TGF-β1-induced expression of Id-1 is associated with tumor progression in gastric cancer.
ORIGINAL PAPER
TGF-b 1-induced expression of Id-1is associated with tumor progression in gastric cancer
Huiying Ma ?Ye Wei ?Yongmei Leng ?Shichao Li ?Lingling Gao ?Heng Hu ?Long Chen ?Fei Wang ?Honglei Xiao ?Chouwen Zhu ?Chunmin Liang
Received:2April 2014/Accepted:30April 2014óSpringer Science+Business Media New York 2014
Abstract Transforming growth factor b 1(TGF-b 1)and inhibitor of differentiation/DNA-binding 1(Id-1)have been shown to be associated with aggressive metastatic behavior of cancer cells in many malignant tumors.How-ever,their role in gastric cancer (GC)has not been estab-lished.In this study,we investigated the relationship between expression of Id-1and TGF-b 1in GC as well as their association with GC progression.The immunohisto-chemical analysis of 71human GC samples indicated that both Id-1and TGF-b 1were markedly upregulated in tumor tissue compared with the adjacent tissue;in addition,a signi?cant positive correlation was found between the expression levels of Id-1and TGF-b 1by Pearson’s corre-lation analysis.Furthermore,the investigation of the association of Id-1and TGF-b 1with patient clinical characteristics revealed that Id-1expression was signi?-cantly correlated with tumor differentiation,while TGF-b 1was associated with lymph node metastasis.The results were validated in vitro by using a GC cell line,AGS.The expression of Id-1was upregulated at 24and 48h after the
treatment with TGF-b 1,whereas it did not affect the pro-liferation of cells.TGF-b 1also in?uenced the expression of N-cadherin and b -catenin.Our results suggested that Id-1and TGF-b 1played important roles in the progression of GC,in which Id-1might act as a downstream mediator of TGF-b 1signaling through a regulatory mechanism involving N-cadherin and b -catenin.The TGF-b 1/Id-1axis might serve as a future therapeutic target for GC.Keywords Inhibitor of differentiation 1áTransforming growth factor b 1áGastric cancer áClinical pathology áAGS
Introduction
Gastric cancer (GC)is one of the most common malig-nancies worldwide.Despite the declining incidence,GC remains the second leading cause of cancer-related deaths [1,2].The advances in diagnostic techniques and treatment strategies ensure an early detection and low mortality rate for early stages of GC [3,4];however,the candidate prognostic biomarkers for patients with advanced metas-tasized GC need to be further explored.
Inhibitor of cell differentiation/DNA-binding (Id)pro-teins is a family of helix–loop–helix (HLH)transcription factors (Id-1–Id-4).They regulate cell cycle and cell dif-ferentiation by antagonizing the DNA-binding activity of basic HLH transcription factors [5].Accumulated evidence suggests that Id-1plays multiple roles in the progression of various cancers via stimulation of angiogenesis [6,7],inhibition of differentiation [8,9],and induction of metastasis [10–13].Clinical studies involving GC patients have revealed a signi?cant association of Id-1overex-pression with cancer invasion and metastasis [14–16].
Huiying Ma,Ye Wei and Yongmei Leng have equally contributed to this article.
H.Ma áL.Gao áH.Hu áL.Chen áF.Wang áH.Xiao áC.Liang (&)
Laboratory of Tumor Immunology,Department of Anatomy and Histology &Embryology,Shanghai Medical College,Fudan University,138Yi Xue Yuan Road,Shanghai 200032,People’s Republic of China e-mail:cmliang@https://www.wendangku.net/doc/0e3409068.html,
Y.Wei áY.Leng áS.Li áC.Zhu (&)
General Surgery Department,Zhongshan Hospital,Shanghai Medical College,Fudan University,180Feng lin Road,Shanghai 200032,People’s Republic of China e-mail:cwzhu@https://www.wendangku.net/doc/0e3409068.html,
Med Oncol (2014)31:19
DOI 10.1007/s12032-014-0019-3
Further studies demonstrate that inhibition of GC cells differentiation by Id-1contributes to GC progression[17, 18].However,the molecular mechanism underlying Id-1 functions in GC progression is not fully elucidated.
Transforming growth factor b1(TGF-b1),polypeptide belonging to the TGF-b family of growth factors,is shown to be upregulated in the tumor microenvironment and contributes to tumor metastasis[19,20].Once TGF-b1 binds to its receptor,the receptor is phosphorylated and then activates the downstream signaling mediator SMAD2/ 3to exert its biological activities[21].It has been reported that overexpression of TGF-b1in head and neck epithelia causes severe in?ammation and angiogenesis,which may consequently contribute to the malignant phenotype med-iated by vascular endothelial growth factor(VEGF)and activin receptor-like kinase1(ALK1)[22–24].Previous ?ndings have also shown that TGF-b1induces migration and invasion of tumor cells and promotes metastasis by upregulating the protein level of matrix metalloproteinase-9[25,26].
Although both Id-1and TGF-b1are involved in tumor progression,their interrelationship in carcinogenesis requires further clari?cation.To date,several reports have suggested that Id-1expression may be involved in TGF-b-signaling pathway,but the data are controversial.Id-1 expression is downregulated by TGF-b1in prostate epi-thelial cell lines[27–29].On the contrary,Id-1proves to be signi?cantly upregulated by stimulating TGF-b3in endo-thelial cells[30],and TGF-b1in metastatic breast tumor cells[31]and in prostate cancer cells[32].However,to the best of our knowledge,there are no reports elucidating the relationship between TGF-b1and Id-1and their functions in GC progression.
In this study,we investigated the relationship between Id-1and TGF-b1in shaping the permissive GC microen-vironment.The results showed that the expression of Id-1 and TGF-b1was increased in GC tissue compared with that in the adjacent tissue and was positively associated with tumor differentiation and lymph node metastasis, respectively.Moreover,a signi?cant positive correlation between the expression of Id-1and TGF-b1was revealed in GC tissue.These results were further validated in GC AGS cells,which showed an increase of Id-1expression,as well as N-cadherin and b-catenin,after stimulation with TGF-b1.
Materials and methods
Tissue specimens
Seventy-one GC patients who received surgical treatment at Zhongshan Hospital(Shanghai,China)between June 2011and December2011were enrolled in our study.The evaluation of the resected tumor specimens was performed according to the guidelines of the Japanese Gastric Carci-noma Association.Stage grading was performed in accor-dance with the TNM classi?cation of gastric carcinoma (UICC).None of the patients received radiotherapy,che-motherapy,or other medical interventions before the sur-gery.Specimens were collected only from patients who underwent complete clinical and pathological evaluation. Informed consent was obtained from all individuals.The study was approved by the Research Ethics Committee of Zhongshan Hospital.
Immunohistochemistry
Tumors and adjacent non-cancerous tissue samples were harvested from the71GC patients,?xed in formalde-hyde and embedded in paraf?n.Immunohistochemistry of paraf?n sections(5l m)was carried out using a two-step protocol.Brie?y,sections were deparaf?nized with xylene and rehydrated with graded ethanol solutions. After blocking the endogenous peroxide activity by incubation in0.3%H2O2,antigen retrieval was per-formed by placing the sections in boiling citrate or ethylenediamine tetraacetic acid(EDTA)buffer for 10min,and non-speci?c binding sites were blocked with 5%goat serum in19phosphate buffered saline(19 PBS,pH7.4).The slides were incubated with primary antibodies against Id-1and TGF-b1(1:25and1:200, respectively;Abcam;MA,USA),horseradish peroxidase (HRP)-conjugated secondary antibodies(1:200;KPL; MD,USA),and3,30-diaminobenzidine(DAB)solution (Sigma-Aldrich;MO,USA).Negative control slides without the primary antibodies were included in all assays.All specimens were counterstained with hema-toxylin and examined under light microscopy. Evaluation of immunohistochemical staining
Each immunostained slide was observed at2009and 4009magni?cations.At least?ve4009magni?cation images were processed and analyzed using ImageJ soft-ware(National Institutes of Health;Bethesda,MD,USA). For each specimen,the percentages of positively stained areas relative to the total observed areas of tumor cell(% area)were determined.The average percentage was cal-culated to ensure the sample representativeness and homogeneity for accurate statistical analysis.
Cell line and culture conditions
The human gastric adenocarcinoma AGS cell line was maintained in a5%CO2-humidi?ed atmosphere at37°C
19Page2of10Med Oncol(2014)31:19
in RPMI-1640medium(Biowest;France)supplemented with10%fetal bovine serum(FBS;Biowest). Immunocytochemistry
AGS cells were seeded in24-well plates with cover slips in RPMI-1640supplemented with10%FBS.After cell attachment,the medium was changed to1%FBS with or without TGF-b1(10ng/mL;PeproTech;NJ,USA)and continuously cultured.The cells were collected at24and 48h,respectively,?xed with4%paraformaldehyde for 15min and permeabilized with0.3%Triton X-100for 10min.After blocking with5%goat serum in19PBS with0.3%Triton X-100,the cells were incubated with mouse anti-Id-1(1:25),rabbit anti-N-cadherin(1:200; Epitomics;USA),and rabbit anti-b-catenin(1:200;Ab-cam)overnight at4°C.Cell monolayers were then incu-bated with?uorescein isothiocyanate(FITC)-labeled secondary antibody(1:200;KPL)for2h at room temper-ature and stained with1l g/l L of40,6-diamidino-2-phe-nylindole(DAPI;Sigma-Aldrich;USA)in PBS with0.3% Triton X-100.After three washes with19PBS,the slides were mounted and analyzed using a?uorescence micro-scope(magni?cation9200;H55OS;Nikon;Japan)or a laser-scanning confocal microscope(magni?cation9400; TCS-SP5;Leica Camera AG;Germany).
Western blotting
Cells were treated as described above and harvested at the indicated time points.Whole-cell lysates were prepared by re-suspending cells in RIPA lysis buffer(Beyotime; China),and protein concentrations were measured using the BCA protein assay kit(Beyotime).Equal amounts of denatured proteins were resolved by polyacrylamide gel electrophoresis and analyzed by immunoblotting with pri-mary antibodies against Id-1(1:50),Snail(1:500),b-cate-nin(1:2,000),Twist(1:100)(all from Abcam),E-cadherin (1:2,000),N-cadherin(1:6,000),and Vimentin(1:3,000) (all from Epitomics);GAPDH(1:10,000;KangChen Bio-tech Inc.,China)was used as a loading control.After the incubation with HRP-conjugated secondary antibodies (1:4,000),the signals were visualized by the ECL system
(Thermo Fisher Scienti?c Inc.,MA,USA)and quanti?ed using a Gel-Pro analyzer(Media Cy-bernetics Inc.,Silver Spring,MD,USA).The experiments were performed in triplicate.
Cell proliferation assay
Cell proliferation was quantitatively evaluated using the Cell Count kit-8(CCK-8;Beyotime,China).Cells were plated in 96-well plates at a density of29104cells/mL.After12h of incubation,RPMI-1640with1%FBS and TGF-b1was added to the experimental group.The cells were incubated for the indicated https://www.wendangku.net/doc/0e3409068.html,K-8solution(10l L)was then added to each well,and cells were incubated for an additional 2h at37°C.The absorbance at450nm(OD450)was determined using a microplate reader(Model680;Bio-Rad, CA,USA);RPMI1640containing10l L CCK-8was used as blank.The proliferation index(PI)was calculated using the formula:PI=OD450of the experimental group/OD450 of the control group.
Table1Characteristics of71gastric cancer patients Characteristics No.of patients% Age(years)a
\623549.3 C623650.7 Gender
Male4766.2 Female2433.8 Tumor size(cm)a
\43447.9 C43752.1 Operation method
Radical distal subtotal gastrectomy4360.6 Radical total gastrectomy2231.0 Palliative distal subtotal gastrectomy4 5.6 Palliative total gastrectomy2 2.8 Differentiation
I00.0 II1521.1 III5678.9 Primary tumor
Tis,T13 4.2 T21216.9 T31216.9 T44462.0 Regional lymph nodes
N02332.4 N11318.3 N21115.5 N32433.8 Distant metastasis
M06490.1 M179.9 TNM stage grouping
IA,IB1115.5 IIA,IIB2028.2 IIIA,IIIB,IIIC3346.5 IV79.8 a Split at median
Med Oncol(2014)31:19Page3of1019
Statistical analysis
Experimental data were presented as the mean?SEM of at least three independent experiments performed in duplicate.Statistical analysis was performed using GraphPad Prism5(GraphPad Software;USA)and SPSS 20.0software(SPSS;Chicago,IL,USA).Differences between tumor and adjacent tissue were analyzed by the Wilcoxon test.To assess the relationship between variables and clinical pathology parameters,all cases were divided into high and low expression groups(classi?ed by the median value),and then a chi-squared test was performed. Pearson’s correlation analysis was used to explore the association between Id-1and TGF-b1.Two-tailed levels of signi?cance were used and P\0.05was considered sta-tistically signi?cant.
Results
Clinical and pathological characteristics of GC patients
The clinic-pathological characteristics of71gastric carci-noma patients were summarized in Table1.The specimens included47male(66.2%)and24female(33.8%).The cutoffs of age and tumor size were set at their median values,62and4cm,respectively.The patients underwent surgical resection including radical(65,91.6%)and pal-liative(6,8.4%)gastrectomy.Differentiated tumors were classi?ed as stage II(15patients,21.1%)and III(56, 78.9%).As de?ned by the location of primary tumor,T1 was diagnosed in3(4.2%)cases,whereas T2in12 (16.9%)cases,T3in12(16.9%)cases,and T4in44 (62.0%)cases.Regional lymph nodes metastasis and distant metastasis were diagnosed in48(67.6%)and7 (9.9%)cases,respectively.The TNM stage grouping was distributed as follows:I,11cases,15.5%;II,20cases, 28.2%;III,33cases,46.5%;and IV,7cases,9.8%.
Expression of Id-1and TGF-b1in GC tissue
Specimens collected from tumor and adjacent tissues of GC patients were analyzed for Id-1and TGF-b1expression by immunohistochemistry.Representative images of Id-1 and TGF-b1immunostaining were shown in Fig.1a–h.Id-1 expression was predominantly observed in the cytoplasm of GC cells.The expression of TGF-b1was identi?ed as positive in the cytoplasm of tumor cells.The expression of Id-1and TGF-b1was quantitatively evaluated as the per-centage of positively stained area relative to the total analyzed cell area(%area);the statistical results were shown in Table2and https://www.wendangku.net/doc/0e3409068.html,pared with the adjacent tissue,GC tissue showed signi?cantly higher levels of both Id-1(P\0.01)and TGF-b1(P\0.01).
Association between Id-1and TGF-b1expression
and clinical characteristics
Further analyses were undertaken to evaluate the associa-tion of the levels of Id-1and TGF-b1in tumors with the clinical parameters of71GC patients.Based on Id-1and TGF-b1expression levels determined as%area by immunohistochemistry(median expression values were 3.407and8.344,respectively),the patients were divided into high and low expression groups.As shown in Table3, the statistical analysis by chi-square test revealed no sig-ni?cant correlation of Id-1and TGF-b1expression with patients’age,gender,tumor size,primary tumor parame-ters(T stage),distant metastasis,and TNM stage grouping. However,Id-1showed a statistically signi?cant association with tumor differentiation(P=0.048),whereas TGF-b1 levels were positively correlated with regional lymph node metastasis(P=0.028).
Correlation between Id-1and TGF-b1expression
The association between Id-1and TGF-b1levels in tumor tissue was assessed by Pearson’s correlation ana-lysis.The results shown in Fig.2revealed a signi?cant positive correlation between Id-1and TGF-b1expression levels(r=0.503,P\0.01):in the scatter plot,the linear regression analysis was carried out to show the linear trend between the two variables,indicating an apparent association between Id-1and TGF-b1in GC.
Id-1expression stimulated by TGF-b1in AGS cells
Based on the veri?ed correlation between Id-1and TGF-b1in human specimens,we further investigated Id-1 expression following the treatment with TGF-b1in GC cell line AGS in vitro.Immunocytochemistry analysis revealed that Id-1was localized to the cell cytoplasm and nucleus(Fig.3a–c),while Western blotting results showed Id-1upregulation in TGF-b1-treated AGS cells compared with untreated cells(P\0.05,Fig.3d,e).The effect of TGF-b1on cellular proliferation was assessed by the treatment of cells with different concentrations of TGF-b1(0,2,5,10,20,and50ng/mL)by CCK-8 assay.The results showed that there was no signi?cant difference in the proliferation between TGF-b1-treated cells and control cells,irrespective of the incubation time (Fig.3f).Overall,these results showed that TGF-b1 upregulated Id-1expression in GC cells independent of cell proliferation.
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Expression of epithelial-mesenchymal transition-related proteins
The epithelial-mesenchymal transition (EMT)occurs as a key process in tumor metastasis [33].To investigate whe-ther TGF-b 1affects EMT in GC,we assessed the expres-sion of EMT-related proteins in TGF-b 1-treated AGS cells.The levels of N-cadherin,Vimentin,b -catenin,Snail,and Twist were evaluated after stimulation by TGF-b 1.Western blotting results revealed that N-cadherin and b -catenin were signi?cantly upregulated by TGF-b 1(P \0.05and P \0.01,respectively),but there was no change in Vimentin,Snail,and Twist levels compared with control cells (Fig.4a,b).These results were corroborated by the cell immuno?uorescence staining (Fig.4c–f).Besides,the staining results further showed the distribu-tions of detected proteins in AGS cells.N-cadherin was localized to cell membrane,whereas b -catenin
was
Fig.1Id-1and TGF-b 1expression in 71human gastric carcinoma.a –h Representative Id-1and TGF-b 1immunohistochemistry images of adjacent tissue and tumor tissue.Magni?cation:a ,c ,e ,and g 9200;b ,d ,f ,and h 9400.i Statistical summary of Id-1and TGF-b 1staining intensity in adjacent tissue and tumor tissue (**P \0.01).Note that increased Id-1and TGF-b 1expression in tumor tissue was observed in adjacent tissue.Error bars represent the mean intensity ?SEM
Table 2Descriptive statistics of immunohistochemical variables
**Compared with the matched adjacent tissues;signi?cance is at 0.01level
Variables Minimum Maximum Mean SE Median P
Adjacent tissues Id-10.00025.739 1.6630.5250.457TGF-b 10.01534.583 3.3130.878 1.185Tumor tissues
Id-10.02720.591 4.4220.486 3.407\0.01**TGF-b 1
0.073
23.303
8.077
0.617
8.344
\0.01**
Med Oncol (2014)31:19Page 5of 1019
detected in cytoplasm (as shown in Fig.4c,d).Vimentin was found in cytoplasm,while Snail was expressed in nucleus (as shown in Fig.4e,f).
Discussion
In recent years,the relationship between Id-1and TGF-b 1has become a promising direction in cancer research.In metastatic breast tumor cells,Id-1levels increase almost twofold in response to TGF-b 1stimulation,suggesting that Id-1may be a mediator of TGF-b -induced responses to facilitate tumor reinitiation [31].In addition,it has been demonstrated that SMAD,the classical downstream mediator of TGF-b 1signaling,can directly interact with Id-1in promoting breast tumors for lung metastasis [34,35].A recent study of prostate cancer cells also demon-strates that TGF-b 1increases the proliferation and migra-tion of cancer cells by upregulating the expression of Id-1[32].Taken together,these ?ndings imply that Id-1is a TGF-b 1target gene and their vital roles in affecting the metastasizing potential of cancer cells.
In this study,we found that the expression levels of Id-1and TGF-b 1in 71human GC samples were higher than those in the adjacent tissue,which was consistent with previous ?ndings.Higher Id-1expression has been also detected in human ovarian tumors compared with border-line tumors [8];similar results have been obtained in prostate cancer biopsy samples [36]and esophageal squa-mous cell carcinoma specimens [11].The aberrant expression of TGF-b 1has been linked to pathological conditions in urinary tract [37],plasma [38],and tumor specimens [39–41].The results of our study showed that the expression of Id-1was related to tumor differentiation,while TGF-b 1expression was associated with regional lymph node metastasis,suggesting that Id-1and TGF-b 1levels could be signi?cant predictors of gastric carcinoma progression.
Another novel ?nding of this study was the positive correlation between the expression of Id-1and TGF-b 1in GC.Id-1has been identi?ed as a regulator of VEGF,and the combination of these two proteins has been proposed as a potential target for cancer therapy [42,43].It has been established that Id-1is co-expressed with a number of
Table 3Association between the expression levels of Id-1and TGF-b 1and clinical characteristics Characteristics
Id-1expression a TGF-b 1expression a Low
High P
Low High P
All patients 3635
36
35
Age (years)a
0.723
0.552
\6217181916C 621917
17
19
Gender 0.358
0.055
Male 22252027Female 1410
16
8
Tumor size (cm)a
0.403
0.718
\419151816C 4
1720
18
19
Differentiation 0.048*0.819
I,II 11487III
2531
28
28
Primary tumor 0.1640.164
Tis,T1,T2105105T3,T426
30
26
30
Regional lymph nodes 0.737
0.028*
N01112167N1,N2,N32523
20
28
Distant metastasis 0.662
0.662
M0
33313331M1
34
3
4
TNM stage grouping 0.2230.069
I 7492II 7131010III,IV
22
18
17
23
*Signi?cance is at 0.05level a
Split at
median
Fig.2Correlation between Id-1and TGF-b 1expression.There was a signi?cantly positive correlation between Id-1and TGF-b 1expression (r =0.503,**P \0.01)in 71human gastric carcinoma specimen
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factors implicated in cancer cell invasiveness,including CD44[44],epidermal growth factor receptor (EGFR)[45],and thrombospondin 1(TSP-1)[46];however,the rela-tionship between Id-1and TGF-b 1remains unclear.Here,we found that the expression of Id-1showed a statistically signi?cant positive correlation with that of TGF-b 1.To the best of our knowledge,this is the ?rst demonstration of a direct association between Id-1and TGF-b 1in GC,which suggests that the combination of Id-1and TGF-b 1might promote the invasion and progression of GC.
In order to validate the clinical ?ndings and further explore the possible mechanism,in vitro experiments on AGS cell line were performed.After the treatment of TGF-b 1,the expression of Id-1increased and this elevation might relate to time.This demonstrated that Id-1might mediate the downstream effects of the TGF-b pathway.These results are in agreement with the ?ndings in breast and prostate cancers [31,32],but incompatible with those in breast epithelial cells,where TGF-b inhibited Id-1expression [47].This switched expression of Id-1in response to TGF-b 1may be caused by the loss of TGF-b growth-inhibitory responses [35].At the same time,we examined the effect of TGF-b 1on the proliferation of AGS at different concentrations.The results showed that Id-1expression induced by TGF-b 1was independent of cell number.
Given the well-established relationship between EMT,tumor metastasis,and TGF-b 1,we also examined the expression of EMT-related proteins [48,49].We found that N-cadherin and b -catenin expression was signi?cantly upregulated by TGF-b 1treatment,which was consistent with previous results showing the association between EMT proteins and TGF-b 1.We proposed that N-cadherin and b -catenin are upregulated by TGF-b 1via Id-1,because earlier data have indicated that the expression of Id-1has a positive correlation with that of N-cadherin and b -catenin,probably via the PI3K/Akt signaling pathway [50,51].Besides,one recent research in breast cancer has
revealed
Fig.3Effect of TGF-b 1on Id-1expression and proliferation in AGS cells.a and b Expression of Id-1protein was detected by immuno-?uorescence at 24h (a )and 48h (b )in the absence or presence of 10ng/mL TGF-b 1.The representative images were acquired with a magni?cation of 9200.c Statistical data were represented as the average gray value ?SEM of three independent experiments (*P \0.05).d and e Western blotting analysis of Id-1protein expression.GAPDH was used as an internal control.Each bar represents the mean ?SEM (*P \0.05).The results were consistent with data of immuno?uorescence.f Effect of different concentrations of TGF-b 1on AGS cells was determined by CCK-8at 24and 48h.No difference was found among the six groups
Med Oncol (2014)31:19Page 7of 1019
that TGF-b 1can induce Id-1expression,while Snail or Twist overexpresses [52].Therefore,based on our data and previous ?ndings,we propose a hypothesis that TGF-b 1stimulates the expression of Id-1,which in turn upregulates the levels of N-cadherin and b -catenin through activation of the PI3K/Akt signaling pathway.This hypothesis needs further experimental support.
In conclusion,our study demonstrated that both Id-1and TGF-b 1were upregulated in GC compared with the adjacent tissue and that this effect was related to GC progression.Moreover,the expression of Id-1was positively correlated with that of TGF-b 1in GC samples.The experiments in vitro showed that Id-1levels were upregulated by TGF-b 1,further con?rming the association between Id-1and TGF-b 1in GC.These results indicate that in gastric tumor cells,Id-1may be a speci?c downstream target of TGF-b 1,suggesting impor-tant roles of Id-1and TGF-b 1in GC development.Thus,this study provides new insights into the mechanism by which TGF-b 1/Id-1axis control tumor progression and may lead to new treatment strategies in
GC.
Fig.4Expression changes of EMT-related proteins.a Expression levels of N-cadherin,vimentin,b -catenin,Snail,Twist,and GAPDH were detected by Western blotting at 24h in the absence or presence of 10ng/mL TGF-b 1.GAPDH was used as an internal control.b Statistical data of Western blotting were represented as the average gray value ?SEM of three independent experiments (*P \0.05;
**P \0.01).All the data were normalized by the expression of GAPDH.c –f Cellular immuno?uorescence staining of N-cadherin,b -catenin,vimentin,and snail.The representative images were acquired with a magni?cation of 9400under laser-scanning confocal microscope
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Acknowledgments This work was supported by grants from the National Science Foundation of China(No.30871312)and the National Basic Research Program of China(973program,No. 2011CB910700).
Con?ict of interest The authors have no con?ict of interest to declare.
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脑白质病变的特点及影像特征
脑白质病变的特点及影像特征 全网发布：2011-06-23 19:48 一、概论 有多种疾病累及中枢神经系统的脑白质，而脑白质病灶又分为原发和继发性两类?继发于中枢神经系统感染、中毒、变性和外伤等疾病的白质病灶，属继发性脑白质病；原发于脑白质的疾病称原发性脑白质病，简称脑白质病( Leukoencephalopathy ).脑白质病按发病时髓 鞘是否发育成熟再进一步分为2类： 1?先天性和遗传性脑白质病 此类脑白质病通常又称之为脑白质营养不良( Leukodystrophy )或遗传性脑白质营养不良(Heredity Leukodystrophy )，髓磷脂的产生、维持和分解异常是脑白质髓鞘形成障碍的病因?这类疾病通常包括：肾上腺脑白质营养不良、异染性脑白质营养不良、类球状细胞型脑白质营养不良、海绵状脑病、亚历山大病、皮质外轴突发育不良等 2. 获得性脑白质病 获得性脑白质病主要指已经发育成熟的正常髓磷脂被破坏，即：脑白质脱髓鞘 (demyelination )疾病?它主要包括：多发硬化、进行性多灶性脑白质病、急性散发性脑脊髓 炎、亚急性硬化性全脑炎、桥脑中央髓鞘溶解症、胼胝体变性、皮层下动脉硬化性脑病和同 心圆硬化等? 2、正常脑白质的结构、发育及影像诊断 (一)脑白质的结构 脑白质主要由神经纤维构成，而神经纤维分有髓和无髓两种?有髓神经纤维的外周有髓样结 构包裹，称之为髓鞘?在电子显微镜下，髓鞘由少突胶质细胞突起末端的扁薄膜包卷轴突而形成?一个
板层”样结构，其主要 少突胶质细胞有多个突起，分别包卷多个轴突，其胞体位于神经纤维之间 ?一个轴 突可被邻近几个少突胶质细胞的突起包绕， 这些突起相互融合，形成轴突外层 绝缘”的髓鞘. 髓鞘伴轴突一起生长，并反复包卷轴突多次，形成多层同心圆的螺旋 化学成份是类脂质和蛋白质， 习惯上称之为髓磷脂?由于类脂质约占髓鞘的 80%， 呈嫌水性， 带离子的水不容易通过， 而起绝缘”作用.当其受损时，较多水进入髓磷脂内， 引起脑白质的 水含量增加. （2） 脑白质的发育 髓鞘形成是脑白质发育的最后阶段 ?胎儿在宫内第3个月~6个月期间，自脊神经根和脊索、 从尾侧向头侧发展开始形成髓鞘 ?出生时，已经有相当数量的髓磷脂位于脑干、桥脑臂、内 囊后肢和半卵圆中心的放射冠等部位 ?其成熟过程主要发生于出生后，并持续到 20岁以前， 脑白质的髓鞘终生都在改建 ?后天性脑白质疾病的病灶在脑内呈弥散分布，通常病灶较小， 不引起脑形态结构的显著改变，但是各种脑白质病的晚期均导致脑萎缩 ?少数先天性脑白质 疾病可引起脑体积增大，多数亦不引起脑的形态改变 （3） 影像学表现 1 . MRI 表现 MRI 是显示脑发育过程中脑内各种解剖结构形态变化的最佳影像学手段，显示脑白质髓鞘 发育成熟过程也以 MRI 为首选?在T1加权像上，无髓鞘的脑白质呈低信号，随 髓磷脂出现 并成熟，脑白质逐渐变为 高信号?相反，在T2力口权像上，无髓鞘脑白质呈高信号，随髓磷 脂成熟，脑白质信号强度 逐渐下降?通常，在出生后头6个月~8个月，监测髓磷脂发育，以 T1加权像为佳；而出生6个月后，则以T2加权像更为敏感?（髓鞘越多、T1信号越高、T2 信号越低） 脑白质各部位髓鞘形成和成熟并非同步进行，而有先后顺序 ?足月健康新生儿，在丘脑、小 脑臂有髓磷脂沉积；1个月后，内囊后肢也可见到髓磷脂沉积 ；6个月时，在视放射区、内囊 前肢、放射冠及中央前回均显示有髓磷脂沉积 ；8个月时，额顶叶脑白质出现髓磷脂沉积 ;1
概念结构设计和逻辑结构设计
概念结构设计和逻辑结构设计 一.系统概述 本系统通过调查从事医药产品的零售，批发等工作的企业，根据其具体情况设计医药销售管理系统。医药管理系统的设计和制作需要建立在调查的数据基础上，系统完成后预期希望实现药品基本信息的处理，辅助个部门工作人员工作并记录一些信息，一便于药品的销售和管理。通过此系统的功能，从事药品零售和批发等部门可以实现一些功能，如：基础信息管理，进货管理，库房管理，销售管理，财务统计，系统维护等。 二．概念结构设计 1.员工属性 2.药品属性 3.客户属性 4.供应商属性 5.医药销售管理系统E--R 图 三．逻辑结构设计 该设计概念以概念结构设计中的E--R 图为主要依据，设计出相关的整体逻辑结构，具体关系模型如下：（加下划线的表示为主码） 药品信息（药品编号，药品名称，药品类别，规格，售价，进价，有效期，生产日期，产地，备注） 供应商信息（供应商编号，供应商名称，负责人，） 员工 姓名 家庭地址 E-maill 电话 员工 编号 年龄 帐号
四．系统各功能模块如何现（数据流实图）；1.基本信息管理子系统 基本信息管理子系统 药品信息员工信息客户信息供应商信息2.库存管理子系统 库存管理子系 统 库存查询库存信息出入库登记库存报表3.销售管理子系统 销售管理 销售登记销售退货销售查询 4.信息预警子系统 信息预警 报废预警库存预警 5.财务统计子系统 财务统计 统计销售额打印报表 6.系统管理子系统
系统管理 权限管理修改密码系统帮助 五．数据库设计（E-R图，数据库表结构） 1.药品基本信息表 列名字段数据类型可否为空说明药品编号 药品名称 药品类别 规格 进价 有效期 生产日期 售价 产地 备注 2.员工基本信息表 列名字段数据类型可否为空说明员工编号 性别 身份证号 员工年龄
关于语文知识结构的构建
关于语文知识结构的构建 （王文君） 前几年，读魏书生老师的书，了解了“知识树”这个名词，也在自己的教学中有意无意的借鉴魏老师的做法，给学生介绍知识树。但从初一教到初四，总有相当一部分学生对“表达方式”、“修辞手法”、“写作方法”、“记叙六要素”、“小说三要素”、“铺垫”、“烘托”等一些列语文知识术语一塌糊涂。面对试卷上的相关阅读理解题，学生总是一头雾水，答非所问。每次阅卷，总是感慨：怎么就教不会学生学语文呢？当然，语文教育的终极目标不是应对考试，但语文素养高的人是不怕考试的。 反思自己多年来的语文教学，学生学不好语文，原因是多方面的，但至少有一点是十分重要的原因，那就是：没有教会学生用必要的语文知识学语文，以至于学生对纷繁复杂的语文万象的认识总是零散的、模糊的、杂乱的。一句话，没有教会学生构建起属于他自己的合理的语文学科知识结构。 上学期，我们大力倡导师生共同构建学科知识结构，培养学生的自主学习能力。学期初，要求每位任课教师通读教材，研读课标，根据课标要求和教材编写意图梳理每单元的知识点，确立单元教学目标和重点、难点，进而整理出本册教材的知识结构图，张贴在办公室和教室，以便师生在教学中适时运用、及时巩固。在这方面，我们只是刚刚起步，边学习边摸索，没什么经验可谈，只是有了一点点行动而已。相信很多老师在自己的教学实践中，一直都在默默坚持这样做着，
而且做得比我们好。 下面，从三方面和大家进行交流：一是构建学科知识结构的必要性，二是构建语文学科知识结构应注意的问题，三是介绍我们上学期整理的知识结构图。抛砖引玉，不当之处，请大家批评指正。 一、为什么要构建学科知识结构 下面与大家交流一下我读到的有关学科知识结构的论述文章和 我的一些粗浅认识，但愿这些交流能使我们对构建语文学科知识结构这一问题有更全面更理性的认识，使学科知识的构建更具科学性、实效性。 (一)、关于“语文知识树”的争鸣 “语文知识树”产生于20世纪70年代末，是魏书生老师有感于当时语文教育考题泛滥、教学缺乏序列的现状，引导学生画出来的。从大的方面基本确定为4部分22项131个知识点：4部分依次为“文言文知识”、“基础知识”、“阅读与写作”和“文学常识”。“文言文知识”具体包括“实词”、“虚词”、“字”和“句式”4项；“基础知识”包括“文字”、“句子”、“修辞”、“标点”、“语音”、“词汇”、“语法”和“逻辑”8项；“阅读与写作”包括“中心”、“结构”、“语言”、“材料”、“表达”和“体裁”6项；“文学常识”包括“古代”、“现代”、“当代”和“外国”4项。每一项下面又包括众多知识点共131个。 “语文知识树”自其产生以来的十多年中，在我国的语文教育界引起了较大的反响。综观各种评论，认为画知识树的作用主要有以下几点：
百度竞价账户结构细分(SEM)
百度竞价账户结构细分(SEM) 目前搜索营销的趋势是关键词越来越多，百度搜索推广产品为了方便用户管理关键词而设置了几个层级，经验表明，合理的账户结构设计以及精细的关键词分组，可以有效提升营销效果。所以在这里先介绍一下账户的结构。 1. 账户结构 一个账户最多可包含100个推广计划，每个推广计划最多可包含1000个推广单元，每个推广单元最多可包含5000个关键词和50个创意。同一个单元的关键词和创意是多对多的关系，如下图所示： 2. 账户设计 百度搜索推广已经为商户准备了一个基本的框架，利用此框架可自由地组织自己的推广计划、推广单元、关键词和创意。 （1）推广计划设置思路 商户需要根据营销目的来划分推广计划。以下划分方法可供参考： 对于关键词数量较少，并且是单一业务推广的账户 既可以将关键词按词性分组，在一个计划下管理；如有需要，也可按照营销目的、地域等因素划分为多个不同的计划。这样划分的好处在于可以以多个维度观察数据的变化，及时找出有利于账户推广的操作。 对于关键词数量较多，或多种业务推广的账户 可根据产品/服务名称、推广预算、推广地域、提供产品/服务地区等维度划分多个计划（还可将以上维度适当组合）；对特殊事件，如促销、活动等可以单独建立一个计划。
计划维度的举例说明： （2）推广单元设置思路 建立好推广计划以后，我们要仔细地考虑合理划分推广单元。一个计划下一般会有多个推广单元，首先，需要参照计划的思路，细分单元，以便逻辑清晰，减少重复，而且更便于后期管理和评估。其次，需要“词义相近，结构相同”的关键词归到同一单元中，保持思路清晰，主题唯一，词性句式统一，这样做的好处同样可以便于商户撰写更相关的创意，有利于创意中嵌入关键词，在搜索结果页吸引更注意，提高点击率。 具体方法可以参考以下两种：为每一个推广单元设置单独的“主题” ，如：可以将“成人英语单元”和“少儿英语单元”分别设置为两个推广单元。因为“成人”和“少儿”分别是不同意义的词，而且推广商户为这两类业务撰写创意的角度也会不同，因此需要分为两个不同的单元。 按照网民的搜索意图建立推广单元，比如可以按照“兴趣、对比、购买”三个消费的阶段来划分。按照潜在受众搜索意图建立推广单元的办法，易于我们了解该品牌或该业务在市场中处于何种位置，便于推广商户及时跟进线下营销活动，提高公司整体效益。对于不同的产品或服务这几个阶段会有所不同，我们只是从这几个角度去考虑，不一定必须遵循这三个阶段，最终还是要根据建立的计划去进一步的细分单元。 单元设置的举例说明：
压紧机构
压滤机的压紧装置蔡忠群压滤机：在过滤介质一侧施加机械力实现过滤的机械。 压滤机是集机电液于一体，具有现代技术水平先进的过离机械产品，它主要由机架部分，过滤部分，压紧部分，电气控制部分，（自动拉板部分）。 压紧部分：手动压紧、机械压紧、液压压紧。 一．手动压紧：主要是以螺旋式机械千斤顶推动压紧板将滤板压紧。螺旋式机械千斤顶是千斤顶当中比较常用的一种。 千斤顶，是一种起重高度小(小于1m)的最简单的起重设备。它有机械式和液压式两种。机械式千斤顶又有齿条式与螺旋式两种，由于起重量小，操作费力，一般只用于机械维修工作，在修桥过程中不适用。液压式千斤顶结构紧凑，工作平稳，有自锁作用，故使用广泛。其缺点是起重高度有限，起升速度慢。千斤顶主要用于厂矿、交通运输等部门作为车辆修理及其它起重、支撑等工作。其结构轻巧坚固、灵活可靠，一人即可携带和操作。千斤顶作为一种使用范围广泛的工具，采用了最优质的材料铸造，保证了千斤顶的质量和使用寿命。 千斤顶分为机械千斤顶和液压千斤顶两种，原理各有不同。从原理上来说，液压千斤顶所基于的原理为帕斯卡原理，即：液体各处的压强是一致的，这样，在平衡的系统中，比较小的活塞上面施加的压力比较小，而大的活塞上施加的压力也比较大，这样能够保持液体的静止。所以通过液体的传递，可以得到不同端上的不同的压力，这样就可以达到一个变换的目的。我们所常见到的液压千斤顶就是利用了这个原理来达到力的传递。机械千斤顶采用机械原理，以往复扳动手柄，拔爪即推动棘轮间隙回转，
小伞齿轮带动大伞齿轮、使举重螺杆旋转从而使升降套筒获得起升或下降，而达到起重拉力的功能。但不如液压千斤顶简易。 按结构特征分千斤顶的结构和技术规格 可分为齿条千斤顶、螺旋（机械）千斤顶和液压（油压）千斤顶3种。 (1). 齿条千斤顶: 由人力通过杠杆和齿轮带动齿条顶举重物。起重量一般不超过20吨，可长期支持重物，主要用在作业条件不方便的地方或需要利用下部的托爪提升重物的场合，如铁路起轨作业。 (2).螺旋千斤顶:采用螺杆或由螺杆推动的升降套筒作为刚性顶举件的千斤顶。即用刚性顶举件作为工作装置，通过顶部托座或底部托爪在行程内顶升重物的轻小起重设备。头部经特殊热处理，梅花形防滑面设计，使产品在使用中不易产生滑脱、顶弯、折断等现象。螺旋千斤顶顶为进一步降低外形高度和增大顶举距离，可做成多级伸缩式的。普通螺旋千斤顶靠螺纹自锁作用支持重物，构造简单，但传动效率低，返程慢。自降螺旋千斤顶的螺纹无自锁作用，但装有制动器。放松制动器，重物即可自行快速下降，缩短返程时间，但这种千斤顶构造较复杂。螺旋千斤顶能长期支持重物，最大起重量已达100吨，应用较广。下部装上水平螺杆后，还能使重物做小距离横移。螺旋千斤顶按其结构和使用场所分为：①普通型螺旋千斤顶，其代号的表征字母为ql。②普通高型螺旋千斤顶，其代号的表征字母为qlg。③普通低型螺旋千斤顶，其代号的表征字母为qld。④钩式螺旋千斤顶,其代号的表征字母为qlg。⑤剪式螺旋千斤顶,其代号的表征字母为qlj。⑥自落式螺旋千斤顶,其代号的表征字母为qlz。 (3). 液压千斤顶: 由人力或电力驱动液压泵，通过液压系统传动，用缸体或活塞作为顶举件。液压千斤顶可分为整体式和分离式。整体式的泵与液压缸联成一体；分离式的泵与液压缸分离，中间用高压软管相联。液压千斤顶结构紧凑，能平稳顶升重物，起重量最大达1000吨，行程1米，传动效率较高，故应用较广；但易漏油，不宜长期支持重物。如长期支撑需选用自锁千斤顶，螺旋千斤顶和液压千斤顶为进一步降低外形高度或增大顶举距离，可做成多级伸缩式。液压千斤顶除上述基本型式外，按同样原理可改装成滑升模板千斤顶、液压升降台、张拉机等，用于各种特殊施工场合。液压千斤顶按其结构、用途分为如下两种：①立式螺纹连接结构的液压千斤顶其代号的表征字母为qyl。②立卧两用液压千斤顶，其代号的表征字母为qw。 可分类为分离式千斤顶，卧式千斤顶，爪式千斤顶，同步千斤顶，一
部编版一上语文全册汉字结构整理
在2500个现代汉语常用字表里，上中下结构、左中右结构和特殊结构的字有以下68个字： ①上中下结构（46字）：鼻、茶、豆、复、高、谷、黄、京、竞、竟、莫、善、率、算、享、言、鱼、葬、曾、蒸、总爱、暴、参、带、帝、害、寒、壶、宫、壳、量、旁、牵、塞、赛、收、兽、索、燕、赢、寨、哀、裹、衰、器（上中下结构和品字结构属于上下结构） ②左中右结构（16字）：撤、缴、微、狱、御、班、斑、瓣、辨、辩、辫，粥、衡、街、衔、激（属于左右结构） ③特殊结构（6字）：办、坐、爽、乖、乘、承【有时也称为镶嵌结构，有时也把它们归到独体字中】
部编版一上汉字结构整理 1.独体字： 田、禾、云、雨、鸟、虫、七、八、九、十、马、土、不、子、文、乐、白、皮、小、儿、车、羊、也、气、了、片、大、飞、个、两、头、里、见、东、西、女、开、正、无、来、少、牛、果、书、尺、业、本、刀、力、木、心、升、中、么、立、午、年、巴、长、串、 （坐、办有时也称为特殊结构、镶嵌结构） 2.上下结构： 足、花、爸、字、桌、学、音、台、雪、草、家、是、走、会、星、南、采、莲、鱼、尖、 条、美、丽、今、前、黑、它、伞、兔、最、公、写、点、要、当、空、真、觉、穿、蓝、 （黄、高也是上中下结构，众、森也是品字结构） 3.左右结构： 船、江、北、说、蛙、就、听、猫、鸭、桃、作、课、校、明、从、双、林、旗、红、歌、晚、昨、影、狗、好、朋、比、谁、短、把、诗、给、们、以、彩、到、没、绿、睡、那、海、师、吗、什、时、候、得、很、服、快、和、娃、挂、活、姐、叔、群、竹、加、洞、鸦、找、许、法、放、住、孩、玩、吧、呀、院 （树也是左中右结构） 4.全包围结构： 四、国、回 5.半包围结构： 风、画、句、在、看、闪、可、反、远、有、近、还、边、包、起、后、左、右、友、尾、过、成、问、老、同、着、向、处、进、发、爬 6.特殊结构：办、坐、爽、乖、乘、承
组织结构的基本类型(全)
组织结构的基本类型 组织结构（organizational structure）是表明组织各部分排列顺序、空间位置、聚散状态、联系方式以及各要素之间相互关系的一种模式，是整个管理系统的“框架”。 1.直线型组织结构又称单线型组织结构，是最古老、最简单的一种组织结构类型。其特点是组织系统职权从组织上层“流向”组织基层。上下级关系是直线关系，即命令与服从的关系。 优点:①结构简单，命令统一；②责权明确；③联系便捷,易于适应环境变化；④管理成本低。 缺点：①有违专业化分工的原则；②权力过分集中，易导致权力的滥用。 2.职能型组织结构又称多线型组织结构。其特点是采用按职能分工实行专业化的管理办法来代替直线型的全能管理者，各职能部门在分管业务范围内直接指挥下属。 优点：①管理工作分工较细；②由于吸收专家参与管理，可减轻上层管理者的负担。 缺点：①多头领导，不利于组织的集中领导和统一指挥；②各职能机构往往不能很好配合；③过分强调专业化。 3、直线职能制组织结构 直线职能制组织形式，是以直线制为基础，在各级行政领导下，设置相应的职能部门。即在直线制组织统一指挥的原则下，增加了参谋机构。 优点：既保证了集中统一的指挥，又能发挥各种专家业务管理的作用。 缺点： 1.各职能单位自成体系，不重视信息的横向沟通，工作易重复，造成效率不高。 2.若授权职能部门权力过大，容易干扰直线指挥命令系统。 3.职能部门缺乏弹性，对环境变化的反应迟钝。
4.可能增加管理费用。 5.注意：直线职能制仍被我国绝大多数企业采用。 直线职能型组织结构图 4、事业部制 事业部制是欧美、日本大型企业所采用的典型的组织形式。有时也称之为“联邦分权化”，因为它是一种分权制的组织形式。 事业部制组织结构图 利弊：事业部制事在一个企业内对具有独立产品市场、独立责任和利益的部门实行分权管理的一种组织形式。 优点：责权利划分比较明确，能较好地调动经营管理人员地积极性；1)事业部制以利润责任为核心，能够保证公司获得稳定地利润；2)通过事业部门独立生产经营活动，能为公司不断培养出高级管理人才。 主要缺点：1)需要较多素质较高地专业人员来管理事业部；2)管理机构多，管理人员比重大，对事业部经理要求高；3)分权可能架空公司领导，削弱对事业部地控制；4)事业部间竞争激烈，可能发生内耗，协调也较困难。 条件：1、具备专业化原则划分的条件，并能确保独立性，以便承担利润责任； 2、事业部间相互依存，不硬性拼凑； 3、保持事业部之间适度竞争； 4、公司有管理的经济机制，尽量避免单纯使用行政手段； 5、适时而动：1)外部环境好：有利于事业部制； 2)外部环境不好，应收缩，集中力量度过难关。
成人脑白质病的CT及MRI诊断
成人脑白质病的ＣＴ及ＭＲＩ诊断 【摘要】目的：探讨成人脑白质病的影像学特征，为临床诊断和治疗提供可靠依据。方法：对经临床证实的６３例脑白质病影像学表现进行总结分析。结果：血管性脱髓鞘４２例，硬化性脱髓鞘７例，感染性脱髓鞘６例，中毒性脱髓鞘４例，脑白质营养不良性脱髓鞘４例。CT表现为脑白质内多发斑片状低密度区，MRI表现为脑白质内多发T2信号。结论：MRI较CT能更清晰地显示脑白质异常，准确地反映病理改变的特点，有助于进一步提高对脑白质病变的诊断水平。 【关键词】脑白质病；成人；体层摄影术；Ｘ线计算机；磁共振成像；诊断 成人脑白质病不是一种独立的疾病，而是各种脑白质病变的总称。本病的正确诊断，可直接影响临床治疗方案，也直接决定患者的预后。笔者收集63例经临床证实的成人脑白质病资料，对其影像学表现进行回顾性分析，旨在进一步认识成人脑白质病变的影像学表现，以期为临床诊断和治疗提供可靠依据。 1 资料和方法 收集近年来经临床证实的成人脑白质病患者63例，男36例，女27例，年龄16~75岁，平均57岁。血管性脱髓鞘病例均有高血压病史5年以上伴反复心肌梗死史，硬化性脱髓鞘病例均有发作性加重和自发缓解史，经治疗随访确诊，中毒性脱髓鞘临床均有明确的中毒病史，感染性脱髓鞘和白质不良性脱髓鞘均经治疗和随访确诊。 使用西门子6排螺旋机和鑫高益OPEN-035磁共振仪。CT检查一般性常规轴位扫描，MRI检查应用FSE和SE以及FLAIR序列行常规横、矢、冠状扫描，层厚6~10 mm，视野256×192，采集次数2~4次。 2 结果 CT及MRI表现：血管性脱髓鞘42例多伴有多发性脑梗死及脑萎缩改变（见图1A、1B、1C）；硬化性脱髓鞘7例，MRI表现为脑室周围、胼胝体、脑桥、延髓和小脑白质多灶性长T1长T2信号，CT上为低密度改变，伴有脑萎缩（见图2A、2B）。感染性脱髓鞘6例，好发于顶枕叶皮质下，远离脑室系统，可多
机械压紧手动拉板结构及原理
机械压紧手动拉板型结构及工作原理 1、机架部分 机架是由固定压板、活动压板、横梁、支架、大小脚组成。 （1）固定压板：它与小脚连接，除起到支承横梁的重要作用外，中间有进料孔，也可作为进气、进洗涤水的通道，暗流还具有出液通道。 （2）活动压板：是用来压紧滤板的。活动压板两侧装有滚轮，供其前后运动时支撑、定位，在压紧或拉开时，滚轮应处于滚动状态。 （3）横梁：它是滤板的运动导轨及支承件。 2、压紧机构 本压滤机采用机械压紧方式 机械传动压紧是采用电力机械驱动来压紧滤板的。在电力机械驱动下，丝杠带动活动压 板向前压紧全部滤板，向后则带动活动压板复位。 压紧机构是电动机、针轮减速机、主从动齿轮、平面轴承、丝杠螺母、丝杠、卡板等组成，它们固定在电机支架上，丝杠前端通过六角端盖固定在活动压板中心。当电机正转时，通过针轮减速机及齿轮的减速，带动丝杠螺母转动，从而带动丝杠向前推动活动压板向固定压板方向前进，使各滤板逐步形成压紧状态，随着丝杠不断的向前，压紧力越来越大，同时电机驱动电流相应增大，当压紧力达到一定程度时，电机驱动电流也将上升到过流继电器预先调定值，使过流继电器动作，电机停转。由于丝杠及丝杠螺母螺旋升角λ＜4.5°小于摩擦角将产生自锁，保证滤板在工作中始终处于压紧状态。松开时，只需电机反转，当活动压板后退到检测感应区时，活动压板停止后退。 3、过滤机构 厢式压滤机的过滤机构由滤板、滤布所组成； 当滤板压紧后，物料进入滤板的滤室内，固体颗粒被滤布截留在滤室内，液体则穿过滤布顺着滤板沟槽进入出液通道，排出机外。
操作程序及使用方法 本系列压滤机运行前必须对泵站加足液压油，并确认各部位正常后按以下程序进行操作： 下 一 次 工 作 循 环 1．压紧滤板 （1）机械压紧：接通总电源，按下“滤板压紧”按钮，活动压板将在丝杠的推动作用下，把全部滤板压向固定压板一端，并施以预定的压紧力。 （2）液压压紧：接通总电源，按下“压板压紧”按钮，启动油泵。活动压板将在活塞杆的推动作用下，把全部滤板压向固定压板一侧，达到预定的压紧力。 2．进料过滤 滤板压紧后，检查各管路阀门开闭状况，确认无误后，启动进料泵。用储槽进料时，开启进料阀时，应缓慢调节到位。浆液即通过固定压板上的进料孔进入各滤室，在规定的压力范围
衣柜内部结构图以及内部功能细分 超详细
衣柜内部结构图以及内部功能细分超详细 卧室很漂亮也很温馨，可是总觉得缺少点什么?人离不开朋友，就像鱼儿离不开水一样，衣服也需要伴，它也怕孤单寂寞，我们就给它找个衣柜作伴，可卧室衣柜该怎么装修呢？内部结构如何?下面就随小编一起看看衣柜装修内部效果图以及功能部件。 常用衣物收纳配件介绍 带盖储物盒 存放使用率低的大件衣服，或者是过季衣物。可将几条被子或是衣物放在一起，看起来比较整洁。在风沙大、有尘土的北京，这种带盖储物盒很实用，可以有效防尘防土，部分产品还带有透明小视窗，方便日常查找，也可以在上面贴上标签，注明衣物种类。 拉篮
有抽屉式、网格式两种。网状拉篮，适合叠放比较薄的衣物，如毛衣、针织衣等。拉篮抽取方便，适合放置拿取频率比较高的衣物。 裤架 用于收纳需要挂起来的正装裤，一个裤架可以收纳20—25条正装裤。 储物箱 存放不常穿的衣服、小杂物，透明设计，方便寻找衣物。
碎物储藏件可将各种领带、袖口以及皮带分类盛放，整洁清晰，也可存放于抽屉中，在出席各种正式场合前能够更方便找到最合适搭配的配饰。 多功能衣架 可以将围巾和挂饰分开挂放，两者不会再因为藏在抽屉里而相互缠绕，方便取用。 挂衣杆 用于挂放熨烫后的衣服。 挂式储物格 可以挂在衣橱中，将内衣内裤、围巾、薄毛衣、针织衣卷放在中间，每个格子都可以放置多件衣物，既便于分类和查找，也可充分利用衣柜的立体空间。 收纳观念十分重要 “生活中之所以会出现装不下、找不到的情况，并不是衣柜本身不够大，而是许多消费者存在不合理的收纳概念仅仅是储存而已，不能进行有效利用衣柜空间。”宜家北京商场室内设计师曹永隽表示，要做好衣柜收纳，第一步就是建立正确的收纳理念做好衣被的具体分
业务结构
定义调查范围：1、业务范围广度，该公司涉及的经营业务2、细分程度：分解到业务 ――部门一一产品系列一一产品分解到产品层级3、分析方法：利润表分析、收支平衡点分 析 建立假设是在实地尽职调查前，对目标企业的价值源泉是什么，有什么增值机会等问题， 预先假设可能的结论和解决方案。 第一步：快速调查。检索新闻报道，短时间了解行业热点话题。可以看商业、行业杂志及分析报告。 第二步：制作业务结构表，不仅仅要求客户提供。展示某业务向客户提供什么样的服务，以及如何提供该服务的示意图即为结构图。一般纵坐标表示该业务提供商品或服务，横坐标 表示商品或服务从开发到推出市场价值传递过程。 制作企业分支结构/组织结构/股权结构图:1、打开WORD2003 2打开插入项下的图片选项 3、图片中选择组织结构图 4、增加分支机构可以用鼠标左键点击某个小框，根据需要插入形状。这类图表可以很好的理解该公司实际架构，一目了然。 副总副总财务总监 图一：公司组织架构图 以上图表可以对企业管理架构有所认识。 四大分析：企业基础设施分析、竞争环境分析（对手、份额）、宏观环境和市场分析（客户、市场环境）、业务流程分析。 第一、企业基础设施分析。 1、人、财、物情况 2、企业经营、组织、人事、IT职能 发生价值创造的制约因素：部门信息共享不足，库存积压；未能实现生产设备、零部件共享；考核偏重指标，忽视利润。
1、公司占地面积 2、土地权属、是否租赁 3、办公楼面积权证 4、研发设备 I I 1、外地办事部， 门市部情 I I 况 > 2、销售网点分 布 | I 工厂（200人 产品B 品及一系 列产品，原 材料外购， 委托外厂 加工，最后 封装和销 售由该公 司负责。 问题2 : 研发制造销售营销 1、车间包括几个？分 别是什么？ 2、车间建筑面积，什 * 么结构，权证，是否租 赁 3、车间内 主要生产设备简要说明，特点，优势 4、仓库建筑面积，什么结构，权证，是否租赁 I I 图二、三企业基础设施情况分析图管理部门（25人） 第二、宏观环境和市场分析 问题1 : （6人） 目前重点 开发A产产品A 销售 部 （40 人） 国际贸易部 （10 人）
脑白质
脑白质 大脑是由上百亿个神经元组成的,而神经元又是由细胞体和神经纤维组成的,细胞体中有细胞核(颜色深)，神经纤维中有细胞质（颜色浅）。 在大脑中细胞体聚集在大脑表层，看起来颜色深，叫做脑灰质；而神经纤维聚集在大脑内部，看起来颜色浅，叫做脑白质。 脑白质病是一种大脑的结构性改变,以中枢神经细胞的髓鞘损害为主要特征,病变累及专门发挥高级大脑功能的白质束。其临床表现从注意力不集中、健忘和个性改变,到痴呆、昏迷,甚至死亡。 而中毒性脑白质病是由多种毒性因素引起脑白质病:颅脑照射;药物治疗,如某些抗肿瘤药、抗生素及免疫制剂;滥用药物,如甲苯、乙醇、海洛因等;还有环境毒素等。在这些因素中,颅脑照射和抗肿瘤化疗是中毒性脑白质病非常确定的病因。随着肿瘤患者放、化疗的广泛应用,出现医源性脑白质损害的肿瘤患者越来越多。为了更好地认识这一病症,笔者就肿瘤放、化疗引起中毒性脑白质病的临床及其研究进行综述。 脑白质病最显著的临床表现是精神状态的改变,即在没有失语的情况下有注意力、记忆力、视觉空间技能、执行功能和情感状态等其中至少一项缺陷。轻度病例表现为慢性意识模糊状态,伴注意力不集中、记忆力丧失和情感功能障碍;更为严重的病例则产生痴呆、意识缺失、木僵和昏迷等严重后遗症。而灰质的疾病则相反,是以累及语言、行为或感觉功能为主。如果脑白质发生了局灶性坏死,
则精神状态改变比一般体征如偏瘫、感觉障碍和视力丧失突出。中毒性脑白质病的病变分布通常是弥漫性的,其临床分度总体上与白质损害的严重程度相平行。 初步精神状态检查,包括评价注意力不集中的试验、鉴定记忆力障碍的三词延迟回忆试验、评价视觉功能障碍的时钟绘画和评价脑功能的交替运动序列。如果精神状态检查结果可疑,可进一步进行神经精神学测试。如果初步精神状态检查的前两类试验未发现任何缺陷,则可确定无可察觉的大脑损害;如果前两类试验发现异常,可进行大脑神经影像学检查。加权磁共振成像是首选检查手段,是鉴别早期或轻微脑白质病与精神疾病的重要手段,而CT仅能显示重度脑白质损害。 确实有脑白质毒素接触史,如放、化疗和免疫治疗等,并排除其他脑白质损害原因,如遗传性脱髓鞘病等;接触毒源后发生精神状态改变,以及可能的剂量症状反应关系;有确凿的神经放射学证据,或典型神经病理结果。 要重视肿瘤放化疗性脑白质病的研究 .为什么说颅脑照射和抗肿瘤化疗是中毒性脑白质病的非常确定病因?因为,随着肿瘤发病率的上升,以及肿瘤放、 化疗和免疫治疗等广泛的应用,抗肿瘤治疗所致的脑白质病越来越多,所以,我们进一步认识肿瘤放化疗引起的脑白质病有着重要的临床意义。
循环结构1
第一节for 循环 for循环是一种自动计数型循环。 [例3.1] 试打印出1~20的自然数。 解：①用a代表1~20各数，同时也用a兼作计数，以控制循环次数； ②让a从1开始； ③输出a； ④a自动计数（加1），如果未超越所规定的循环范围则重复步骤③，否则结束循环。 Pascal程序: Program Exam12； Var a: byte； Begin for a:=1 to 20 do Writeln (a)； Readln End. 程序中for a:=1 to 20 do Writeln (a)；是for循环语句。 for 循环语句有两种格式: (1) for循环变量:=初值To 终值do 语句； (2) for循环变量:=初值downto 终值do 语句； 第(1)种格式的初值小于等于终值，循环变量值按自动加1递增变化； 第(2)种格式的初值大于或等于终值，循环变量值按自动减1递减变化。for 循环是(以递增1或以递减1) 计数型循环。 比如: 若将[例3.1]程序改为倒计数(递减)循环，则输出20～1的自然数数: Program Exam31； Var a: byte； Begin for a:=20 downto 1 do Writeln(a) ； Readln End. [例3.2]打印出30至60的偶数。] 解： 方法一： = 1 \* GB3 ①设a表示30至60的所有的数，可用for循环列出； = 2 \* GB3 ②用式子 a mod 2=0筛选出其中的偶数并输出。 Pascal程序： Program ex32; Var a : integer; Begin For a := 30 to 60 do If (a mod 2=0) then writeln(a);
语文短语结构
主谓短语述宾短语偏正短语述补短语联合短语 1、主谓短语 主谓短语是由主语和谓语组成的短语。 主谓短语的内部结构成分之间有陈述与被陈述、说明与被说明的关系。例如：祖国繁荣精神振奋历史悠久观点明确月光皎洁 前途光明转播中断会议开始心眼儿好运转正常 阴云密布面无表情胡子拉碴办事精明明天星期二领导干部要全心全意为人民服务我们简直不敢相信自己的眼睛 同其他类型的短语相比较，主谓短语直接成分之间的关系比较松散，主语与谓语之间可以有停顿，也可加上相应的语气词。例如： 白雪皑皑的喜马拉雅山，巍然屹立在西藏南侧 那时候的学生啊，都喜欢朗诵徐志摩的诗歌 2.述宾短语 述宾短语又叫“动宾短语”，是由述语和宾语组成，结构成分之间有支配与被 支配关系的短语。例如： 买饭作画挖坑蒸馒头看电影盖房子说英语装箱子承受重负 喜欢唱歌打太极拳展开调查自愿献血热爱劳动具备优良品质钻进防空洞成为知名学者相距数公里改革和完善外商投资的审批程序 应当注意的是： 主语和谓语是相对应的句子成分，述语和宾语是相对应的句子成分，主语和宾 语之间没有直接的联系。 主语和施事，宾语和受事也不存在必然的联系，主语不一定是施事，也可以是受事或与事主语；宾语不一定是受事，也可以是施事、结果、工具、处所或数量宾语。主语和宾语是语法学上的概念，施事和受事是语义学上的概念。 3.偏正短语 偏正短语是由修饰语和中心语组成，结构成分之间有修饰与被修饰关系的短语。
根据充当中心语的成分的语法特点，可以将偏正短语分为： 定中短语 状中短语 ①定中短语 定中短语也叫“体词性偏正短语”，是语法功能相当于体词的偏正短语。定中短语的修饰语是定语，充当中心语的一般是体词性成分，定语从领属、范围、质料、形式、性质、数量、用途、时间、处所等方面描写或限制中心语。 例如： 胖师傅这个家语法分析野生动物壮丽的山河新建的校舍 一张写字台古生物学家用旧了的自行车勇往直前的决心阴云密布的傍晚面无表情的样子胡子拉碴的年轻人办事精明的老王 根据是否加结构助词“的”，可以将定中短语分为粘合式和组合式定中短语。定中短语的中心语一般是体词性成分，例如名词、代词、数词、定中短语、体词性联合短语等。有时谓词性成分也可以充当中心语，例如“经济的振兴”、“智力的开发”、“框框的束缚”、“满腹的怨恨”。 充当定语的成分比较灵活，如名词、动词、形容词、代词、介词短语等。 ①定中短语 定中短语也叫“体词性偏正短语”，是语法功能相当于体词的偏正短语。定中短语的修饰语是定语，充当中心语的一般是体词性成分，定语从领属、范围、质料、形式、性质、数量、用途、时间、处所等方面描写或限制中心语。 例如： 胖师傅这个家语法分析野生动物壮丽的山河新建的校舍 一张写字台古生物学家用旧了的自行车勇往直前的决心阴云密布的傍晚面无表情的样子胡子拉碴的年轻人办事精明的老王 根据是否加结构助词“的”，可以将定中短语分为粘合式和组合式定中短语。定中短语的中心语一般是体词性成分，例如名词、代词、数词、定中短语、体词性联合短语等。有时谓词性成分也可以充当中心语，例如“经济的振兴”、
循环结构 Word版含解析 (1)
课时作业(五) 1．下列说法不正确的是() A．顺序结构是由若干个依次执行的处理步骤组成的，每一个算法都离不开顺序结构B．循环结构中一定包含条件结构 C．循环结构中不一定包含条件结构 D．循环结构中反复执行的步骤叫做循环体 ★答案★ C 解析循环结构不能是永无终止的“死循环”，一定要在某个条件下终止循环，这就需要条件结构来做出判断，故循环结构中一定包含条件结构．所以选C. 2. 如图所示是一个循环结构的算法，下列说法不正确的是() A．①是循环变量初始值，循环就要开始 B．②为循环体 C．③是判断是否继续循环的终止条件 D．①可以省略不写 ★答案★ D 解析①②③都是循环结构中必须具备的． 3. 读右图所示的程序框图，运行相应的程序，输出的结果是() A．2B．4 C．8 D．16 ★答案★ C 解析输入S＝2，n＝1；当n＝1时，S＝ 1 1－2 ＝－1；
当n ＝2时，S ＝11－（－1）＝12 ；当n ＝4时，S ＝1 1－12＝2，n ＝8. 符合条件，故输出8. 4．某程序框图如图所示，若输出的S ＝57，则判断框内为( ) A ．k>4? B ．k>5? C ．k>6? D ．k>7? ★答案★ A 解析 第一次执行后，k ＝2，S ＝2＋2＝4；第二次执行后，k ＝3，S ＝8＋3＝11；第三次执行后，k ＝4，S ＝22＋4＝26；第四次执行后，k ＝5，S ＝52＋5＝57，此时结束循环，故判断框中填k>4？. 5．(高考真题·全国新课标Ⅰ卷)执行下面的程序框图，如果输入的N 是6，那么输出的p 是 ( ) A ．120 B ．720 C ．1 440 D ．5 040 ★答案★ B 解析 由程序框图可得，输出的p ＝1×2×3×4×5×6＝720. 6．如图所示，程序框图所进行的求和运算是( )
概念结构理论
概念结构理论 刘壮虎 北京大学哲学系，liuzhh@https://www.wendangku.net/doc/0e3409068.html, 摘要 本文不从概念的外延和内涵出发，而是将概念作为初始出发点，按照概念结构整体论的观点，在思想—概念—语言三者统一的基础上，建立概念结构的形式理论，讨论其基本性质及其意义，并在此基础上研究若干相关的问题。 实际中使用的推理，比我们通常说的逻辑推理要更广泛，本文建立依赖于语言的相对于主体的推理，并根据这种相对的推理建立相对的一致的概念。通过这种一致的概念，讨论不一致信念集的特征。这种推理也可以部分地用于概念的分类上，本文通过两个简单的实例来说明这种方法的应用。 词项的同义是语言学中的重要问题，按整体论的观点，比同义更一般的不可分辨性更为重要，本文给出了概念的不可分辨性的定义，并讨论其在语言中的表现。不同语言间的翻译也是语言学中的重要问题，本文在概念结构的形式理论基础上的对不同语言间的翻译进行了一些初步的讨论。 本文只是在对最简单的语言进行讨论，通过这样的讨论体现概念结构形式理论的思想、方法和研究框架。 §1前言 一、外延和内涵 概念有外延和内涵，是概念研究中的一个教条。我认为，这个教条是错误的，至少是不准确的。 概念有不同类型的，如亚里士多德就提出了十大范畴，而在三段论中使用的只是实体范畴和性质范畴。在讨论概念的外延和内涵时，也往往集中在个体、类和性质的范围内（与实体范畴和性质范畴相当），就算有所推广，也不是所有的概念。就是在个体、类和性质的范围内，概念有外延和内涵也是存在质疑的，如不可数名词的外延、性质化归为类等问题。 对外延和内涵的形式化的研究中，大多数说的是语句的外延和内涵，如各种内涵逻辑，它们与概念的外延和内涵是完全不同。 将内涵看作可能世界到外延的函数（或者在此基础上的修改），对于处理语句的内涵确实是一种比较好的方法，但将这种方法用于处理概念的内涵和外延，却带
网页常见的布局结构
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循环结构(答案)
作业3 循环结构学号姓名 1.有以下程序 main() { int y=10; while(y--); printf("y=%d\n",y); } 程序执行后的输出结果是B A）y=0 B）y=-1C）y=1 D）while构成无限循环2.有以下程序 main() { int k=5; while(--k) printf("%d",k-=3); printf("\n"); } 执行后的输出结果是A A）1 B）2 C）4 D）死循环 3.若变量已正确定义，有以下程序段 i=0; do printf("%d,",i); while(i++); printf("%d\n",i) 其输出结果是B A）0，0 B）0，1 C）1，1 D）程序进入无限循环4.有以下程序段D int n,t=1,s=0; scanf("%d",&n); do{ s=s+t; t=t-2; }while (t!=n); 为使此程序段不陷入死循环，从键盘输入的数据应该是 A）任意正奇数B）任意负偶数C）任意正偶数 D）任意负奇数 5.有以下程序 #include
printf("%d, ",x--); continue; } printf("%d, ",--x); } } 程序的运行结果是D A）7，4，2 B）8，7，5，2 C）9，7，6，4 D）8，5，4，2 6.以下不构成无限循环的语句或者语句组是A A）n=0; B）n=0; do{++n;}while(n<=0); while(1){n++;} C）n=10; D）for(n=0,i=1; ;i++) n+=i; while(n); {n--;} 7.有以下程序 main( ) { int i,n=0; for(i=2;i<5;i++) { do { if(i%3) continue; n++; } while(!i); n++; } printf("n=%d\n",n); } 程序执行后的输出结果是D A）n=5 B）n=2 C）n=3 D）n=4 8.有以下程序 main() { int i,j,x=0; for(i=0;i<2;i++) { x++; for(j=0;j<=3;j++) { if(j%2) continue; x++;