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121.
Anske Van den Abbeele Sarah De Clercq Ariane De Ganck Veerle De Corte Berlinda Van Loo Sameh Hamdy Soror Vasundara Srinivasan Jan Steyaert Joël Vandekerckhove Jan Gettemans 《Cellular and molecular life sciences : CMLS》2010,67(9):1519-1535
RNA interference has tremendously advanced our understanding of gene function but recent reports have exposed undesirable
side-effects. Recombinant Camelid single-domain antibodies (VHHs) provide an attractive means for studying protein function without affecting gene expression.
We raised VHHs against gelsolin (GsnVHHs), a multifunctional actin-binding protein that controls cellular actin organization
and migration. GsnVHH-induced delocalization of gelsolin to mitochondria or the nucleus in mammalian cells reveals distinct
subpopulations including free gelsolin and actin-bound gelsolin complexes. GsnVHH 13 specifically recognizes Ca2+-activated gelsolin (K
d ~10 nM) while GsnVHH 11 binds gelsolin irrespective of Ca2+ (K
d ~5 nM) but completely blocks its interaction with G-actin. Both GsnVHHs trace gelsolin in membrane ruffles of EGF-stimulated
MCF-7 cells and delay cell migration without affecting F-actin severing/capping or actin nucleation activities by gelsolin.
We conclude that VHHs represent a potent way of blocking structural proteins and that actin nucleation by gelsolin is more
complex than previously anticipated. 相似文献
122.
Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy 总被引:6,自引:0,他引:6
Jordanova A Irobi J Thomas FP Van Dijck P Meerschaert K Dewil M Dierick I Jacobs A De Vriendt E Guergueltcheva V Rao CV Tournev I Gondim FA D'Hooghe M Van Gerwen V Callaerts P Van Den Bosch L Timmermans JP Robberecht W Gettemans J Thevelein JM De Jonghe P Kremensky I Timmerman V 《Nature genetics》2006,38(2):197-202
Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration. 相似文献
123.
A conserved microRNA module exerts homeotic control over Petunia hybrida and Antirrhinum majus floral organ identity 总被引:3,自引:0,他引:3
Cartolano M Castillo R Efremova N Kuckenberg M Zethof J Gerats T Schwarz-Sommer Z Vandenbussche M 《Nature genetics》2007,39(7):901-905
It is commonly thought that deep phylogenetic conservation of plant microRNAs (miRNAs) and their targets indicates conserved regulatory functions. We show that the blind (bl) mutant of Petunia hybrida and the fistulata (fis) mutant of Antirrhinum majus, which have similar homeotic phenotypes, are recessive alleles of two homologous miRNA-encoding genes. The BL and FIS genes control the spatial restriction of homeotic class C genes to the inner floral whorls, but their ubiquitous early floral expression patterns are in contradiction with a potential role in patterning C gene expression. We provide genetic evidence for the unexpected function of the MIRFIS and MIRBL genes in the center of the flower and propose a dynamic mechanism underlying their regulatory role. Notably, Arabidopsis thaliana, a more distantly related species, also contains this miRNA module but does not seem to use it to confine early C gene expression to the center of the flower. 相似文献
124.
H Zhang C Peng Y Hu H Li Z Sheng Y Chen C Sullivan J Cerny L Hutchinson A Higgins P Miron X Zhang MA Brehm D Li MR Green S Li 《Nature genetics》2012,44(8):861-871
A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers. 相似文献
125.
Pansuriya TC van Eijk R d'Adamo P van Ruler MA Kuijjer ML Oosting J Cleton-Jansen AM van Oosterwijk JG Verbeke SL Meijer D van Wezel T Nord KH Sangiorgi L Toker B Liegl-Atzwanger B San-Julian M Sciot R Limaye N Kindblom LG Daugaard S Godfraind C Boon LM Vikkula M Kurek KC Szuhai K French PJ Bovée JV 《Nature genetics》2011,43(12):1256-1261
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation. 相似文献
126.
Hoischen A van Bon BW Rodríguez-Santiago B Gilissen C Vissers LE de Vries P Janssen I van Lier B Hastings R Smithson SF Newbury-Ecob R Kjaergaard S Goodship J McGowan R Bartholdi D Rauch A Peippo M Cobben JM Wieczorek D Gillessen-Kaesbach G Veltman JA Brunner HG de Vries BB 《Nature genetics》2011,43(8):729-731
Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous. 相似文献
127.
Sun J Zheng SL Wiklund F Isaacs SD Purcell LD Gao Z Hsu FC Kim ST Liu W Zhu Y Stattin P Adami HO Wiley KE Dimitrov L Sun J Li T Turner AR Adams TS Adolfsson J Johansson JE Lowey J Trock BJ Partin AW Walsh PC Trent JM Duggan D Carpten J Chang BL Grönberg H Isaacs WB Xu J 《Nature genetics》2008,40(10):1153-1155
We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP. 相似文献
128.
Raychaudhuri S Remmers EF Lee AT Hackett R Guiducci C Burtt NP Gianniny L Korman BD Padyukov L Kurreeman FA Chang M Catanese JJ Ding B Wong S van der Helm-van Mil AH Neale BM Coblyn J Cui J Tak PP Wolbink GJ Crusius JB van der Horst-Bruinsma IE Criswell LA Amos CI Seldin MF Kastner DL Ardlie KG Alfredsson L Costenbader KH Altshuler D Huizinga TW Shadick NA Weinblatt ME de Vries N Worthington J Seielstad M Toes RE Karlson EW Begovich AB Klareskog L Gregersen PK Daly MJ Plenge RM 《Nature genetics》2008,40(10):1216-1223
To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall). 相似文献
129.
This study evaluated the prevalence and risk factors for asthma, allergy and related symptoms; and breastfeeding patterns and durations for 5479 Beijing children aged 3–6. Parents of children in randomly selected kindergartens wrote responses to a questionnaire used previously. The study aimed to evaluate trends in the prevalence of asthma and related illnesses, and to determine whether “more” breastfeeding, defined as exclusive, > 6 months, was associated with reduced prevalence. Asthma has increased in this age group between 1990 and 2011, with the steepest increase in the last 2–3 years. Of the total, 14.2% (779) children were breastfed exclusively for > 6 months. The efficacy of “more” breastfeeding was tested in a subset with two strong risk factors, positive family history (for asthma and/or allergy) and male gender. “More” breastfeeding was found to be significantly protective (aOR 0.42, P < 0.05) for this subset against Doctor-diagnosed asthma (D-asthma). Protection that did not reach statistical significance was also found for this subset against Wheeze ever, Cough at night, Rhinitis ever, Doctor-diagnosed rhinitis (D-rhinitis) and Eczema. The greatest protective effects were found for girls with no family history of asthma or allergy, reaching statistical significance for Wheeze ever (aOR 0.48, P < 0.01), Cough at night (aOR 0.47, P < 0.01), D-asthma (aOR 0.14, P < 0.01) and Rhinitis ever (aOR 0.67, P < 0.05). “More” breastfeeding was not consistently associated with either a protective or risk effect for Eczema. 相似文献
130.
This paper describes in short a new approach to the solution of a practical design problem. The procedures for the approach are based on the use of a systems methodology. The main topics present the development of a project from the external assignment through detailed algorithms of systems modeling to the identification of the solution system. 相似文献