简介：AbstractObjective:Observational studies have reported malnutrition and vitamin deficiency in patients with schizophrenia (SZ), which can lead to serious metabolic syndromes and decrease anti-psychiatric drug outcomes. Whereas, vitamin intake along with psychiatric medication can enhance the medication outcomes. However, it is still unknown if SZ induces vitamin deficiency. Herein, we conduct theMendelianrandomizationanalysis to explore the causal relationship between schizophrenia and vitamins supplementation.Methods:We retrieved the genome-wide summary statistical data for schizophrenia from recent SZ GWAS data (43,175 cases and 65,166 controls) and vitamins supplementation GWAS data from Neale’s GWAS datasets (more than 337,000 samples from the European population) and performed a two-sampleMendelianrandomizationanalysis to determine the causal association of SZ with vitamin supplementation, in addition, we conduct the sensitivity analysis to obtain reliable results and remove confounding bias.Results:SZ have causal relationships with vitamins A, B, C, D, and E (SZ/vitamin A: β = 0.002, se= 0.001, 95% confidence interval (CI): 0.001 to 0.004, P= 1.41E-05, heterogeneity P= 0.4486; SZ/vitamin B: β= 0.004, se= 0.001, 95% CI: 0.002-0.005, P= 7.0E-05, heterogeneity P= 0.2217; SZ/vitamin C: β= 0.004, se= 0.001, 95% CI: 0.002-0.007, P= 0.001, heterogeneity P= 0.1349; SZ/vitamin D: β= 0.003, se= 0.001, 95% CI: 0.002-0.005, P= 0.001, heterogeneity P= 0.433; SZ/vitamin E: β= 0.003, se= 0.001, 95% CI: 0.002-0.005, P= 5.0E-05, heterogeneity P= 0.1382).Conclusion:Our findings suggest that vitamin levels and supplementation should be carefully controlled in patients with SZ, which in turn may enhance the therapeutic effects of antipsychotic drug treatments.

简介：AbstractBackground:Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The presentstudyaimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termedMendelianrandomization(MR).Methods:The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism.Results:The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids.Conclusion:Taken together, the results of the presentstudysuggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.

简介：AbstractBackground:High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sampleMendelianrandomization(MR) approach.Methods:For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays.Results:Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = －5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = －8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = －1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ2 = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ2 = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min－1·1.73 m－2, χ2 = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ2 = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ2 = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ2 = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.Conclusions:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

简介：AbstractObjective:The impact of dairy fat on inflammatory bowel disease remained inconclusive. We aimed to compare the effects of whole-milk and skimmed-milk consumption on the risk of inflammatory bowel disease using aMendelianrandomizationanalysis.Methods:We conducted a genome-wide associationstudyof the preference for whole versus skimmed milk using data for 20,200 whole-milk consumers and 67,847 skimmed-milk consumers from the UK Biobank. The lead single nucleotide polymorphisms in the associated loci were identified at the genome-wide significance level, and were further employed as instrumental variables for whole-milk preference. We conducted a two-sampleMendelianrandomizationanalysis with whole-milk preference as the exposure and inflammatory bowel disease as the outcome. The pleiotropic effects and heterogeneity of the instrumental variables were estimated usingMendelianrandomization-Egger regression and Cochran Q test, respectively. Thisstudywas conducted using the UKB resources under the application "53536" . The UK Biobank was approved by the North West Multi-center Research Ethics Committee, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland.Results:The genome-wide associationstudyidentified five lead nucleotide polymorphisms associated with whole-milk preference.Mendelianrandomizationindicated that whole-milk preference significantly decreased the risk of inflammatory bowel disease (β=-1.735, P=0.048). Of the two subtypes, whole-milk preference was associated with a lower risk of Crohn disease (β=-2.549, P=0.032), but had no significant effect on the risk of ulcerative colitis (β=-1.002, P=0.44).Conclusion:Consumption of whole-milk fat may protect against Crohn disease, compared with skimmed milk. This conclusion was based on causal inference in a cohortstudy, and further validation in randomized controlled trials is warranted.

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简介：AbstractTargeted sequencing and whole exome sequencing are the most common approaches used to detect causative variants inMendeliandiseases; however, using DNA-based sequencing techniques, the current molecular diagnostic yield is at best 50%. In recent years, RNA sequencing has been shown to be able to provide a genetic diagnosis in patients whose conditions were previously unable to be identified by DNA analysis. RNA sequencing can reveal expression outliers, aberrant splicing events, allele-specific expression, and new pathogenic variants, and as such can complement and expand on the traditional genomic methods used to diagnoseMendeliandiseases. Therefore, RNA sequencing is expected to become a routine method for genetic diagnosis in the future. This article reviews the applications and challenges of RNA sequencing in the genetic diagnosis ofMendeliandiseases.

简介：BackgroundAlcoholdehydrogenase(ADH)andaldehydedehydrogenase2(ALDH2)arethekeyenzymesforalcoholmetabolism.SeveralgeneticstudieshaveinvestigatedtheassociationbetweenADHandALDH2geneticpolymorphismsandserumlipidprofile(SLP),however,theresultswereinconsistent.MethodsFourteenarticlesinvolving27,917participantswereincludedinthismeta-analysis.Weightedmeandifference(WMD)and95%confidenceintervals(CIs)werepresentedusingrandomeffectsmodel.PublicationbiaswasevaluatedbyfunnelplotandBegg’stest.Inaddition,tofurtherexploretheheterogeneity,subgroupanalysiswereperformed.ResultsOverall,therewasnoassociationbetweenADHgeneticpolymorphismsandSLPwithnoregardfordrinkingstatus.However,comparedwithALDH2wildhomozygousgenotype,ALDH2mutantgenotypeswereassociatedwithsignificantdecreaseinserumhighdensitylipoproteincholesterol(HDLC)(WMD-1.80mg/dL,95%CI-1.88to-1.72,P<0.001)andtotalcholesterol(TC)levels(WMD-1.10mg/dL,95%CI-1.59to-0.62,P<0.001),andsignificantincreaseinserumlowdensitylipoproteincholesterol(LDL-C)level(WMD0.30mg/dL,95%CI0.18to0.43,P<0.001).Althoughtherewasnosignificantdifferenceinserumtriglyceridelevelintheoverallpopulation,subgroupanalysisrevealedthatcomparedwithALDH2*1wildhomozygote,ALDH2*2alleledisplayedasignificantdifferenceinserumtriglyceridelevelbetweenthefemaleandmale(female:WMD1.69mg/dl,95%CI1.08to2.30,P<0.001;male:WMD-6.42mg/dL,95%CI-12.15to-0.68,P=0.028).ConclusionADHgeneticpolymorphismhasnoassociationwithSLP,regardlessofsexcategoryanddrinkingstatus.ALDH2geneticpolymorphismhasslightassociationwithHDL-C,LDL-CandTClevelsandsex-specificassociationwithserumtriglyceridelevel.WhetherornottheassociationbetweenADH2geneticpolymorphismsandSLPisresultedfromalcoholconsumptionneedsfurtherinvestigation.

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简介：and to make use of this or not according to need. Hanfeizi also had the same attitude .He advocated his ideas about the,one should know the dividing line of the encouragement and punishment and use these them wisely. The emperor should learn to get rid of the opponents and use law to rule the country so that all the citizen would know what they should do and what they should not. III Their different result ,In The Prince Niccolo Machiavelli presents a view of governing

简介：话题呈现“研学旅行”(studytrip)是一种以组织中小学生集体旅行的方式走出校园,通过参观工厂、访农村、赏山水、进教育基地等形式亲近社会与自然而开展的研究性学习与旅行体验相结合的校外教育活动。

简介：and would try every means to reach ones aims.3.On the image of emperor.In The Prince Niccolo Machiavelli presents a view of governing 摘要,one should know the dividing line of the encouragement and punishment and use these them wisely. The emperor should learn to get rid of the opponents and use law to rule the country so that all the citizen would know what they should do and what they should not.,state that is drastically different from that of humanists of his time. Machiavelli believes the ruling Prince should be the sole authority determining every aspect of the state and put in effect a policy

简介：one should know the dividing line of the encouragement and punishment and use these them wisely. The emperor should learn to get rid of the opponents and use law to rule the country so that all the citizen would know what they should do and what they should not.,Machiavelli further went on to question the loyalty of the citizens and advised the Prince that "...because men a wretched creatures who would not keep their word to you,In The Prince Niccolo Machiavelli presents a view of governing

简介：ThisresearchexaminesEnglishteachingandlearningatMadrasasinBangladesh.ThisstudyemploysaqualitativeapproachandattemptstoidentifytheproblemsintheprogramsthatdebarfromachievingexpectedEnglishlearningoutcome.Weconductedasemi-structuredinterviewwithinterviewees,includingrelevantMadrasateachers,trainers,traineeteachers,Educationofficers,andEnglishresourcepersonsatNationalAcademyforEducationalManagement(NAEM),DhakaTeachers’TrainingCollege(TTC),andBangladeshMadrasaTeachers’TrainingInstitute(BMTTI)locatedinDhaka.WefoundthatteachertrainingforEnglishlanguagelearningisurgentlyrequired.CurriculumandsyllabusinEnglishneedtobemadethefocusonfourskills—reading,writing,speaking,andlistening.Leadingedgetechnologyisidentifiedasanindispensableitemforlearners.TherecruitingsystemofEnglishteachersneedstobereformed.ThebestpracticewouldbetaggedittoBangladeshPublicServiceCommission(BPSC),soastogeteffectiveandqualifiedteachers.Thisstudyidentifiedthesupervisoryandadministrativedeficiencies.Toimprovemonitoring,supervisionprocesses,student-friendlyMadrasaadministration,andMadrasamanagingcommitteeisaninstrumental.

简介：Peopleoftenaskmewhatthewayofmystudyis.Ialwaysdon'tknowhowtoanswerthem.Becauseeveryone'swayisn'tthesame,isit?Now,letmetellyouthewayofmystudy.

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简介：a letter by Machiavelli was discovered in which he reveals that he wrote The Prince to endear himself to the ruling Medici family in Florence. To liberate Italy from the influence of foreign governments,he adopted the same attitude with Hanfeizi towards how an emperor should rule his country. In this paper,From the experience Machiavelli learned that weak countries had no diplomatic relationship with other counties. In his work he put forward that the weakest thing in the world was the power that was exaggerated. He tried to persuade the emperor to make a strong army

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