视网膜血管新生体外三维模型。

儿童肝囊型包虫病诊治进展

肝包虫病是一种全世界广泛分布的由棘球蚴感染引起的人畜共患寄生虫病.儿童处于特殊的年龄阶段,不仅是棘球蚴病的重点防治人群,也是大规模防治中的重点监测对象.儿童肝囊性包虫病症状不典型,易误诊,治疗不规范易导致复发甚至死亡,因此本文从儿童肝囊型包虫病的诊断和治疗方式作一综述.

腹腔镜治疗儿童肝囊型包虫病的研究进展

肝囊型包虫病是一种流行于畜牧业区的人兽共患性寄生虫疾病,目前该疾病仍以手术治疗为主;相对于传统开腹手术,近年来随着微创手术及精准手术理念的发展,腹腔镜手术治疗肝囊型包虫病已在临床广泛应用;目前成人应用腹腔镜技术治疗肝囊型包虫病已得到临床肯定,但儿童肝囊型包虫病由于其腹腔空间小、囊壁薄、易破裂等因素目前临床尚未普及,故本文根据国内外相关文献归纳并着重阐述腹腔镜下治疗儿童肝囊型包虫病的不同手术方式在临床中的应用情况,为儿童肝囊型包虫病的微创手术治疗提供一定的参考.

Rh-incompatible hemolytic disease of the newborn in Hefei

BACKGROUND Anti-D antibody is not the common cause of Rh-isoimmunization in Chinese neonatal jaundice.Recent change in national population policy has followed by an increase in Rh-isoimmunization related hemolytic disease of the newborn(HDN).Unfortunately,regional status of Rh-HDN is unavailable.We hypothesize that Rh-HDN in our region is most commonly due to anti-E antibody.AIM To investigate the prevalence of hemolytic disease of the newborn due to Rhisoimmunization in Hefei City.METHODS Retrospective review of data obtained from Children’s Hospital of Anhui and Hefei Blood Center between January 2017 and June 2019.Status of minor blood group antibody was studied in the corresponding mothers.RESULTS Totally 4138 newborns with HDN admitted during the study period and 116(2.8%)received blood exchange transfusion(BET).Eighteen newborns(0.43%)with proven Rh-incompatible HDN were identified.All were not the first-born baby.Thirteen mothers were RhD(+)(72%)and five were RhD(-).The distribution of Rh-related antibodies in mothers was ten anti-E(55%),five anti-D(27%),and for one anti-C,anti-c,and anti-E/c(6%)each.Thirteen(72.2%)were qualified for BET,relative risk for BET was 28.9 as compared to other types of HDN,but only 10 received due to parenteral refusal.All(100%)RhD related HDN received BET which is not significantly different from RhE related HDN(81.8%).CONCLUSION As expected,all Rh-incompatible HDN newborns were not the first-born.Contrary to the Caucasian population,anti-D induced HDN is not the most common etiology.In our region,anti-E(11/18,61%)is the most common cause of Rh-HDN.

Focal choroidal excavation: a preliminary interpretation based on clinic and review

AIM: To describe the clinical and imaging characteristics associated with focal choroidal excavation(FCE), analyze the possible complication, and interpret its probable etiopathogenesis.METHODS: Retrospective descriptive case series of 37 eyes of 32 patients with FCE. Findings of spectral-domain optical coherence tomography(SD-OCT),fluorescein angiography, indocyanine green angiography,and clinical features were analyzed. RESULTS: All patients were Chinese. Five patients(15.6%) were bilaterally involved. Patients’ ages ranged from 7 to 66 y. Refractive error ranged between +2.0 D and 11.0 D. Mean best-corrected visual acuity was 0.6(range, 0.1 to 1.2). Fundus examinations exhibited mild-moderate localized pigmentary disturbances in the corresponding area of 17 eyes. Fluorescein angiography performed in 18 patients showed varying degrees of hyperfluorescence and hypofluorescence related to a range of retinal pigment epithelium(RPE) alterations.Indocyanine green angiography performed in 7 patients showed hypofluorescence at the excavation. SD-OCT demonstrated choroidal excavation in all 37 eyes.Twenty-nine eyes showed a single lesion of FCE, and three eyes showed 2-3 separated lesions. Fifteen eyes showed separation between the photoreceptor tips andRPE consistent with nonconforming FCE. Central serous chorioretinopathy(CSC, n =1) and choroidal neovascularization(CNV, n =1) developed during follow-up.CONCLUSION: FCE could be interpreted as congenital focal choroidal dysplasia involving the RPE,choriocapillaris, and photoreceptor associated with the faulty anatomy. The abnormal anatomy of FCE was similar to anatomy at risk of CSC and CNV.

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate:A case report and review of the literature

BACKGROUND Familial hemophagocytic lymphohistiocytosis type 2(FHL2)is a rare genetic disorder presenting with fever,hepatosplenomegaly,and pancytopenia secondary to perforin-1(PRF1)mutation.FLH2 has been described in Chinese but usually presents after 1 year old.We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old.We review Chinese FHL2 patients in the literature for comparison.CASE SUMMARY A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae.She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation.No resuscitation was required at birth.She was described to be very sleepy with poor appetite since birth.She developed a fever up to 39.5°C at 7 d of life.Leukocytosis,anemia,and thrombocytopenia were detected at a local medical facility CONCLUSION A literature review identified 75 Chinese FHL2 patients,with only five presenting in the first year of life.Missense and frameshift mutations are the most common PRF1 mutations in Chinese,with 24.8%having c.1349C>T followed by 11.6%having c.65delC.The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic,at least in the presence of another pathogenic mutation such as c.1066C>T.

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis,a worldwide prevalent inflammatory disease.However,a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking.Here,we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging,by which a panel of cell type-specific signatures were elucidated.Epithelial cells were identified as the most affected cell types by aging in the gingiva.Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis,which declined during aging in epithelial cells,especially in basal cells.The decline of YAP activity during aging was confrmed in the human gingival tissues,and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects.Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases,with the ultimate goal of advancing periodontal health and promoting healthy aging.

DNA methylation clocks for estimating biological age in Chinese cohorts

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation(DNAm)at specific CpG sites.However,a systematic comparison between DNA methylation data and other omics datasets has not yet been performed.Moreover,available DNAm age predictors are based on datasets with limited ethnic representation.To address these knowledge gaps,we generated and analyzed DNA methylation datasets from two independent Chinese cohorts,revealing age-related DNAm changes.Additionally,a DNA methylation aging clock(iCAS-DNAmAge)and a group of DNAm-based multi-modal clocks for Chinese individuals were developed,with most of them demonstrating strong predictive capabilities for chronological age.The clocks were further employed to predict factors influencing aging rates.The DNAm aging clock,derived from multi-modal aging features(compositeAge-DNAmAge),exhibited a close association with multi-omics changes,lifestyles,and disease status,underscoring its robust potential for precise biological age assessment.Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace,providing the basis for evaluating aging intervention strategies.

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly understood.Herein,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries.From a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian aging.Further,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ovary.Moreover,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal outward.Our study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

Ethical concerns in aging research:perspectives of global frontline researchers

This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health span.Our global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging,a consensus regarding the feasibility of delaying aging,and multiple perspectives regarding lifespan extension.The present findings underscore a paradigm shift toward inclusive and ethically sound research,emphasizing the need for an approach that strikes a balance between basic and clinical research.In addition,this study highlighted key ethical concerns in aging research,including the effects of misleading advertising,potential inequality in access to aging interventions,and risks pertaining to the extrapolation of research findings from lower-model organisms to humans.The insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint diseases.However,the mechanism underlying human synovial aging remains poorly characterized.Here,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals.By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two subsets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs.Moreover,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue fibrosis.In particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differentially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged synovium.In human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors.These data indicate an important role of FOXO1 in the regulation of human synovial aging.Overall,our study improves our understanding of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

Degeneration Directory:a multi-omics web resource for degenerative diseases

Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).