Genetic variations in RORa are associated with chronic obstructive pulmonary disease

ORIGINAL ARTICLE

Genetic variations in ROR a are associated with chronic obstructive pulmonary disease

Yiming Yuan 1,Xiaoming Hou 2,Jinlong Zhang 2,Yulong Chen 2,Yulin Feng 3and Zhiguang Su 2

Retinoic acid receptor-related orphan receptor-a (ROR a )plays a key role in the regulation of lipid and cholesterol metabolism that has been implicated in the development of chronic obstructive pulmonary disease (COPD).The aim of this study was to determine the frequencies of single-nucleotide polymorphisms (SNPs)in ROR a gene in a Chinese population and their possible association with COPD susceptibility.Nine tagging SNPs,including rs17270181,rs1898413,rs17270216,rs8033552,rs8036966,rs7169364,rs340002,rs340023and rs11630262,were screened in 279COPD patients and 367controls by the SNaPshot method.Association analysis of genotypes and haplotypes constructed from these loci with COPD was conducted under different genetic models.Alleles or genotypes of rs8033552distributed signi?cantly differently in COPD patients and controls (allele:P ?0.0001,false discovery rate (FDR)Q ?0.004,odds ratios (OR):1.62and 95%con?dence interval (CI):1.27–2.07;genotype:P ?0.0005,FDR Q ?0.008).The allele A at rs8033552was potentially associated with an increased risk of COPD in additive model,displaying ORs of 1.62(95%CI:1.17–2.26,P ?0.004,FDR Q ?0.019)in subjects with genotypes AG vs GG and 2.69(95%CI:1.47–4.93,P ?0.001,FDR Q ?0.011)in subjects with genotypes AA vs GG,respectively.In haplotype analysis,we observed haplotypes GGAGATGTG and GGAGCTGTG had protective effects,whereas haplotypes GGAGATACA and GGAGATACG were signi?cantly associated with the increased risk of COPD.These data suggest that ROR a may be a potential risk gene for COPD.

Journal of Human Genetics (2014)59,430–436;doi:10.1038/jhg.2014.48;published online 19June 2014

INTRODUCTION

Chronic obstructive pulmonary disease (COPD)is a major global disease that has been predicted to be the third leading cause of mortality worldwide by the year 2020,1and it is estimated to affect nearly 8.2%of the Chinese adult population.2Although cigarette smoke is a main risk factor for COPD,only B 20%of smokers develop this pathology;3thus,there are additional factors that are implicated in the pathogenesis of COPD.The variation in the susceptibility to cigarette smoke,in combination with the familial inheritance pattern of COPD,suggests that there may be a genetic component to the development of COPD.4,5The associations between COPD and polymorphisms in genes with potential importance in COPD pathogenesis have been investigated;6however,only a 1-antitrypsin has been unequivocally identi?ed as relevant to the development of COPD.Recently,polymorphisms in the CHRNA3-CHRNA5-IREB2,HHIP and FAM13A loci have been found to in?uence susceptibility to COPD by genome-wide association studies,7–10but they explained little more than 3%of the variance in lung function.

There is increasing evidence of lipid/cholesterol metabolism in the pathophysiology of COPD,11–15and the polymorphisms in genes for apolipoprotein M,a component of high-density lipoprotein,are associated with emphysema.12Retinoic acid receptor-related

orphan receptor-a (ROR a )is a member of the nuclear hormone receptor superfamily.16ROR a is known to play a key role in the regulation of circadian rhythms and pathways including in?ammation,lipid metabolism and cholesterol.17Cholesterol and cholesterol derivatives have been identi?ed as natural ligands of ROR a .18In addition to binding cholesterol,ROR a has also been shown to regulate lipoproteins,such as high-density lipoprotein HDL,apolipoprotein A1(the major constituent of high-density lipoprotein HDL),apolipoprotein A5and apolipoprotein CIII.19–21Further evidence for the role of ROR a in cholesterol metabolism comes from phenotypic examination of the ROR a -de?cient staggerer mouse (ROR a sg/sg ).Staggerer mice have decreased expression of the reverse cholesterol transporters Abca1and Abca8/g1in their liver and intestine.22On a normal diet,staggerer mice have lower levels of total plasma cholesterol,high-density lipoprotein,apolipoprotein A1,apolipoprotein CIII,apolipoprotein A2and triglycerides compared with wild-type mice.22,23

With these considerations in mind,we hypothesized that poly-morphisms in the ROR a gene might modulate susceptibility to COPD.T o test this hypothesis,we investigated the association of common genetic variants in the ROR a gene with the risk of COPD in a Chinese Han population.

1Department

of Geriatrics,West China Hospital,Sichuan University,Chengdu,China;2Molecular Medicine Research Center,West China Hospital,and State Key Laboratory of

Biotherapy,Sichuan University,Chengdu,China and 3Department of Respiratory Disease,West China Hospital,Sichuan University,Chengdu,China

Correspondence:Professor Z Su,Molecular Medicine Research Center,West China Hospital,Sichuan University,1Keyuan 4th Road,Gaopeng Street,Chengdu 610041,China.E-mail:zhiguang_su@https://www.sodocs.net/doc/4f4409151.html,

Received 12March 2014;revised 14May 2014;accepted 21May 2014;published online 19June 2014

Journal of Human Genetics (2014)59,430–436

&2014The Japan Society of Human Genetics All rights reserved 1434-5161/14

https://www.sodocs.net/doc/4f4409151.html,/jhg

MATERIALS AND METHODS

Subjects

As described previously,24,25279patients with COPD and367age-matched non-COPD control subjects were recruited for this study.The subjects in both groups were unrelated ethnic Han Chinese individuals recruited from Chengdu city or surrounding regions in the Sichuan province of western China.All subjects underwent physical examinations including chest X-ray,anthropometric measurements including body mass index(BMI),assessment of lung function and blood sampling.The recruitment and the clinical analyses were conducted at the Department of Respiratory Medicine in West China Hospital of Sichuan University;clinical analyses were performed according to the Global Initiative for Chronic Obstructive Lung Disease(GOLD)criteria.26COPD patients were enrolled when they suffered from cough,sputum production and dyspnea at least upon exertion and showed chronic irreversible air?ow limitation de?ned by an FEV1(forced expiratory volume in1s)to FVC(forced vital capacity)ratio o70%,and FEV1predicted o80%after the inhalation of a b2agonist.Patients were excluded from this study if they had other signi?cant respiratory diseases, such as bronchial asthma,bronchiectasis,lung cancer or pulmonary tuberculosis based on their chest X-ray test.Atopic patients determined by the serum levels of the total and allergen-speci?c IgE were also excluded from this study.The age-matched non-COPD control subjects were volunteers who came to the West China Hospital of Sichuan University for physical examination only.The inclusion criteria for controls were as follows:(1)FEV1/FVC ratio470%, FEV1%and FVC%predicted480%and(2)without pulmonary disease. Individuals were excluded if they had a history of chronic lung disease,atopy,an acute pulmonary infection in the4weeks before assessment for this study or a family history of COPD.

This study was approved by the Ethical Committee of the West China Hospital,Sichuan University,and written informed consent was obtained from all subjects before their participation in the study.The investigator explained the nature,purpose and risks of the study and provided the subject with a copy of the information sheet.

Biochemical measurements

Blood samples were collected at baseline from patients and controls after an overnight fast.Plasma separated from cells by centrifugation at500g for 10min at room temperature was used for lipid and glucose analyses.The plasma levels of total cholesterol,triglycerides and glucose were determined with an enzymatic kit(Boehringer Mannheim,Mannheim,Germany)and calibrated with a plasma calibrator.Serum total and allergen-speci?c IgE were assessed using the ImmunoCAP System(Thermo Fisher Scienti?c,Uppsala, Sweden).Serum-speci?c IgE was determined against common inhalant allergens of birch,timothy,mugwort,Dermatophagoides pteronyssinus and farinae,horse,dog and cat epithelium and Cladosporium herbarum.Atopic sensitization was indicated if the individual had at least one allergen-speci?c serum IgE level X0.35kU là1.

SNP selection and genotyping

ROR a is located on chromosome15q and spans B730kilobases(RORA: ENST00000069667)(https://www.sodocs.net/doc/4f4409151.html,/index.html).Genotype data of the Chinese population for the ROR a region were obtained from the HapMap website(https://www.sodocs.net/doc/4f4409151.html,/),and nine tag single-nucleotide polymorph-isms(SNPs)were selected using the Tagger software implemented in the Haploview software,27with an r2threshold of0.8and minor allele frequencies of0.1(Supplementary Table1).

Genomic DNA was extracted from peripheral blood leukocytes using a commercial extraction kit(Bioteke Corporation,Beijing,China)according to the manufacturer’s instructions.SNPs were genotyped using the ABI SNaPshot method(Applied Biosystems,Foster City,CA,USA)as described previously.25 The genomic regions of interest were ampli?ed by primers shown in Supplementary Table1.The PCR products were then puri?ed by incubating with shrimp alkaline phosphatase and exo-nuclease I.The puri?ed PCR products were used as the templates for SNaPshot reaction using the speci?c SNaPshot primers(Supplementary Table1).Next,3m l of pooled PCR products,1m l of pooled SNaPshot primers and1m l of deionized water were incubated in a GeneAmp9600thermal cycler(Applied Biosystems,Carlsbad,CA,USA)by25cycles at961C for10s,501C for5s and601C for30s,and

?nally601C for30s.Then,1U of shrimp alkaline phosphatase was added to SNaPshot product and incubated at371C for1h to deactivate the enzyme.The SNaPshot reaction products were mixed with Hi-Di formamide and GeneScan-

120LIZ internal size standard(Applied Biosystems),and analyzed on an ABI

3130Genetic Analyzer(Applied Biosystems).The data were analyzed by the software of GeneMapper4.0(SoftGenetics,LLC.,State College,PA,USA). Genotype analysis was performed in a blinded manner so that the staff was unaware of the cases or control status.For quality control,a10%masked random sample of cases and controls was tested repetitively by different investigators and all the results were completely concordant.

Statistical analyses

The demographic and clinical data between the COPD patients and the control subjects were compared using the w2test and Student’s t-test.A two-sided

signi?cance level of a o0.05was used for all signi?cant tests.Statistical analyses

were performed in SPSS version17.0(SPSS Inc,Chicago,IL,USA)and Microsoft Excel(Microsoft Corporation,Redmond,WA,USA).

The Hardy–Weinberg equilibrium test using two-sided w2analysis was done

for each SNP among cases and controls.Differences in the distribution of genotypes or alleles under different genetic models(including dominant, recessive and additive models)between the COPD patients and the controls

were estimated by using the w2test,and the best genetic model for each SNP

was determined using Akaike’s information criterion.Odds ratios(ORs)and

95%con?dence intervals(CIs)were calculated by unconditional logistic regression analyses.28,29Multiple testing corrections were carried out using

false discovery rate(FDR).30Q-values(?corrected P-values)were adjusted

with gender,age,BMI and cigarette smoking.The signi?cance level was set at

Q o0.05.FDR calculations were done using R language package fdrtool (https://www.sodocs.net/doc/4f4409151.html,/software/fdrtool/index.html).In addition to the overall association analysis,we performed a strati?ed analysis according to BMI and smoking status to explore the association between genotypes and the risk of COPD in each stratum.

Pairwise linkage disequilibrium(LD)estimation and haplotype reconstruc-

tion were performed using SHEsis(https://www.sodocs.net/doc/4f4409151.html,).31For haplotype analysis,only haplotypes with a frequency of43%in at least one group were tested.We also used Haploview4.2to estimate LD.27

RESULTS

General characteristics of the subjects

The baseline characteristics,biochemical features and the results of

the pulmonary function tests for the279patients with COPD and367

Table1Characteristics of COPD patients and control subjects

Variable Controls(n?367)Cases(n?279)P-value

Age,years65±863±9NS

Sex(men/women)323/44239/40NS

BMI(kg mà2)23.91±2.4822.03±2.27o0.01

Total cholesterol(mmol là1) 4.87±0.22 4.96±0.47NS Triglycerides(mmol là1) 1.24±0.57 1.19±0.48NS

Glucose(mmol là1) 5.13±0.12 5.86±0.16o0.01

Total serum IgE(kU là1)112.71±36.64109.89±41.65NS

Smoking history

0–20pack-years8875NS

X20pack-years279204NS

FEV1 1.87±0.600.97±0.32o0.01

FEV1of predicted,%93.7±3.446.0±0.4o0.01

FEV1/FVC,%78.0±4.649.2±8.3o0.01 Abbreviations:BMI,body mass index;COPD,chronic obstructive pulmonary disease;FEV1,

forced expiratory volume in1s;FVC,forced vital capacity;NS,no signi?cant difference

(P40.05).

Data are presented as means±s.d.

Pack years?(number of cigarettes smoked per day?number of years smoked)/20.

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Journal of Human Genetics

control subjects are presented in Table 1.All patients had FEV 1values o 80%of predicted and thus were diagnosed with moderate-to-severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease.The COPD cases and control subjects did not signi?cantly differ in sex,age or smoking history.The FEV1,FEV1/predicted and FEV1/FVC were signi?cantly lower in the COPD patients compared with the controls (P o 0.01).Compared with control subjects,the COPD patients showed statistically higher glucose concentrations (5.86±0.16vs 5.13±0.12mmol l à1,P o 0.01)and lower BMI (22.03±2.27vs 23.91±2.48kg m à2,P o 0.01).The serum levels cholesterol,triglycerides and total IgE had no difference between COPD patients and control subjects.

Distribution of the SNPs in ROR a between COPD patients and controls

Nine SNPs in ROR a ,including rs17270181,rs1898413,rs17270216,rs8033552,rs8036966,rs7169364,rs340002,rs340023and rs11630262,were screened in all 279patients with COPD and 367controls using the SNaPshot method.The genotype and allele frequencies of each SNP in both COPD patients and controls are presented in Table 2.All of the tested SNPs did not signi?cantly deviate from that expected for a Hardy–Weinberg equilibrium in the COPD patients and controls (Table 2,all P-values were 40.05),illustrating that our subjects presented the source population well.

We compared the differences in frequency distributions of geno-types or alleles of every SNP between COPD patients and controls by w 2test.As shown in Table 2,signi?cant differences in allele or genotype frequencies were observed between COPD patients and controls at rs8033552(allele:P ?0.0001,FDR Q ?0.004,OR:1.62and 95%CI:1.27–2.07;genotype:P ?0.0005,FDR Q ?0.008).Association of genotypes with COPD under different genetic models

For each SNP ,if one allele frequency is relatively lower compared with another one,it is recognized as the minor allele (Table 2).We assumed that the minor allele of each SNP was a risk allele compared with the wild-type allele.We compared the genotype frequencies of every polymorphism between groups under the dominant,recessive and additive genetic models,respectively.As shown in Table 3,the minor allele A at rs8033552was observed to be associated with an increasing COPD risk using an additive model as determined by Akaike information criterion (AG vs GG:P ?0.004,FDR Q ?0.019,OR:1.62,95%CI:1.17–2.26;AA vs GG:P ?0.001,FDR Q ?0.011,OR:2.69,95%CI:1.47–4.93).

The association between the rs8033552genotypes and the risk of COPD was further investigated after strati?cation according to BMI and smoking status (Table 4).Compared with the genotype GG at rs8033552,genotype AG or AA was associated with a signi?cantly increased risk of COPD in lower-BMI subjects (AG vs GG,P ?0.017,

Table 2Distributions of the ROR a SNPs in COPD patients and controls

Genotype

HWE

Allele

SNP Group

Number (freq.)P -value

FDR Q

P -value

Freq.P -value

FDR Q

OR (95%CI)

rs17270181

AA AG GG A G COPD 16(5.7)125(44.8)138(49.5)0.6320.7870.10228.271.80.3660.489 1.12(0.88–1.44)

Control

18(4.9)154(42.0)

195(53.1)

0.10125.974.1rs1898413

AA AG GG A G COPD 8(2.9)72(25.8)199(71.3)0.931

0.931

0.65115.884.20.801

0.927

1.04(0.77–1.41)

Control

11(3.0)90(24.5)266(72.5)0.31315.384.7rs17270216

AA AG GG A G COPD 212(76.0)60(21.5)7(2.5)0.4860.5480.29386.713.30.2230.369 1.23(0.88–1.73)

Control

292(79.6)

69(18.8)6(1.6)0.42189.011.0rs8033552

AA AG GG A G COPD 31(11.1)126(45.2)122(43.7)0.0005

0.008

0.89433.766.30.0001

0.004

1.62(1.27–

2.07)

Control

20(5.4)135(36.8)212(57.8)0.88623.876.2rs8036966

AA AC CC A C COPD 180(64.5)83(29.8)16(5.7)0.9870.9870.14279.420.60.8710.932 1.02(0.78–1.34)

Control

235(64.0)

110(30.0)

22(6.0)0.08279.021.0rs7169364

AA AT TT A T COPD 10(3.6)105(37.6)164(58.8)0.613

0.823

0.22722.477.60.704

0.897

0.95(0.73–1.24)

Control

19(5.2)133(36.2)215(58.6)0.88423.376.7rs340002

AA AG GG A G COPD

37(13.3)148(53.0)94(33.7)0.0630.0920.08239.860.20.04970.066 1.26(1.00–1.58)

rs340023Control 43(11.7)167(45.5)

157(42.8)

1.00034.565.5rs340023

CC CT TT C T COPD 36(12.9)149(53.4)94(33.7)0.220

0.367

0.06139.660.40.101

0.211

1.21(0.96–1.52)

Control

37(10.1)184(50.1)146(39.8)0.06735.164.9rs11630262

AA AG GG A G COPD 11(3.9)89(31.9)179(64.2)0.2600.412 1.00019.980.10.1300.289 1.25(0.94–1.66)

Control 8(2.2)

106(28.9)

253(68.9)

0.571

16.6

83.4

Abbreviations:CI,con?dence interval;COPD,chronic obstructive pulmonary disease;FDR Q :false discovery rate Q-value;Freq.,frequency;HWE,Hardy–Weinberg equilibrium;OR,odds ratio;ROR a ,retinoic acid receptor-related orphan receptor-a ;SNP ,single-nucleotide polymorphism.P or Q value o 0.05was in bold face type.

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FDR Q ?0.038,OR:1.74,95%CI:1.10–2.73;AA vs GG:P ?0.003,FDR Q ?0.018,OR:2.88,95%CI:1.30–6.36),whereas there was no association in heavier subjects with BMI more than 22kg m à2.When strati?ed by the median pack-years of smoking,the minor allele A at rs8033552signi?cantly increased the risk of COPD in heavy smokers under additive model (AG vs GG,P ?0.002,FDR Q ?0.016,OR:1.84,95%CI:1.26–2.70;AA vs GG:P ?0.009,FDR Q ?0.027,OR:2.51,95%CI:1.25–5.08).

LD between SNPs and haplotype analysis

The extent of LD in pairwise combinations of alleles in different SNPs was estimated by means of maximum likelihood from the genotype frequency in the COPD and control groups.Pairwise LD between the nine SNPs is shown in Table 5and Figure 1.Based on LD determinations,two blocks with moderate LD were detected:block 1is composed of rs17270181and rs1898413and block 2is composed of rs340002,rs340023and rs11630262.

We estimated the frequencies of haplotypes constructed from phased multilocus genotypes in ROR a .The haplotypes with a frequency 43%in at least one group were involved in the haplotype analysis (Table 5).The global result for block 1(rs17270181and rs1898413)was:w 2?23.32and d.f.?3,P ?3.82?10à6.The global result for block 2(rs340002,rs340023and rs11630262)was:w 2?113.98and d.f.?4,P ?4.31?10à18.The overall frequency

Table 3Association between ROR a SNPs and the risk of COPD under different genetic models

SNP Genetic model a

P -value FDR Q OR (95%CI)rs17270181Dominant (AG tAA)vs GG 0.3550.547 1.16(0.85–1.58)rs1898413Dominant (AG tAA)vs GG 0.0680.092 1.06(0.75–1.50)rs17270216Dominant (AG tGG)vs AA 0.2770.434 1.23(0.85–1.79)rs8033552Additive AG vs GG 0.0040.019 1.62(1.17–2.26)AA vs GG 0.0010.011 2.69(1.47–4.93)rs8036966Recessive AA vs (CC tAC)0.8990.921 1.02(0.74–1.41)rs7169364Recessive AA vs (TT tAT)0.3330.4970.68(0.31–1.49)rs340002Dominant (AG tAA)vs GG 0.0620.088 1.44(0.86–2.39)rs340023Dominant (CT tCC)vs TT 0.1130.267 1.30(0.94–1.80)rs11630262

Recessive

AA vs (GG tAG)

0.262

0.318

1.32(0.81–

2.15)

Abbreviations:CI,con?dence interval;COPD,chronic obstructive pulmonary disease;FDR Q :false discovery rate Q-value;Freq.,frequency;HWE,Hardy–Weinberg equilibrium;OR,odds ratio;ROR a ,retinoic acid receptor-related orphan receptor-a ;SNP ,single-nucleotide polymorphism.

The ORs and CIs that are statistically signi?cant are in bold,along with the rs number of the corresponding SNP .

a Only the estimates for the best genetic model for each SNP ,as determined by Akaike’s information criterion (AIC),are provided.

Table 4Associations between rs8033552and the risk of COPD according to BMI and smoking status

AG vs GG

AA vs GG

Variables AA

AG

GG

OR (95%CI)

P -value

FDR Q

OR (95%CI)

P -value

FDR Q

BMI (kg m à2)p 2218/12a 67/7361/117 1.74(1.10–2.73)0.0170.038 2.88(1.30–6.36)0.0030.018422

13/8

59/62

61/95

1.51(0.93–

2.44)

0.095

0.176

2.53(0.96–6.46)

0.051

0.104

Pack-year of smoking p 2010/426/3139/53 1.14(0.59–2.22)0.6990.872 3.40(0.97–9.64)0.0500.176420

21/16

100/104

83/159

1.84(1.26–

2.70)

0.002

0.016

2.51(1.25–5.08)

0.009

0.027

Abbreviations:BMI,body mass index;CI,con?dence interval;COPD,chronic obstructive pulmonary disease;FDR Q :false discovery rate Q-value;OR,odds ratio.a Number of cases/number of controls.

P or Q value o 0.05was in bold face type.

Table 5Pairwise linkage disequilibrium analysis of SNPs of the ROR a gene

D 0

rs1898413rs17270216rs8033552

rs8036966rs7169364rs340002rs340023rs11630262rs172701810.8030.36300.0480.1280.0750.0440.248rs1898413—0.3620.0340.0720.1620.1640.2250.123rs17270216——0.290.0810.1370.0590.0650.231rs8033552———0.3170.0790.0040.0560.007rs8036966————0.0650.0930.0610.151rs7169364—————0.1630.0880.081rs340002——————0.7870.82rs340023

—

—

—

—

—

—

—

0.877

Abbreviations:ROR a ,retinoic acid receptor-related orphan receptor-a ;SNP ,single-nucleotide polymorphism.D 0:linkage disequilibrium coef?cient.D’value 40.5was in bold face type.

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distribution of haplotype composed of all nine SNPs was signi?cantly different between cases and controls (total global w 2?90.72and d.f.?9,P ?4.22?10à15).

The results of the association between the ROR a haplotype and the risk of COPD are listed in Table 6.Haplotype AA in block 1was found to be associated with an increased risk of COPD (OR:1.39,

95%CI: 1.01–1.92,P ?0.042),whereas haplotype GA was not observed in COPD patients (P ?2.18?10à6).In block 2,two haplotypes were observed to be associated with the risk of COPD (ACA:OR:1.52,95%CI:1.13–2.04,P ?0.006;ACG:OR:1.71,95%CI:1.26–2.32,P ?0.001),whereas haplotypes ATG (OR:0.02,95%CI:0.00–0.13,P ?1.43?10à5)and GCG (P ?2.47?10à11)were protective from COPD.Global haplotype association analyses showed that three haplotypes,including GGAGATACA,GGAGATACG and GGAAATACG,were signi?cantly associated with the risk of COPD (all P o 0.01).In addition,three protective haplotypes,GGAGATGTG (OR:0.56,95%CI:0.41–0.75,P ?0.0001),GGAGCTGTG (OR:0.50,95%CI:0.28–0.89,P ?0.017)and GGAGATATG (P ?1.84?10à6),were associated with a decreased risk of COPD.

DISCUSSION

In this case–control study in a Han Chinese population,we carried out the ?rst investigation of the possible association between the SNPs in ROR a and COPD risk.Our current ?ndings suggested that rs8033552is associated with the risk of COPD.In comparison with allele G at rs8033552,the allele A could increase the risk of COPD under all dominant,recessive and additive genetic models.In addition to the genotype analysis,our study also adopted a haplotype-based approach.Haplotype analysis,in which several SNPs within the same gene are evaluated simultaneously,can provide more information than a single SNP and thus elevates the statistical power of the analysis.32Using this approach,we provided strong support that ROR a variations contributed to the susceptibility to COPD.LD analysis showed that some SNPs in ROR a gene were in moderate LD,and some haplotypes with low frequency were found to affect the risk of COPD dramatically.Haplotypes GGAGATGTG,

GGAGCTGTG

Figure 1Linkage disequilibrium (LD)plots for retinoic acid receptor-related orphan receptor-a (ROR a ).The LD plots were generated by Haploview 4.2.Polymorphisms are identi?ed by their single-nucleotide polymorphism database (dbSNP)rs numbers.The numbers within squares indicate the D 0value,expressed as a percentile.A full color version of this ?gure is available at the Journal of Human Genetics journal online.

Table 6Frequencies of pairwise haplotype constructed by SNPs in ROR a

Block Haplotype a Freq.(case)Freq.(control)w 2Fisher’s P OR (95%CI)b 1

AA 0.1580.119 4.160.042 1.39(1.01–1.92)AG 0.1240.1400.760.3820.86(0.62–1.20)GG 0.7190.7070.210.650 1.06(0.83–1.35)

GA

0.0000.03419.38 2.18?10à6Global 23.32 3.82?10à6

2

ACA 0.1990.1367.720.006 1.52(1.13–2.04)ACG 0.1970.12212.160.001 1.71(1.26–2.32)ATG 0.0020.08749.74 1.43?10à5

0.02(0.00–0.13)GTG 0.6020.540 2.630.105 1.20(0.96–1.51)

GCG 0.0000.85151.510.000Global

113.98 4.31?10à18

Total

GGAGATGTG 0.0470.0310.990.320 1.34(0.75–2.40)GGAAATGTG 0.0420.056 3.300.0700.61(0.36–1.04)GGAACTGTG 0.0370.0290.080.774 1.10(0.59–2.05)GGAGAAGTG 0.0710.040 3.210.073 1.57(0.96–2.59)GGAGATACA 0.1020.0479.480.002 2.00(1.28–3.14)GGAGATACG 0.0810.02218.34 5.85?10à5

3.37(1.88–6.05)GGAGATGTG 0.1860.2311

4.450.00010.56(0.41–0.75)GGAGCTGTG 0.0330.054

5.730.0170.50(0.28–0.89)GGAAATACG 0.037023.46 1.72?10à6GGAGATATG 0

0.0326

22.02 1.84?10à6Global

90.72

4.22?10à15

Abbreviations:CI,con?dence interval;Freq.,frequency;OR,odds ratio;ROR a ,retinoic acid receptor-related orphan receptor-a ;SNP ,single-nucleotide polymorphism.

a Only haplotypes with a frequency of 43%in at least one group were listed.The order of SNPs from left to right is:rs17270181and rs1898413for block 1;rs340002,rs340023and rs11630262for block 2;rs17270181,rs1898413,rs17270216,rs8033552,rs8036966,rs7169364,rs340002,rs340023and rs11630262for total.

b The OR could not be calculated for the haplotype GA in block 1,GCG in block 2and GGAAATACG and GGAGATATG because of the zero value in the population.P value o 0.05was in bold face type.

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and GGAGATATG were associated with a reductive risk of COPD, whereas haplotypes GGAGATACA,GGAGATACG and GGAAATACG increased the risk of developing COPD,indicating the complexity of ROR a gene in the development of COPD.

The signi?cant ROR a variants associated with COPD in this unrelated case–control cohort occur within the intron region of the ROR a that is usually removed during the gene-splicing process. Although there is no apparent functional change,intronic SNPs may modify gene function by affecting the regulation of gene expression.33In addition,the associated SNP with the statistical signal might just play a role as a surrogate marker for the causal functional SNP or SNPs.Therefore,rs8033552in ROR a gene could be in LD with another polymorphism of the gene that may impact the ROR a expression level.However,it is also likely that the causal sequence change(s)in this region has yet to be identi?ed as suggested by analysis of the signi?cant haplotypes.For example, SNP rs340002was signi?cantly associated with COPD risk as part of a haplotype but not individually(Table6).We selected SNPs with minor allele frequencies of410%in the Han Chinese population using HapMap project data,but this is not suited for situations where genetic architecture is such that multiple rare disease-causing variants contribute signi?cantly to disease risk. Recent studies demonstrate that identi?cation of rare variants may lead to critically important insights about disease etiology through implication of new genes and/or pathways.34,35The rare variants in the ROR a gene should be investigated to clarify their susceptibility to the development of COPD.

In addition to the regulation of cholesterol/lipid metabolism,data suggest the role of ROR a in in?ammation that has been implicated in the development and progression of COPD.36–38De?ciency of ROR a had been reported to lead paradoxically to increased lipopolysaccharide-induced lung in?ammation and decreased allergic in?ammation.39,40Compared with the wild-type counterparts,ROR a-de?cient staggerer(ROR a sg/sg)mice show a signi?cantly reduced expression of several macrophage markers,such as F4/80,Mac-2, Mpeg1and Msr1.The reduced in?ammation in ROR a sg/sg mice is further indicated by the greatly reduced levels of the proin?ammatory cytokines interleukin-1a,-1b and-6,and tumor necrosis factor-a.41 ROR a has been shown to mediate transcriptional inhibition of the pro-in?ammatory transcription factor nuclear factor-k B.42In addition,ROR a is identi?ed as a participant in cell-fate decisions in response to DNA damage,and the absence of ROR a can protect against airspace enlargement in animal models of emphysema.43These observations suggest that genetic variants of ROR a might affect COPD risk through a combination of multiple pathways.

We are aware that the signi?cant results in this study could prove to be false positives because of the relatively small sample size.The279 COPD patients and367control subjects were not relatively large among COPD association studies published to date,and further studies using larger populations are needed.But even with a larger sample,the functional and biological impacts of the described polymorphisms would require further study.Given the number of processes/pathways in which ROR a functions and the signi?cance of association between ROR a and COPD,it is unlikely that ROR a alone contributes to the sequelae of events in COPD but rather that genes regulated by ROR a,or those that regulate ROR a,may in?uence the disease.Therefore,although one gene may be modestly associated with COPD risk,it may be the combination of variants within sets of genes that can lead to small changes in the way the genes/proteins interact that,when combined with environmental effects,can have a huge impact on biological systems culminating in disease.44As a result,the investigation of ROR a-related pathways and gene networks

may lead to a better understanding of the pathophysiology of COPD.

In conclusion,our comprehensive analysis of SNPs in the ROR a

gene suggests that ROR a genotypes and haplotypes are associated

with COPD risk.Because this is the?rst case–control study investigating the association of ROR a with the risk of COPD, additional studies are required to con?rm our?ndings.

CONFLICT OF INTEREST

The authors declare no con?ict of interest.

ACKNOWLEDGEMENTS

This study was supported by the National High-tech R&D Program of China

(863Program2014AA021604),National Natural Science Foundation of China (Grant31071108)and the Program for New Century Excellent Talents in University,Education Ministry of China(Grant NCET-10-0600).

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小学joinin剑桥英语单词汇总

JOIN IN 学生用书1 Word List Starter Unit 1.Good afternoon 下午好 2.Good evening 晚上好 3.Good morning 早上好 4.Good night 晚安 5.Stand 站立 Unit 1 6.count [kaunt] （依次）点数 7.javascript:;eight [eit] 八 8.eleven [i'levn] 十一 9.four [f?:] 四 10.five [faiv] 五 11.flag [fl?g] 旗 12.guess [ges] 猜 13.jump [d??mp] 跳 14.nine [nain] 九 15.number ['n?mb?] 数字 16.one [w?n] 一 17.seven ['sevn] 七 18.six [siks] 六 19.ten [ten] 十 20.three [θri:] 三 21.twelve [twelv] 十二 22.two [tu:] 二 23.your [ju?] 你的 24.zero ['zi?r?u] 零、你们的 Unit 2 25.black [bl?k] 黑色26.blue [blu:] 蓝色 27.car [kɑ:] 小汽车 28.colour ['k?l?] 颜色 29.door [d?:] 门 30.favourite [feiv?rit]javascript:; 特别喜爱的 31.green [gri:n] 绿色 32.jeep [d?i:p] 吉普车 33.orange ['?:rind?] 橙黄色 34.pin k [pi?k] 粉红色 35.please [pli:z] 请 36.purple ['p?:pl] 紫色 37.red [red] 红色 38.white [wait] 白色 39.yellow ['jel?u] 黄色 Unit 3 40.blackboard ['bl?kb?:d] 黑板 41.book [buk] 书 42.chair [t???] 椅子 43.desk [desk] 桌子 44.pen [pen] 钢笔 45.pencil ['pensl] 铅笔 46.pencil case [keis] 笔盒 47.ruler ['ru:l?] 尺、直尺 48.schoolbag [sku:l] 书包 49.tree [tri:] 树 50.window ['wind?u] 窗、窗口 Unit 4 51.brown [braun] 棕色 52.cat [k?t] 猫

常用二极管参数

常用整流二极管 型号VRM/Io IFSM/ VF /Ir 封装用途说明1A5 600V/1.0A 25A/1.1V/5uA[T25] D2.6X3.2d0.65 1A6 800V/1.0A 25A/1.1V/5uA[T25] D2.6X3.2d0.65 6A8 800V/6.0A 400A/1.1V/10uA[T60] D9.1X9.1d1.3 1N4002 100V/1.0A 30A/1.1V/5uA[T75] D2.7X5.2d0.9 1N4004 400V/1.0A 30A/1.1V/5uA[T75] D2.7X5.2d0.9 1N4006 800V/1.0A 30A/1.1V/5uA[T75] D2.7X5.2d0.9 1N4007 1000V/1.0A 30A/1.1V/5uA[T75] D2.7X5.2d0.9 1N5398 800V/1.5A 50A/1.4V/5uA[T70] D3.6X7.6d0.9 1N5399 1000V/1.5A 50A/1.4V/5uA[T70] D3.6X7.6d0.9 1N5402 200V/3.0A 200A/1.1V/5uA[T105] D5.6X9.5d1.3 1N5406 600V/3.0A 200A/1.1V/5uA[T105] D5.6X9.5d1.3 1N5407 800V/3.0A 200A/1.1V/5uA[T105] D5.6X9.5d1.3 1N5408 1000V/3.0A 200A/1.1V/5uA[T105] D5.6X9.5d1.3 RL153 200V/1.5A 60A/1.1V/5uA[T75] D3.6X7.6d0.9 RL155 600V/1.5A 60A/1.1V/5uA[T75] D3.6X7.6d0.9 RL156 800V/1.5A 60A/1.1V/5uA[T75] D3.6X7.6d0.9 RL203 200V/2.0A 70A/1.1V/5uA[T75] D3.6X7.6d0.9 RL205 600V/2.0A 70A/1.1V/5uA[T75] D3.6X7.6d0.9 RL206 800V/2.0A 70A/1.1V/5uA[T75] D3.6X7.6d0.9 RL207 1000V/2.0A 70A/1.1V/5uA[T75] D3.6X7.6d0.9 RM11C 1000V/1.2A 100A/0.92V/10uA D4.0X7.2d0.78 MR750 50V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 MR751 100V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 MR752 200V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 MR754 400V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 MR756 600V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 MR760 1000V/6.0A 400A/1.25V/25uA D8.7x6.3d1.35 常用整流二极管(全桥） 型号VRM/Io IFSM/ VF /Ir 封装用途说明RBV-406 600V/*4A 80A/1.10V/10uA 25X15X3.6 RBV-606 600V/*6A 150A/1.05V/10uA 30X20X3.6 RBV-1306 600V/*13A 80A/1.20V/10uA 30X20X3.6 RBV-1506 600V/*15A 200A/1.05V/50uA 30X20X3.6 RBV-2506 600V/*25A 350A/1.05V/50uA 30X20X3.6 常用肖特基整流二极管SBD 型号VRM/Io IFSM/ VF Trr1/Trr2 封装用途说明EK06 60V/0.7A 10A/0.62V 100nS D2.7X5.0d0.6 SK/高速 EK14 40V/1.5A 40A/0.55V 200nS D4.0X7.2d0.78 SK/低速 D3S6M 60V/3.0A 80A/0.58V 130p SB340 40V/3.0A 80A/0.74V 180p SB360 60V/3.0A 80A/0.74V 180p SR260 60V/2.0A 50A/0.70V 170p MBR1645 45V/16A 150A/0.65V <10nS TO220 超高速

英语各种词性的用法

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反向工作 峰值电压 URM/V 额定正向 整流电流 整流电流 IF/A 正向不重 复浪涌峰 值电流 IFSM/A 正向 压降 UF/V 反向 电流 IR/uA 工作 频率 f/KHZ 外形 封装
型 号
1N4000 1N4001 1N4002 1N4003 1N4004 1N4005 1N4006 1N4007 1N5100 1N5101 1N5102 1N5103 1N5104 1N5105 1N5106 1N5107 1N5108 1N5200 1N5201 1N5202 1N5203 1N5204 1N5205 1N5206 1N5207 1N5208 1N5400 1N5401 1N5402 1N5403 1N5404 1N5405 1N5406 1N5407 1N5408
25 50 100 200 400 600 800 1000 50 100 200 300 400 500 600 800 1000 50 100 200 300 400 500 600 800 1000 50 100 200 300 400 500 600 800 1000
1
30
≤1
＜5
3
DO-41
1．5
75
≤1
＜5
3
DO-15
2
100
≤1
＜10
3
3
150
≤0.8
＜10
3
DO-27
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1N系列稳压管

快恢复整流二极管

常用整流二极管型号和参数 05Z6.2Y 硅稳压二极管 Vz=6~6.35V,Pzm=500mW, 05Z7.5Y 硅稳压二极管 Vz=7.34~7.70V,Pzm=500mW, 05Z13X硅稳压二极管 Vz=12.4~13.1V,Pzm=500mW, 05Z15Y硅稳压二极管 Vz=14.4~15.15V,Pzm=500mW, 05Z18Y硅稳压二极管 Vz=17.55~18.45V,Pzm=500mW, 1N4001硅整流二极管 50V, 1A,(Ir=5uA,Vf=1V,Ifs=50A) 1N4002硅整流二极管 100V, 1A, 1N4003硅整流二极管 200V, 1A, 1N4004硅整流二极管 400V, 1A, 1N4005硅整流二极管 600V, 1A, 1N4006硅整流二极管 800V, 1A, 1N4007硅整流二极管 1000V, 1A, 1N4148二极管 75V, 4PF,Ir=25nA,Vf=1V, 1N5391硅整流二极管 50V, 1.5A,(Ir=10uA,Vf=1.4V,Ifs=50A) 1N5392硅整流二极管 100V,1.5A, 1N5393硅整流二极管 200V,1.5A, 1N5394硅整流二极管 300V,1.5A, 1N5395硅整流二极管 400V,1.5A, 1N5396硅整流二极管 500V,1.5A, 1N5397硅整流二极管 600V,1.5A, 1N5398硅整流二极管 800V,1.5A, 1N5399硅整流二极管 1000V,1.5A, 1N5400硅整流二极管 50V, 3A,(Ir=5uA,Vf=1V,Ifs=150A) 1N5401硅整流二极管 100V,3A, 1N5402硅整流二极管 200V,3A, 1N5403硅整流二极管 300V,3A, 1N5404硅整流二极管 400V,3A,

有限合伙企业登记注册操作指南

有限合伙企业登记注册操作指南 风险控制部 20xx年x月xx日

目录 一、合伙企业的概念 (4) 二、有限合伙企业应具备的条件 (4) 三、有限合伙企业设立具备的条件 (4) 四、注册有限合伙企业程序 (5) 五、申请合伙企业登记注册应提交文件、证件 (6) （一）合伙企业设立登记应提交的文件、证件： (6) （二）合伙企业变更登记应提交的文件、证件： (7) （三）合伙企业注销登记应提交的文件、证件： (8) （四）合伙企业申请备案应提交的文件、证件： (9) （五）其他登记应提交的文件、证件： (9) 六、申请合伙企业分支机构登记注册应提交的文件、证件 (9) （一）合伙企业分支机构设立登记应提交的文件、证件 (10) （二）合伙企业分支机构变更登记应提交的文件、证件： (10) （三）合伙企业分支机构注销登记应提交的文件、证件： (11) （四）其他登记应提交的文件、证件： (12) 七、收费标准 (12) 八、办事流程图 (12) （一）有限合伙企业创办总体流程图（不含专业性前置审批） (12) （二）、工商局注册程序 (15)

（三）、工商局具体办理程序（引入网上预审核、电话预约方式） (16) 九、有限合伙企业与有限责任公司的区别 (16) （一）、设立依据 (16) （二）、出资人数 (16) （三）、出资方式 (17) （四）、注册资本 (17) （五）、组织机构 (18) （六）、出资流转 (18) （七）、对外投资 (19) （八）、税收缴纳 (20) （九）、利润分配 (20) （十）、债务承担 (21) 十、常见问题解答与指导 (21)

英语词性的分类及用法

英语词性的分类及用法 词类又叫词性，英语单词根据其在句子中的功用，可以分成十个大类。 1 名词noun n. student 学生 2 代词pronoun pron. you 你 3 形容词adjective adj. happy 高兴的 4 副词adverb adv. quickly 迅速地 5 动词verb v. cut 砍、割 6 数词numeral num. three 三 7 冠词article art. a 一个8 介词preposition prep. at 在... 9 连词conjunction conj. and 和10 感叹词interjection interj. oh 哦 前六类叫实词，后四类叫虚词。 名词(表示人或物名称的词) ?名词可以分为专有名词和普通名词. ?专有名词是某个（些）人，地方，机构等专有的名称，如Beijing，China, the United States,等。 ?普通名词是一类人或东西或是一个抽象概念的名词，如：book，sadness等。(普 通名词包括可数名词和不可数名词) ?普通名词又可分为下面四类： 1）个体名词：表示某类人或东西中的个体，如：gun 2）集体名词：表示若干个个体组成的集合体，如:family ?(以上两类属于可数名词) 3）物质名词：表示无法分为个体的实物，如:air 4）抽象名词：表示动作、状态、品质、感情等抽象概念，如：work ?(以上两类属于不可数名词) 代词(代替名词的词) ?代词可以分为下列九类： ? 1. 人称代词：They are my school mates. ? 2. 物主代词：Our friends have great concern for each other. ? 3. 反身代词：Take good care of yourselves. ? 4. 相互代词：We should help each other. ? 5. 指示代词：Who are these people? ? 6. 疑问代词：What are you doing? ?7. 关系代词：She married Tony Harper, who is a student too. ?8. 连接代词：Do you know who did it? ?9. 不定代词：Do you know anything about it? ? ?代词是非常活跃的词，特别是不定代词，比较复杂，我们要熟练掌握。 形容词(修饰名词等，说明事物或人的性质或特征的词) ?形容词可分成性质形容词和叙述形容词两类，其位置不一定都放在名词前面。 1) 直接说明事物的性质或特征的形容词是性质形容词，它有级的变化，可以用程度 副词修饰，在句中可作定语、表语和补语。例如：hot ,good ,wonderful等. 2) 叙述形容词只能作表语，所以又称为表语形容词。这类形容词没有级的变化，也 不可用程度副词修饰。大多数以a开头的形容词都属于这一类。例如：afraid, alone 等.

公司注册登记流程(四证)

→客户提供：场所证明租赁协议身份证委托书三张一寸相片 →需准备材料：办理税务登记证时需要会计师资格证与财务人员劳动合同 →提交名称预审通知书→公司法定代表人签署的《公司设立登记申请书》→全体股东签署的《指定代表或者公共委托代理人的证明》（申请人填写股东姓名）→全体股东签署的公司章程（需得到工商局办事人员的认可）→股东身份证复印件→验资报告（需到计师事务所办理：需要材料有名称预审通知书复印件公司章程股东身份证复印件银行开具验资账户进账单原件银行开具询证函租赁合同及场所证明法人身份证原件公司开设临时存款账户的复印件）→任职文件（法人任职文件及股东董事会决议）→住所证明（房屋租赁合同）→工商局（办证大厅）提交所有材料→公司营业执照办理结束 →需带材料→公司营业执照正副本原件及复印件→法人身份证原件→代理人身份证→公章→办理人开具银行收据交款元工本费→填写申请书→组织机构代码证办

理结束 →需带材料→工商营业执照正副本复印件原件→组织机构正副本原件及复印件→公章→公司法定代表人签署的《公司设立登记申请书》→公司章程→股东注册资金情况表→验资报告书复印件→场所证明（租赁合同）→法人身份证复印件原件→会计师资格证（劳动合同）→税务登记证办理结束 →需带材料→工商营业执照正副本复印件原件→组织机构正副本原件及复印件→税务登记证原件及复印件→公章→法人身份证原件及复印件→代理人身份证原件及复印件→法人私章→公司验资账户→注以上复印件需四份→办理时间个工作日→办理结束 →需带材料→工商营业执照正副本复印件原件→组织机构正副本原件及复印件→公章→公司法定代表人签署的《公司设立登记申请书》→公司章程→股东注册资金情况表→验资报告书复印件→场所证明（租赁合同）→法人身份证复印件原件→会计师资格证（劳动合同）→会计制度→银行办理的开户许可证复印件→税务登记证备案办理结束

英文各种词性的用法知识

精品文档 英文各种词性的用法及句子结构讲解： 十大词类： 1, 名词，Nou ns (n.) 表示人或事物的名称 box, pen, tree,apple 2, 代词，Pronouns (pron.) 代替名词、数词、形容词 We, this, them,myself 3，形容词，Adjectives(adj.) 用来修饰名词，表示人或事物的特征good, sad, high, short 4，数词，Numerals(num.)表示数目或顺序 one,two, first 5，动词，Verb (v.) 表示动作或状态Jump,sing,visit vt.是及物动词，vt.后必须跟宾语：sing a song vi.是不及物动词，vi.后不直接带宾语或不带宾语:jump high 6，副词，Adverbs (adv.) 修饰动、形、副等词，表示动作特征there,widely,suddenly 7，冠词，Articles (art.) 用在名词前，帮助说明名词所指的范围a, an, the 8，介词，Prepositions (prep.) 用在名词或代词前，说明它与别的词的关系in,on,down,up 9，连词，Conjunctions (conj.) 表示人或事物的名称 if,because,but 10，感叹词，In terjectio ns (in t.) 代替名词、数词、形容词等 oh,hello,hi,yeah 组成句子的各个部分叫句子成分。英语句子成分有主语，谓语，表语，宾语，宾语补足语，定语，状语等。 顺序是主语，谓语，宾语，宾语补足语，而表语，定语，状语的位置要根据情况而定。 1、主语 主语表示句子主要说明的人或事物，一般由名词，代词，数词，不定式等充当。 2、谓语 谓语说明主语的动作，状态或特征。 一般可分为两类： 1) ，简单谓语 由动词(或短语动词)构成。 可以有不同的时态，语态和语气。 2) ，复合谓语：情态动词+动词原形 3、表语 表语是谓语的一部分，它位于系动词如be之后，说明主语身份，特征，属性或状态。一般由名词，代词，形容词，副词，不定式，介词短语等充当。 4、宾语 宾语表示动作行为的对象，跟在及物动词之后，能作宾语的有名词，代词，数词，动词不定式等。 有些及物动词可以带两个宾语，往往一个指人，一个指物，指人的叫间接宾语，指物的叫直接宾语。有些及物动词的宾语后面还需要有一个补足语，意思才完整，宾语和它的补足语构成复合宾语。 5、定语 在句中修饰名词或代词的成分叫定语。 用作定语的主要是形容词，代词，数词，名词，副词，动词不定式，介词短语等。形容词，代词， 数词，名词等作定语时，通常放在被修饰的词前面。 但副词，动词不定式，介词短语等作定语时，则放在被修饰的词之后。

三年级下学期英语(Joinin剑桥英语)全册单元知识点归纳整理-

Starter Unit Good to see you again知识总结 一. 短语 1. dance with me 和我一起跳舞 2. sing with me 和我一起唱歌 3. clap your hands 拍拍你的手 4. jump up high 高高跳起 5.shake your arms and your legs晃晃你的胳膊和腿 6. bend your knees 弯曲你的膝盖 7. touch your toes 触摸你的脚趾8. stand nose to nose鼻子贴鼻子站 二. 句子 1. ---Good morning. 早上好。 ---Good morning, Mr Li. 早上好，李老师。 2. ---Good afternoon. 下午好。 ---Good afternoon, Mr Brown. 下午好，布朗先生。 3. ---Good evening，Lisa. 晚上好,丽莎。 ---Good evening, Bob. 晚上好，鲍勃。 4. ---Good night. 晚安。 ----Good night. 晚安。 5. ---What’s your name? 你叫什么名字？ ---I’m Bob./ My name is Bob. 我叫鲍勃。 6. ---Open the window, please. 请打开窗户。 ---Yes ,Miss. 好的，老师。 7. ---What colour is it? 它是什么颜色？ 它是蓝红白混合的。 ---It’s blue, red and white. 皮特的桌子上是什么？ 8. ---What’s on Pit’s table? ---A schoolbag, an eraser and two books. 一个书包，一个橡皮和两本书。 9. ---What time is it? 几点钟？ 两点钟。 ---It’s two. 10.---What’s this? 这是什么？ ---My guitar. 我的吉他。

很全的二极管参数

G ENERAL PURPOSE RECTIFIERS – P LASTIC P ASSIVATED J UNCTION 1.0 M1 M2 M3 M4 M5 M6 M7 SMA/DO-214AC G ENERAL PURPOSE RECTIFIERS – G LASS P ASSIVATED J UNCTION S M 1.0 GS1A GS1B GS1D GS1G GS1J GS1K GS1M SMA/DO-214AC 1.0 S1A S1B S1D S1G S1J S1K S1M SMB/DO-214AA 2.0 S2A S2B S2D S2G S2J S2K S2M SMB/DO-214AA 3.0 S3A S3B S3D S3G S3J S3K S3M SMC/DO-214AB F AST RECOVERY RECTIFIERS – P LASTIC P ASSIVATED J UNCTION MERITEK ELECTRONICS CORPORATION

U LTRA FAST RECOVERY RECTIFIERS – G LASS P ASSIVATED J UNCTION

S CHOTTKY B ARRIER R ECTIFIERS

S WITCHING D IODES Power Dissipation Max Avg Rectified Current Peak Reverse Voltage Continuous Reverse Current Forward Voltage Reverse Recovery Time Package Part Number P a (mW) I o (mA) V RRM (V) I R @ V R (V) V F @ I F (mA) t rr (ns) Bulk Reel Outline 200mW 1N4148WS 200 150 100 2500 @ 75 1.0 @ 50 4 5000 SOD-323 1N4448WS 200 150 100 2500 @ 7 5 0.72/1.0 @ 5.0/100 4 5000 SOD-323 BAV16WS 200 250 100 1000 @ 7 5 0.8 6 @ 10 6 5000 SOD-323 BAV19WS 200 250 120 100 @ 100 1.0 @ 100 50 5000 SOD-323 BAV20WS 200 250 200 100 @ 150 1.0 @ 100 50 5000 SOD-323 BAV21WS 200 250 250 100 @ 200 1.0 @ 100 50 5000 SOD-323 MMBD4148W 200 150 100 2500 @ 75 1.0 @ 50 4 3000 SOT-323-1 MMBD4448W 200 150 100 2500 @ 7 5 0.72/1.0 @ 5.0/100 4 3000 SOT-323-1 BAS16W 200 250 100 1000 @ 7 5 0.8 6 @ 10 6 3000 SOT-323-1 BAS19W 200 250 120 100 @ 100 1.0 @ 100 50 3000 SOT-323-1 BAS20W 200 250 200 100 @ 150 1.0 @ 100 50 3000 SOT-323-1 BAS21W 200 250 250 100 @ 200 1.0 @ 100 50 3000 SOT-323-1 BAW56W 200 150 100 2500 @ 75 1.0 @ 50 4 3000 SOT-323-2 BAV70W 200 150 100 2500 @ 75 1.0 @ 50 4 3000 SOT-323-3 BAV99W 200 150 100 2500 @ 75 1.0 @ 50 4 3000 SOT-323-4 BAL99W 200 150 100 2500 @ 75 1.0 @ 50 4 3000 SOT-323- 5 350mW MMBD4148 350 200 100 5000 @ 75 1.0 @ 10 4 3000 SOT-23-1 MMBD4448 350 200 100 5000 @ 75 1.0 @ 10 4 3000 SOT-23-1 BAS16 350 200 100 1000 @ 75 1.0 @ 50 6 3000 SOT-23-1 BAS19 350 200 120 100 @ 120 1.0 @ 100 50 3000 SOT-23-1 BAS20 350 200 200 100 @ 150 1.0 @ 100 50 3000 SOT-23-1 BAS21 350 200 250 100 @ 200 1.0 @ 100 50 3000 SOT-23-1 BAW56 350 200 100 2500 @ 70 1.0 @ 50 4 3000 SOT-23-2 BAV70 350 200 100 5000 @ 70 1.0 @ 50 4 3000 SOT-23-3 BAV99 350 200 100 2500 @ 70 1.0 @ 50 4 3000 SOT-23-4 BAL99 350 200 100 2500 @ 70 1.0 @ 50 4 3000 SOT-23-5 BAV16W 350 200 100 1000 @ 75 0.86 @ 10 6 3000 SOD-123 410-500mW BAV19W 410 200 120 100 @ 100 1.0 @ 100 50 3000 SOD-123 BAV20W 410 200 200 100 @ 150 1.0 @ 100 50 3000 SOD-123 BAV21W 410 200 250 100 @ 200 1.0 @ 100 50 3000 SOD-123 1N4148W 410 150 100 2500 @ 75 1.0 @ 50 4 3000 SOD-123 1N4150W 410 200 50 100 @ 50 0.72/1.0 @ 5.0/100 4 3000 SOD-123 1N4448W 500 150 100 2500 @ 7 5 1.0 @ 200 4 3000 SOD-123 1N4151W 500 150 75 50 @ 50 1.0 @ 10 2 3000 SOD-123 1N914 500 200 100 25 @ 20 1.0 @ 10 4 1000 10000 DO-35 1N4148 500 200 100 25 @ 20 1.0 @ 10 4 1000 10000 DO-35 LL4148 500 150 100 25 @ 20 1.0 @ 10 4 2500 Mini-Melf SOT23-1 SOT23-2 SOT23-3 SOT23-4 SOT23-5 SOT323-1 SOT323-2 SOT323-3 SOT323-4 SOT323-5