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961.
Davis EE Zhang Q Liu Q Diplas BH Davey LM Hartley J Stoetzel C Szymanska K Ramaswami G Logan CV Muzny DM Young AC Wheeler DA Cruz P Morgan M Lewis LR Cherukuri P Maskeri B Hansen NF Mullikin JC Blakesley RW Bouffard GG;NISC Comparative Sequencing Program Gyapay G Rieger S Tönshoff B Kern I Soliman NA Neuhaus TJ Swoboda KJ Kayserili H Gallagher TE Lewis RA Bergmann C Otto EA Saunier S Scambler PJ Beales PL Gleeson JG Maher ER Attié-Bitach T Dollfus H Johnson CA Green ED Gibbs RA Hildebrandt F 《Nature genetics》2011,43(3):189-196
Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ~5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders. 相似文献
962.
Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 总被引:1,自引:0,他引:1
Kilpeläinen TO Zillikens MC Stančákova A Finucane FM Ried JS Langenberg C Zhang W Beckmann JS Luan J Vandenput L Styrkarsdottir U Zhou Y Smith AV Zhao JH Amin N Vedantam S Shin SY Haritunians T Fu M Feitosa MF Kumari M Halldorsson BV Tikkanen E Mangino M Hayward C Song C Arnold AM Aulchenko YS Oostra BA Campbell H Cupples LA Davis KE Döring A Eiriksdottir G Estrada K Fernández-Real JM Garcia M Gieger C Glazer NL Guiducci C Hofman A Humphries SE Isomaa B Jacobs LC Jula A Karasik D Karlsson MK 《Nature genetics》2011,43(8):753-760
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. 相似文献
963.
Witt H Sahin-Tóth M Landt O Chen JM Kähne T Drenth JP Kukor Z Szepessy E Halangk W Dahm S Rohde K Schulz HU Le Maréchal C Akar N Ammann RW Truninger K Bargetzi M Bhatia E Castellani C Cavestro GM Cerny M Destro-Bisol G Spedini G Eiberg H Jansen JB Koudova M Rausova E Macek M Malats N Real FX Menzel HJ Moral P Galavotti R Pignatti PF Rickards O Spicak J Zarnescu NO Böck W Gress TM Friess H Ockenga J Schmidt H Pfützer R Löhr M Simon P Weiss FU Lerch MM Teich N Keim V Berg T Wiedenmann B Luck W 《Nature genetics》2006,38(6):668-673
Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis. 相似文献
964.
Kaufmann P Török M Zahno A Waldhauser KM Brecht K Krähenbühl S 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2415-2425
We investigated mitochondrial toxicity of four lipophilic stains (cerivastatin, fluvastatin, atorvastatin, simvastatin) and one hydrophilic statin (pravastatin). In L6 cells (rat skeletal muscle cell line), the four lipophilic statins (100 micromol/l) induced death in 27-49% of the cells. Pravastatin was not toxic up to 1 mmol/l. Cerivastatin, fluvastatin and atorvastatin (100 micromol/l) decreased the mitochondrial membrane potential by 49-65%, whereas simvastatin and pravastatin were less toxic. In isolated rat skeletal muscle mitochondria, all statins, except pravastatin, decreased glutamate-driven state 3 respiration and respiratory control ratio. Beta-oxidation was decreased by 88-96% in the presence of 100 micromol/l of the lipophilic statins, but only at higher concentrations by pravastatin. Mitochondrial swelling, cytochrome c release and DNA fragmentation was induced in L6 cells by the four lipophilic statins, but not by pravastatin. Lipophilic statins impair the function of skeletal muscle mitochondria, whereas the hydrophilic pravastatin is significantly less toxic. 相似文献
965.
van der Burg M van Zelm MC Driessen GJ van Dongen JJ 《Cellular and molecular life sciences : CMLS》2012,69(1):59-73
Primary antibody deficiencies (PAD) form the largest group of inherited disorders of the immune system. They are characterized
by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation and by a poor response
to vaccination. PAD can be divided into agammaglobulinemia, Ig class switch recombination deficiencies, and idiopathic hypogammaglobulinemia.
Over the past 20 years, defects have been identified in 18 different genes, but in many PAD patients the underlying gene defects
have not been found. Diagnosis of known PAD and discovery of new PAD is important for good patient care. In this review, we
present the effects of genetic defects in the context of normal B cell differentiation, and we discuss how new technical developments
can support understanding and discovering new genetic defects in PAD. 相似文献
966.
Paternoster L Standl M Chen CM Ramasamy A Bønnelykke K Duijts L Ferreira MA Alves AC Thyssen JP Albrecht E Baurecht H Feenstra B Sleiman PM Hysi P Warrington NM Curjuric I Myhre R Curtin JA Groen-Blokhuis MM Kerkhof M Sääf A Franke A Ellinghaus D Fölster-Holst R Dermitzakis E Montgomery SB Prokisch H Heim K Hartikainen AL Pouta A Pekkanen J Blakemore AI Buxton JL Kaakinen M Duffy DL Madden PA Heath AC Montgomery GW Thompson PJ Matheson MC Le Souëf P;Australian Asthma Genetics Consortium 《Nature genetics》2012,44(2):187-192
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. 相似文献
967.
KU Ludwig E Mangold S Herms S Nowak H Reutter A Paul J Becker R Herberz T Alchawa E Nasser AC Böhmer M Mattheisen MA Alblas S Barth N Kluck C Lauster B Braumann RH Reich A Hemprich S Pötzsch B Blaumeiser N Daratsianos T Kreusch JC Murray ML Marazita I Ruczinski AF Scott TH Beaty FJ Kramer TF Wienker RP Steegers-Theunissen M Rubini PA Mossey P Hoffmann C Lange S Cichon P Propping M Knapp MM Nöthen 《Nature genetics》2012,44(9):968-971
We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16). 相似文献
968.
Jöran Friberg 《Archive for History of Exact Sciences》2014,68(1):1-34
Most of what is told in this paper has been told before by the same author, in a number of publications of various kinds, but this is the first time that all this material has been brought together and treated in a uniform way. Smaller errors in the earlier publications are corrected here without comment. It has been known since the 1920s that quadratic equations played a prominent role in Babylonian mathematics. See, most recently, Høyrup (Hist Sci 34:1–32, 1996, and Lengths, widths, surfaces: a portrait of old Babylonian algebra and its kin. Springer, New York, 2002). What has not been known, however, is how quadratic equations came to play that role, since it is difficult to think of any practical use for quadratic equations in the life and work of a Babylonian scribe. One goal of the present paper is to show how the need to find solutions to quadratic equations actually arose in Mesopotamia not later than in the second half of the third millennium BC, and probably before that in connection with certain geometric division of property problems. This issue was brought up for the first time in Friberg (Cuneiform Digit Lib J 2009:3, 2009). In this connection, it is argued that the tool used for the first exact solution of a quadratic equation was either a clever use of the “conjugate rule” or a “completion of the square,” but that both methods ultimately depend on a certain division of a square, the same in both cases. Another, closely related goal of the paper is to discuss briefly certain of the most impressive achievements of anonymous Babylonian mathematicians in the first half of the second millennium BC, namely recursive geometric algorithms for the solution of various problems related to division of figures, more specifically trapezoidal fields. For an earlier, comprehensive (but less accessible) treatment of these issues, see Friberg (Amazing traces of a Babylonian origin in Greek mathematics. WorldScientific, Singapore 2007b, Ch. 11 and App. 1). 相似文献
969.
Nurdan Özkucur Bing Song Sharanya Bola Lei Zhang Brian Reid Guo Fu Richard H. W. Funk Min Zhao 《Cellular and molecular life sciences : CMLS》2014,71(23):4653-4663
Endogenous electric fields (EF) may provide an overriding cue for directional cell migration during wound closure. Perceiving a constant direction requires active sodium-hydrogen exchanger (pNHE3) at the leading edge of HEK 293 cells but its activation mechanism is not yet fully understood. Because protein kinase C (PKC) is required in electrotaxis, we asked whether NHE3 is activated by PKC during wound healing. Using pharmacological (pseudosubstrate and edelfosine) inhibition, we showed that inhibition of PKCη isoform impairs directional cell migration in HEK 293 cells in the presence of a persistent directional cue (0.25–0.3 V/mm of EF for 2 h). Further, we found that pNHE3 forms complexes with both PKCη and ?-tubulin, suggesting that these molecules may regulate the microtubule-organizing center. In addition, cellular pNHE3 content was reduced significantly when PKCη was inhibited during directional cell migration. Taken together, these data suggest that PKCη-dependent phosphorylation of NHE3 and the formation of pNHE3/PKCη/?-tubulin complexes at the leading edge of the cell are required for directional cell migration in an EF. 相似文献
970.
Galanin – 25 years with a multitalented neuropeptide 总被引:2,自引:0,他引:2
Xu XJ Hökfelt T Wiesenfeld-Hallin Z 《Cellular and molecular life sciences : CMLS》2008,65(12):1813-1819
Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics. 相似文献