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排序方式: 共有569条查询结果,搜索用时 15 毫秒
431.
Albagha OM Wani SE Visconti MR Alonso N Goodman K Brandi ML Cundy T Chung PY Dargie R Devogelaer JP Falchetti A Fraser WD Gennari L Gianfrancesco F Hooper MJ Van Hul W Isaia G Nicholson GC Nuti R Papapoulos S Montes Jdel P Ratajczak T Rea SL Rendina D Gonzalez-Sarmiento R Di Stefano M Ward LC Walsh JP Ralston SH;Genetic Determinants of Paget's Disease 《Nature genetics》2011,43(7):685-689
Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study. Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 × 10(-14)), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 × 10(-11)) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 × 10(-10)). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 × 10(-17)) with PDB. These seven loci explained ~13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB. 相似文献
432.
Rafnar T Gudbjartsson DF Sulem P Jonasdottir A Sigurdsson A Jonasdottir A Besenbacher S Lundin P Stacey SN Gudmundsson J Magnusson OT le Roux L Orlygsdottir G Helgadottir HT Johannsdottir H Gylfason A Tryggvadottir L Jonasson JG de Juan A Ortega E Ramon-Cajal JM García-Prats MD Mayordomo C Panadero A Rivera F Aben KK van Altena AM Massuger LF Aavikko M Kujala PM Staff S Aaltonen LA Olafsdottir K Bjornsson J Kong A Salvarsdottir A Saemundsson H Olafsson K Benediktsdottir KR Gulcher J Masson G 《Nature genetics》2011,43(11):1104-1107
Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer. 相似文献
433.
Xu B Roos JL Dexheimer P Boone B Plummer B Levy S Gogos JA Karayiorgou M 《Nature genetics》2011,43(9):864-868
Despite its high heritability, a large fraction of individuals with schizophrenia do not have a family history of the disease (sporadic cases). Here we examined the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exomes of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2, a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region. A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of non-synonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function. Our analyses suggest a major role for de novo mutations in schizophrenia as well as a large mutational target, which together provide a plausible explanation for the high global incidence and persistence of the disease. 相似文献
434.
Gemma Olmos María I. Arenas Raquel Bienes María Jose Calzada Julián Aragonés Maria Laura Garcia-Bermejo Manuel O. Landazuri Javier Lucio-Cazaña 《Cellular and molecular life sciences : CMLS》2009,66(13):2167-2180
Hypoxia-inducible factor-1α (HIF-1α) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL)
and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) accumulate HIF-1α in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We
found that 15d-PGJ2 induced an over-accumulation of HIF-1α in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome
pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain
them. We have identified a new lysosomal-dependent mechanism of HIF-1α degradation as a target for 15d-PGJ2 based on: (1) HIF-1α colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ2 inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation
of HIF-1α in 15d-PGJ2-treated cells. Therefore, expression of HIF-1α is also modulated by lysosomal degradation. 相似文献
435.
Giovanni Di Maira Francesca Brustolon Lorenzo A. Pinna Maria Ruzzene 《Cellular and molecular life sciences : CMLS》2009,66(20):3363-3373
Akt (PKB) is a critical kinase in cell-survival pathways. Its activity depends on the phosphorylation of Thr308 and Ser473,
by PDK1 and mTORC2, respectively. We found that Akt can be further stimulated through phosphorylation of Ser129 by another
kinase, CK2. Here we show that phosphorylation of Akt at Ser129 also facilitates its association with Hsp90 chaperone, thus
preventing Thr308 dephosphorylation. This is supported by the following observations: (1) phospho-Thr308 decreases when Ser129
is mutated to alanine, (2) this decrease is abolished by cell treatment with okadaic acid (to inactivate PP2A) or geldanamycin
(to inactivate Hsp90), (3) phosphorylation of Ser129 neither enhances the activity of PDK1 nor hampers the in vitro activity
of PP2A on Thr308, but increases the Hsp90 association to Akt. These data support the view that the antiapoptotic potential
of CK2 is at least in part mediated by its ability to maintain Akt in its active form. 相似文献
436.
Di Bernardo MC Crowther-Swanepoel D Broderick P Webb E Sellick G Wild R Sullivan K Vijayakrishnan J Wang Y Pittman AM Sunter NJ Hall AG Dyer MJ Matutes E Dearden C Mainou-Fowler T Jackson GH Summerfield G Harris RJ Pettitt AR Hillmen P Allsup DJ Bailey JR Pratt G Pepper C Fegan C Allan JM Catovsky D Houlston RS 《Nature genetics》2008,40(10):1204-1210
We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL. 相似文献
437.
Valente EM Silhavy JL Brancati F Barrano G Krishnaswami SR Castori M Lancaster MA Boltshauser E Boccone L Al-Gazali L Fazzi E Signorini S Louie CM Bellacchio E;International Joubert Syndrome Related Disorders Study Group Bertini E Dallapiccola B Gleeson JG 《Nature genetics》2006,38(6):623-625
Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies. 相似文献
438.
Service S DeYoung J Karayiorgou M Roos JL Pretorious H Bedoya G Ospina J Ruiz-Linares A Macedo A Palha JA Heutink P Aulchenko Y Oostra B van Duijn C Jarvelin MR Varilo T Peddle L Rahman P Piras G Monne M Murray S Galver L Peltonen L Sabatti C Collins A Freimer N 《Nature genetics》2006,38(5):556-560
The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping. 相似文献
439.
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule 总被引:10,自引:0,他引:10
Lalioti MD Zhang J Volkman HM Kahle KT Hoffmann KE Toka HR Nelson-Williams C Ellison DH Flavell R Booth CJ Lu Y Geller DS Lifton RP 《Nature genetics》2006,38(10):1124-1132
The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC. 相似文献
440.
Cristina Antonella Nadalutti Ilma Rita Korponay-Szabo Katri Kaukinen Martin Griffin Markku Mäki Katri Lindfors 《Cellular and molecular life sciences : CMLS》2014,71(7):1315-1326
We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of β1-integrin. We also observed that celiac patient IgA-treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell-extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility. 相似文献