简介：AbstractBackground:Prenatal evaluation of fetal lung maturity (FLM) is a challenge, and an effective non-invasive method for prenatal assessment of FLM is needed. The study aimed to establish a normal fetal lung gestational age (GA) grading model based on deep learning (DL) algorithms, validate the effectiveness of the model, and explore the potential value of DL algorithms in assessing FLM.Methods:A total of 7013 ultrasound images obtained from 1023 normal pregnancies between 20 and 41 + 6 weeks were analyzed in this study. There were no pregnancy-related complications that affected fetal lung development, and all infants were born without neonatal respiratory diseases. The images were divided into three classes based on the gestational week: class I: 20 to 29 + 6 weeks, class II: 30 to 36 + 6 weeks, and class III: 37 to 41 + 6 weeks. There were 3323, 2142, and 1548 images in each class, respectively. First, we performed a pre-processing algorithm to remove irrelevant information from each image. Then, a convolutional neural network was designed to identify different categories of fetal lung ultrasound images. Finally, we used ten-fold cross-validation to validate the performance of our model. This new machine learning algorithm automatically extracted and classified lung ultrasound image information related to GA. This was used to establish a grading model. The performance of the grading model was assessed using accuracy, sensitivity, specificity, and receiver operating characteristic curves.Results:A normal fetal lung GA grading model was established and validated. The sensitivity of each class in the independent test set was 91.7%, 69.8%, and 86.4%, respectively. The specificity of each class in the independent test set was 76.8%, 90.0%, and 83.1%, respectively. The total accuracy was 83.8%. The area under the curve (AUC) of each class was 0.982, 0.907, and 0.960, respectively. The micro-average AUC was 0.957, and the macro-average AUC was 0.949.Conclusions:The normal fetal lung GA grading model could accurately identify ultrasound images of the fetal lung at different GAs, which can be used to identify cases of abnormal lung development due to gestational diseases and evaluate lung maturity after antenatal corticosteroid therapy. The results indicate that DL algorithms can be used as a non-invasive method to predict FLM.

简介：AbstractBackground:Age-related macular degeneration (AMD) is the leading cause of vision loss worldwide. However, the mechanisms involved in the development and progression of AMD are poorly delineated. We aimed to explore the critical genes involved in the progression of AMD.Methods:The differentially expressed genes (DEGs) in AMD retinal pigment epithelial (RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564, which were downloaded from the gene expression omnibus database. The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The hub genes were identified from these DEGs through protein-protein interaction network analyses. The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866. Following the identification of AMD-related key genes, the potential small molecule compounds targeting the key genes were predicted by PharmacoDB. Finally, a microRNA-gene interaction network was constructed.Results:Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples. These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Among the top ten hub genes, HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in the senescent ARPE-19 cells. Additionally, the drugs targeting HSP90AA1, CHEK1, and PSMA4 were identified. We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.Conclusions:Based on our findings, HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD. Targeting HSP90AA1, CHEK1, PSMA4, PSMD4, and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.

简介：AbstractBackground:Excessive exposure to fluoride can reduce intelligence. Methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1) polymorphisms have important roles in neurodevelopment. However, the association of MTHFD1 polymorphisms with children’s intelligence changes in endemic fluorosis areas has been rarely explored.Methods:A cross-sectional study was conducted in four randomly selected primary schools in Tongxu County, Henan Province, from April to May in 2017. A total of 694 children aged 8 to 12 years were included in the study with the recruitment by the cluster sampling method. Urinary fluoride (UF) and urinary creatinine were separately determined using the fluoride ion-selective electrode and creatinine assay kit. Children were classified as the high fluoride group and control group according to the median of urinary creatinine-adjusted urinary fluoride (UFCr) level. Four loci of MTHFD1 were genotyped, and the Combined Raven’s Test was used to evaluate children’s intelligence quotient (IQ). Generalized linear model and multinomial logistic regression model were performed to analyze the associations between children’s UFCr level, MTHFD1 polymorphisms, and intelligence. The general linear model was used to explore the effects of gene-environment and gene-gene interaction on intelligence.Results:In the high fluoride group, children’s IQ scores decreased by 2.502 when the UFCr level increased by 1.0 mg/L (β= –2.502, 95% confidence interval [CI]: –4.411, –0.593), and the possibility for having "excellent" intelligence decreased by 46.3% (odds ratio = 0.537, 95% CI: 0.290, 0.994). Children with the GG genotype showed increased IQ scores than those with the AA genotype of rs11627387 locus in the high fluoride group (P < 0.05). Interactions between fluoride exposure and MTHFD1 polymorphisms on intelligence were observed (Pinteraction < 0.05).Conclusion:Our findings suggest that excessive fluoride exposure may have adverse effects on children’s intelligence, and changes in children’s intelligence may be associated with the interaction between fluoride and MTHFD1 polymorphisms.

简介：AbstractBackground:Osteoarthritis (ΟΑ) is characterized by cartilage breakdown and subchondral sclerosis. Micro-fractures of the calcified tissues have been, also, detected, but their exact role has not been elucidated yet. This study was to examine the frequency of cracks during OA progression and to correlate them with the underlying cellular modifications and matrix metalloproteinase-2 (MMP-2) expression using histological/immunohistological methods.Methods:Overall, 20 patients and 3 controls (9 specimens per patient), aged 60-89 years, diagnosed with hip/knee OA were included. The development of cracks was examined in 138 sections, whereas the expression of MMP-2 was examined in 69 additional sections.Results:Based on Mankin score, three groups of OA severity were analyzed: Group I (mild) was constituted of sections with score 1-5 while Groups II (moderate) and III (severe) with score 6-7 and greater or equal to 8, respectively. Demographic characteristics did not reveal any association between the number of microdefects and age or body mass index (BMI). Cartilage micro-cracks were increased during moderate and severe OA, while bone cracks were increased during mild and severe OA. In knee OA, cartilage cracks were not correlated with Mankin score, whereas in hip OA they appeared association with severity score. Bone cracks were positively correlated with matrix apoptotic osteocytes and osteoblastic cells, but not with osteoclasts. MMP-2 immunostaining was increasing by OA severity in the osteochondral unit. Similarly, MMP-2 was expressed on the microcracks’ wall mainly in Group III.Conclusion:Our data displayed that bone cracks during primary OA stages, represent an early adaptative mechanism aiming to maintain cartilage integrity. Accumulation of bone defects and concomitant increase of apoptotic osteocytes activated an abnormal remodeling due to osteoblastic activity, in which MMP-2 played a pivotal role, leading to subchondral sclerosis promoting further osteochondral deformities.

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简介：TheEastChinaSea(ECS)isariver-dominatedepicontinentalsea,linkingtheAsiancontinenttothenorthwesternPacificviathelargeriversoriginatingfromTibetanPlateau.TherelevanthugeinfluxofriverinedetritushasdevelopeduniquesedimentarysystemsintheECSduringtheQuaternary,offeringidealterrestrialarchivesforreconstructingQuaternarypaleoenvironmentalchangesandstudyingland-seainteractions.Overall,twocharacteristicriversystemsdominatethesedimentarysystemsandsedimentsourcetosinktransportpatternsintheECS,representedbytheChangjiang(YangtzeRiver)andHuanghe(YellowRiver)forthelargeriversystemandTaiwanriversforthesmallriversystem.Giventhis,thesedimentsderivedfrombothriversystemsbeardistinctfeaturesintermsofparentrocklithology,provenanceweatheringandsedimenttransport.Previousstudiesmostlyfocusoneitherthe‘source’discriminationorthe‘sink’recordsofthesedimentarysystemintheECS,whilethesourcetosinkprocesslinkingthelandandsea,inparticularitstimescale,hasbeenpoorlyunderstood.Hereweintroduceanewly-developeddatingtechnique,the‘comminutionage’method,whichoffersaquantitativeconstraintonthetimescaleofsedimenttransferfromitsultimatesourcetothefinaldepositionalsink.Thisnovelmethodisofgreatsignificanceforimprovingourunderstandingontheearthsurfaceprocessesincludingtectonic-climatedrivenweathering,andsedimentrecyclinginrelationtolandscapeevolutionandmarineenvironmentalchanges.TheapplicationofcomminutionagemethodintheECSwillprovideimportantconstraintsonsedimentsource-to-sinkprocessandmoreevidencesfortheconstructionoflateQuaternarypaleoenvironmentalchangesundertheseuniquesedimentarysystems.更多还原

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简介：AbstractBackground:The casein kinase 2-interacting protein-1 (CKIP-1) is important in the development of osteoblasts and cardiomyocytes. However, the effects of CKIP-1 on osteoblast precursor mesenchymal stem cells (MSCs) remain unclear. This study aimed to determine whether CKIP-1 affects osteogenic differentiation in MSCs and explore the relationship of CKIP-1 and inflammation.Methods:Bone marrow MSCs of CKIP-1 wild type (WT) and knockout (KO) mice were cultivated in vitro. Cell phenotype was analyzed by flow cytometry, colony formation was detected to study the proliferative ability. Osteogenic and adipogenic induction were performed. The osteogenic ability was explored by alizarin red staining, alkaline phosphatase (ALP) staining and ALP activity detection. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to determine the mRNA expression levels of osteoblast marker genes. The adipogenic ability was detected by oil red O staining. Content of the bone was analyzed to observe the differences of bone imaging parameters including trabecular bone volume/tissue volume (BV/TV), bone surface area fraction/trabecular BV, trabecular number (Tb.N), and trabecular spacing (Tb.sp). Interleukin (IL)-1β was injected on WT mice of 2 months old and 18 months old, respectively. Difference in CKIP-1 expression was detected by RT-PCR and western blot. The relationship between CKIP-1 and inflammation was explored by RT-PCR and western blot.Results:ALP assays, alizarin red staining, and qRT-PCR showed that MSCs derived from CKIP-1 KO mice exhibited a stronger capability for osteogenesis. Micro-computed tomography detection showed that among 18-month-old mice, CKIP-1 KO mice presented significantly higher bone mass compared with WT mice (P = 0.02). No significant difference was observed in 2-month-old mice. In vivo data showed that expression of CKIP-1 was higher in the bone marrow of aging mice than in young mice (4.3-fold increase at the mRNA level, P = 0.04). Finally, the expression levels of CKIP-1 in bone marrow (3.2-fold increase at the mRNA level, P = 0.03) and cultured MSCs were up-regulated on chronic inflammatory stimulation by IL-1β.Conclusions:CKIP-1 is responsible for negative regulation of MSC osteogenesis with age-dependent effects. Increasing levels of inflammation with aging may be the primary factor responsible for higher expression levels of CKIP-1 but may not necessarily affect MSC aging.

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简介：TheTruongSonFoldBelt,locatedatthenortheasternmarginoftheIndochinaBlock,isconsideredtobetectonicallylinkedtothesubductionofthePaleotethysOceanandsubsequentcollision.SeponisoneofthemostimportantsuperlargedepositsoftheTruongSonFoldBelt.OurLA-ICP-MSzirconU-PbdatingresultsshowthatgranodioriteporphyrysamplesfromtheSepondeposithaveagesof302.1-4-2.9Ma,whichisacrucialphaseformagmatic-tectonicalactivitiesfromtheLateCarboniferoustoEarlyPermianandhasavitalinfluenceonthemineralizationofcopperandgold.ZirconfromgranodioriteporphyryyieldsεHf(t)valuesof4.32to9.64,andTDM2hasanaverageageof914Ma,suggestingthatthesourceofthegranodioriteporphyryintheregionweremainlymantlecomponentsbutunderwentmixingandcontaminationofcrustmaterials.TheCe^4+/Ce^3+valueofzirconinthegranodioriteporphyryvarysgreatlyfrom2.4to1438.29,whichshowsmagmamixingmightoccur.Consideringthecharacteristicsoftraceelementsinthezirconandthewholerockgeochemicalcharacteristicsofintrusionrocksaswellasthecharacteristicsofregionalvolcanic-sedimentaryassociation,itisindicatedthatthetectonicsettingmaybethecontinentalarcenvironment.TheSeponAu-Cudepositisderivedfromemplacementofcalc-alkalineintermediate-acidmagmawithcomingfromdeepsourcesinthesubductionprocessofthePaleotethysOcean,formingporphyryMo-Cu,skamCu-Aumineralizationandahydrothermalsedimentary-hostedAumineralizationinthewallrocks.

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简介：AbstractBackground:China and the United States (US) ranked first and third in terms of new liver cancer cases and deaths globally in 2020. Therefore, a comprehensive assessment of trends in the incidence of primary liver cancer with four major etiological factors between China and the US during the past 30 years with age-period-cohort (APC) analyses is warranted.Methods:Data were obtained from the Global Burden of Disease 2019, and period/cohort relative risks were estimated by APC modeling from 1990 to 2019.Results:In 2019, there were 211,000 new liver cancer cases in China and 28,000 in the US, accounting for 39.4% and 5.2% of global liver cancer cases, respectively. For China, the age-standardized incidence rate (ASIR) consecutively decreased before 2005 but increased slightly since then, whereas the ASIR continuously increased in the US. Among the four etiological factors of liver cancer, the fastest reduction in incidence was observed in hepatitis B virus-related liver cancer among Chinese women, and the fastest increase was in nonalcoholic steatosis hepatitis (NASH)-related liver cancer among American men. The greatest reduction in the incidence of liver cancer was observed at the age of 53 years in Chinese men (-5.2%/year) and 33 years in Chinese women (-6.6%/year), while it peaked at 58 years old in both American men and women (4.5%/year vs. 2.8%/year). Furthermore, the period risks of alcohol- and NASH-related liver cancer among Chinese men have been elevated since 2013. Simultaneously, leveled-off period risks were observed in hepatitis C viral-related liver cancer in both American men and women.Conclusions:Currently, both viral and lifestyle factors have been and will continue to play an important role in the time trends of liver cancer in both countries. More tailored and efficient preventive strategies should be designed to target both viral and lifestyle factors to prevent and control liver cancer.

简介：AIM:Tocomparetheefficacyandsafetyofcombinationofranibizumabwithphotodynamictherapy(PDT)vsranibizumabmonotherapyinthetreatmentofage-relatedmaculardegeneration(AMD).METHODS:TheCochraneCentralRegisterofControlledTrials(CENTRAL)intheCochraneLibrary,Pubmed,andEmbaseweresearched.Therewerenolanguageordatarestrictionsinthesearchfortrials.Onlyrandomizedcontrolledtrials(RCTs)wereincluded.MethodologicalqualityoftheliteratureswasevaluatedaccordingtotheJadadScore.RevMan5.2.6softwarewasusedtodothemeta-analysis.RESULTS:Sevenstudieswereincludedinoursystematicreview,amongwhichfourofthemwereincludedinquantitativeanalysis.Theresultshowsthattheranibizumabmonotherapygrouphadabettermeanbestcorrectedvisualacuity(BCVA)changevsbaselineatmonth12comparedwiththatofthecombinationtreatmentgroup,andthestatisticaldifferencewassignificant(WMD,-2.61;95%CI,-5.08to-0.13;P=0.04).However,aftertheremovalofonestudy,thedifferencebetweenthetwogroupsshowednosignificantdifference(WMD,-2.29;95%CI,-4.81to0.23;P=0.07).Meanwhile,nosignificantcentralretinalthickness(CRT)reductionwasfoundinthecombinationtreatmentgroupandtheranibizumabmonotherapygroupat12monthsfollow-up.Nevertheless,thecombinationgrouptendedtohaveagreaterreductioninCRT(WMD,-4.13μm;95%CI,-25.88to17.63,P=0.71).Theproportionofpatientsgainingmorethan3linesatmonth12intheranibizumabgroupwashigherthaninthecombinationgroupandtherewasasignificantdifference(RR,0.72;95%CI,0.54to0.95;P=0.02).Whereastherewasnosignificantdifferencefortheproportionofpatientsgainingmorethan0lineatmonth12betweenthetwogroups(RR,0.93;95%CI,0.76to1.15;P=0.52).Thegeneraltendencyshowsareductioninranibizumabretreatmentnumberinthecombinationtreatmentgroupcomparedwiththeranibizumabmonotherapygroup.Asmajoradverseevents,thedifferencesinthenumberofeyepain,endophthalmitis,hypertensionandarterialt

简介：摘要目的探析西罗莫司对于抑制肾移植后AGE诱导动脉粥样硬化产生的临床机制。方法选取我院8例接受肾移植后的动脉粥样硬化患者的第5代的主动脉平滑肌细胞（VSMC）为研究对象，将其分为四组，分别给予牛血清蛋白、西罗莫司&AGE、AGE和西罗莫司培养。对四组培养α平滑肌肌动蛋白（α-SMA）、骨桥蛋白（OPN）、增殖细胞核抗原（PCNA）的表达进行对比分析。结果经AGE培养，α-SMA表达明显减少（P＜0.05）；OPN和PCNA的表达明显升高（P＜0.05）；观察组中的OPN和PCNA明显低于AGE组，且α-SMA高于AGE组（P＜0.05）。结论西罗莫司对于抑制肾移植后AGE诱导动脉粥样硬化具有极其重要的临床作用。

简介：AbstractBackground:Human epididymis secretory protein 4 (HE4) is a new ovarian cancer biomarker. The factors influencing HE4 levels are not clear, and the reference data in China are limited. Here, we aim to evaluate the effects of menopause and age on HE4 levels and to provide a possible reference value for HE4 in healthy Chinese people.Methods:A total of 2493 healthy females aged 40 years or older were recruited from March 2013 to March 2017 with the cooperation of four medical institutions across Beijing, China. The serum levels of HE4 and cancer antigen 125 (CA125) were measured by enzyme-linked immunosorbent assay. The Wilcoxon rank-sum test of variance and a stratified analysis were used to analyze the relationships among age, menopausal status, and levels of HE4 or CA125. Confidence intervals (5%-95%) were determined for reference ranges in different populations.Results:There was a statistically significant difference in median HE4 levels between the post-menopausal (n = 2168) and premenopausal groups (n = 325) (36.46 vs. 24.04 pmol/L, Z = -14.41, P < 0.001). HE4 increased significantly with age in the post-menopausal groups (H= 408.18, P < 0.001) but not in the pre-menopausal subjects (Z=-0.43, P= 0.67). The upper 95th percentile of HE4 levels were 44.63 pmol/L for pre-menopausal women, 78.17 pmol/L for post-menopausal women, and 73.3 pmol/L for all women. In the post-menopausal population, the HE4 reference ranges were 13.15 to 47.31, 14.31 to 58.04, 17.06 to 73.51, 24.50 to 115.25, and 35.71 to 212.37 pmol/L for different age groups from forty divided by decade. The CA125 level was affected mainly by menopausal status and not age.Conclusions:Menopausal status and age were both important factors influencing the level of HE4, and age affected HE4 levels mainly in post-menopausal women. The HE4 level was higher in the post-menopausal population than in the pre-menopausal population and increased with age.

简介：ReasonforObservation:EntrancetothemostpopularoldagenursinghomeinBeijingwillneedaqueueforcheckinof100years!Ourreportersdiscoveredininterviewsandinvestigationsthattheastonishingfigurereflectedthemisallocationofmarketresourcesofold-ageservice.Afewofstarnursinghomeshavequalityservicewithcheappricesduetosupportfromthecentralgovernment.There,only2,250Yuanpermonthisneededforasingleroom,butinnursinghomesattheperi-urbanareas,thesamecost