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排序方式: 共有1189条查询结果,搜索用时 62 毫秒
921.
Bis JC Kavousi M Franceschini N Isaacs A Abecasis GR Schminke U Post WS Smith AV Cupples LA Markus HS Schmidt R Huffman JE Lehtimäki T Baumert J Münzel T Heckbert SR Dehghan A North K Oostra B Bevan S Stoegerer EM Hayward C Raitakari O Meisinger C Schillert A Sanna S Völzke H Cheng YC Thorsson B Fox CS Rice K Rivadeneira F Nambi V Halperin E Petrovic KE Peltonen L Wichmann HE Schnabel RB Dörr M Parsa A Aspelund T Demissie S Kathiresan S Reilly MP Taylor K Uitterlinden A Couper DJ Sitzer M 《Nature genetics》2011,43(10):940-947
Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events. 相似文献
922.
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
923.
B. Schäfer C. Götz J. Dudek A. Hessenauer U. Matti M. Montenarh 《Cellular and molecular life sciences : CMLS》2009,66(2):339-349
Protein kinase CK2 is a highly conserved serine/threonine kinase that is ubiquitously expressed in eukaryotic cells. CK2 is
a constitutively active tetrameric enzyme composed of two catalytic α and/or α’-subunits and two regulatory β-subunits. There
is increasing evidence that the individual subunits may have independent functions and that they are asymmetrically distributed
inside the cell. To gain a better understanding of the functions of the individual subunits, we employed a yeast-two-hybrid
screen with CK2α and CK2α’. We identified the motor neuron protein KIF5C as a new binding partner for CK2. The interaction
found in the yeast-two-hybrid screen was confirmed by co-sedimentation analysis on a sucrose density gradient and by co-immunoprecipitation
analysis. Pull-down experiments and surface plasmon resonance spectrometry revealed a direct binding of KIF5C to CK2α’. Co-localization
studies with neuroblastoma cells, bone marrow and with primary neurons confirmed the biochemical analysis that KIF5C preferentially
bound to CK2α’.
Received 8 August 2008; received after revision 3 November 2008; accepted 4 November 2008 相似文献
924.
P. Schläfli E. Borter P. Spielmann R. H. Wenger 《Cellular and molecular life sciences : CMLS》2009,66(5):876-883
The PAS domain kinase PASKIN, also termed PAS kinase or PASK, is an evolutionarily conserved potential sensor kinase related
to the heme-based oxygen sensors of nitrogen-fixing bacteria. In yeast, the two PASKIN homologs link energy flux and protein
synthesis following specific stress conditions. In mammals, PASKIN may regulate glycogen synthesis and protein translation.
Paskin knock-out mice do not show any phenotype under standard animal husbandry conditions. Interestingly, these mice seem to be
protected from the symptoms of the metabolic syndrome when fed a high-fat diet. Energy turnover might be increased in specific
PASKIN-deficient cell types under distinct environmental conditions. According to the current model, binding of a putative
ligand to the PAS domain disinhibits the kinase domain and activates PASKIN auto- and target phosphorylation. Future research
needs to be conducted to elucidate the nature of the putative ligand and the molecular mechanisms of downstream signalling
by PASKIN.
Received 2 November 2008; received after revision 10 December 2008; accepted 5 January 2009 相似文献
925.
Prion diseases are fatal neurodegenerative and infectious disorders of humans and animals, characterized by structural transition
of the host-encoded cellular prion protein (PrPc) into the aberrantly folded pathologic isoform PrPSc. RNA, DNA or peptide aptamers are classes of molecules which can be selected from complex combinatorial libraries for high
affinity and specific binding to prion proteins and which might therefore be useful in diagnosis and therapy of prion diseases.
Nucleic acid aptamers, which can be chemically synthesized, stabilized and immobilized, appear more suitable for diagnostic
purposes, allowing use of PrPSc as selection target. Peptide aptamers facilitate appropriate intracellular expression, targeting and re-routing without losing
their binding properties to PrP, a requirement for potential therapeutic gene transfer experiments in vivo. Elucidation of
structural properties of peptide aptamers might be used as basis for rational drug design, providing another attractive application
of peptide aptamers in the search for effective anti-prion strategies. 相似文献
926.
Budde BS Namavar Y Barth PG Poll-The BT Nürnberg G Becker C van Ruissen F Weterman MA Fluiter K te Beek ET Aronica E van der Knaap MS Höhne W Toliat MR Crow YJ Steinling M Voit T Roelenso F Brussel W Brockmann K Kyllerman M Boltshauser E Hammersen G Willemsen M Basel-Vanagaite L Krägeloh-Mann I de Vries LS Sztriha L Muntoni F Ferrie CD Battini R Hennekam RC Grillo E Beemer FA Stoets LM Wollnik B Nürnberg P Baas F 《Nature genetics》2008,40(9):1113-1118
Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders. 相似文献
927.
Bilguvar K Yasuno K Niemelä M Ruigrok YM von Und Zu Fraunberg M van Duijn CM van den Berg LH Mane S Mason CE Choi M Gaál E Bayri Y Kolb L Arlier Z Ravuri S Ronkainen A Tajima A Laakso A Hata A Kasuya H Koivisto T Rinne J Ohman J Breteler MM Wijmenga C State MW Rinkel GJ Hernesniemi J Jääskeläinen JE Palotie A Inoue I Lifton RP Günel M 《Nature genetics》2008,40(12):1472-1477
Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm. 相似文献
928.
Katajisto P Vaahtomeri K Ekman N Ventelä E Ristimäki A Bardeesy N Feil R DePinho RA Mäkelä TP 《Nature genetics》2008,40(4):455-459
Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFbeta, and defective TGFbeta signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS. 相似文献
929.
STAR Consortium Saar K Beck A Bihoreau MT Birney E Brocklebank D Chen Y Cuppen E Demonchy S Dopazo J Flicek P Foglio M Fujiyama A Gut IG Gauguier D Guigo R Guryev V Heinig M Hummel O Jahn N Klages S Kren V Kube M Kuhl H Kuramoto T Kuroki Y Lechner D Lee YA Lopez-Bigas N Lathrop GM Mashimo T Medina I Mott R Patone G Perrier-Cornet JA Platzer M Pravenec M Reinhardt R Sakaki Y Schilhabel M Schulz H Serikawa T Shikhagaie M Tatsumoto S Taudien S Toyoda A Voigt B Zelenika D Zimdahl H Hubner N 《Nature genetics》2008,40(5):560-566
The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies. 相似文献
930.
Fagerholm R Hofstetter B Tommiska J Aaltonen K Vrtel R Syrjäkoski K Kallioniemi A Kilpivaara O Mannermaa A Kosma VM Uusitupa M Eskelinen M Kataja V Aittomäki K von Smitten K Heikkilä P Lukas J Holli K Bartkova J Blomqvist C Bartek J Nevanlinna H 《Nature genetics》2008,40(7):844-853
NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer. 相似文献