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141.
AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus 总被引:1,自引:0,他引:1
Minokoshi Y Alquier T Furukawa N Kim YB Lee A Xue B Mu J Foufelle F Ferré P Birnbaum MJ Stuck BJ Kahn BB 《Nature》2004,428(6982):569-574
Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance. 相似文献
142.
Sarah Strohkamp Timo Gemoll Sina Humborg Sonja Hartwig Stefan Lehr Sandra Freitag-Wolf Susanne Becker Bo Franzén Ralph Pries Barbara Wollenberg Uwe J. Roblick Hans-Peter Bruch Tobias Keck Gert Auer Jens K. Habermann 《Cellular and molecular life sciences : CMLS》2018,75(2):323-334
Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers (n = 12) and patients with early- (n = 7) and late-stage (n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected (p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities (p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls (n = 15), early-stage CRCs (n = 15), late-stage CRCs (n = 15)]. Two proteins—clusterin and glutathione synthetase (GSH-S)—featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial. 相似文献
143.
大熊猫电刺激采精及精液冷冻保存研究 总被引:6,自引:1,他引:5
对卧龙自然保护区大熊猫研究中心的9只5.5-16.5岁的雄性大熊猫进行了17次电刺激采精,其中3只是能进行自然交配并繁殖了后代的种公兽,比较研究了精液离心、不同稀释液和冷冻方法对大熊猫精液超低温冷冻保存后的活力、运动状态、精子和顶体形态的影响。细冷冻是1种较好的超低温冷冻精液的方法。 相似文献
144.
Logan CV Lucke B Pottinger C Abdelhamed ZA Parry DA Szymanska K Diggle CP van Riesen A Morgan JE Markham G Ellis I Manzur AY Markham AF Shires M Helliwell T Scoto M Hübner C Bonthron DT Taylor GR Sheridan E Muntoni F Carr IM Schuelke M Johnson CA 《Nature genetics》2011,43(12):1189-1192
Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia. 相似文献
145.
Simpson MA Irving MD Asilmaz E Gray MJ Dafou D Elmslie FV Mansour S Holder SE Brain CE Burton BK Kim KH Pauli RM Aftimos S Stewart H Kim CA Holder-Espinasse M Robertson SP Drake WM Trembath RC 《Nature genetics》2011,43(4):303-305
We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling. 相似文献
146.
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 总被引:19,自引:0,他引:19
Weisenberger DJ Siegmund KD Campan M Young J Long TI Faasse MA Kang GH Widschwendter M Weener D Buchanan D Koh H Simms L Barker M Leggett B Levine J Kim M French AJ Thibodeau SN Jass J Haile R Laird PW 《Nature genetics》2006,38(7):787-793
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors. 相似文献
147.
Curnis F Gasparri AM Longhi R Colombo B D'Alessio S Pastorino F Ponzoni M Corti A 《Cellular and molecular life sciences : CMLS》2012,69(16):2791-2803
Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp(45)Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp(45)Glu mutants, could selectively recognize the αvβ6-integrin on keratinocytes (a cell-adhesion receptor that is up-regulated during wound healing) and regulate keratinocyte adhesion, proliferation, and migration. No binding was observed to other integrins such as αvβ3, αvβ5, αvβ8, α5β1, α1β1, α3β1, α6β4, α6β7 and α9β1. Structure-activity studies showed that the entire CgA(39-63) region is crucial for αvβ6 recognition (K(i) = 7 nM). This region contains an RGD site (residues CgA(43-45)) followed by an amphipathic α-helix (residues CgA(47-63)), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/α-helix motif of CgA with αvβ6 regulates keratinocyte physiology in wound healing. 相似文献
148.
Many sequence variants affecting diversity of adult human height 总被引:1,自引:0,他引:1
Gudbjartsson DF Walters GB Thorleifsson G Stefansson H Halldorsson BV Zusmanovich P Sulem P Thorlacius S Gylfason A Steinberg S Helgadottir A Ingason A Steinthorsdottir V Olafsdottir EJ Olafsdottir GH Jonsson T Borch-Johnsen K Hansen T Andersen G Jorgensen T Pedersen O Aben KK Witjes JA Swinkels DW den Heijer M Franke B Verbeek AL Becker DM Yanek LR Becker LC Tryggvadottir L Rafnar T Gulcher J Kiemeney LA Kong A Thorsteinsdottir U Stefansson K 《Nature genetics》2008,40(5):609-615
Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene. 相似文献
149.
Benzinou M Creemers JW Choquet H Lobbens S Dina C Durand E Guerardel A Boutin P Jouret B Heude B Balkau B Tichet J Marre M Potoczna N Horber F Le Stunff C Czernichow S Sandbaek A Lauritzen T Borch-Johnsen K Andersen G Kiess W Körner A Kovacs P Jacobson P Carlsson LM Walley AJ Jørgensen T Hansen T Pedersen O Meyre D Froguel P 《Nature genetics》2008,40(8):943-945
Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity. 相似文献
150.
Müller T Hess MW Schiefermeier N Pfaller K Ebner HL Heinz-Erian P Ponstingl H Partsch J Röllinghoff B Köhler H Berger T Lenhartz H Schlenck B Houwen RJ Taylor CJ Zoller H Lechner S Goulet O Utermann G Ruemmele FM Huber LA Janecke AR 《Nature genetics》2008,40(10):1163-1165
Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID. 相似文献