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841.
Cilia‐localized LKB1 regulates chemokine signaling,macrophage recruitment,and tissue homeostasis in the kidney 下载免费PDF全文
Kamile Lukas Abhijeet P Todkar Manuel Knoll Toma A Yakulov Alexis Hofherr Oliver Kretz Martin Helmstädter Wilfried Reichardt Simone Braeg Tom Aschman Annette Merkle Dietmar Pfeifer Verónica I Dumit Marie‐Claire Gubler Roland Nitschke Tobias B Huber Fabiola Terzi Jörn Dengjel Florian Grahammer Michael Köttgen Hauke Busch Melanie Boerries Gerd Walz Antigoni Triantafyllopoulou E Wolfgang Kuehn 《The EMBO journal》2018,37(15)
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy‐related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell‐autonomous manner and results in peritubular accumulation of CCR2+ mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis. 相似文献
842.
Species distribution modeling and molecular markers suggest longitudinal range shifts and cryptic northern refugia of the typical calcareous grassland species Hippocrepis comosa (horseshoe vetch) 下载免费PDF全文
Martin Leipold Simone Tausch Peter Poschlod Christoph Reisch 《Ecology and evolution》2017,7(6):1919-1935
Calcareous grasslands belong to the most diverse, endangered habitats in Europe, but there is still insufficient information about the origin of the plant species related to these grasslands. In order to illuminate this question, we chose for our study the representative grassland species Hippocrepis comosa (Horseshoe vetch). Based on species distribution modeling and molecular markers, we identified the glacial refugia and the postglacial migration routes of the species to Central Europe. We clearly demonstrate that H. comosa followed a latitudinal and due to its oceanity also a longitudinal gradient during the last glacial maximum (LGM), restricting the species to southern refugia situated on the Peninsulas of Iberia, the Balkans, and Italy during the last glaciation. However, we also found evidence for cryptic northern refugia in the UK, the Alps, and Central Germany. Both species distribution modeling and molecular markers underline that refugia of temperate, oceanic species such as H. comosa must not be exclusively located in southern but also in western of parts of Europe. The analysis showed a distinct separation of the southern refugia into a western cluster embracing Iberia and an eastern group including the Balkans and Italy, which determined the postglacial recolonization of Central Europe. At the end of the LGM, H. comosa seems to have expanded from the Iberian refugium, to Central and Northern Europe, including the UK, Belgium, and Germany. 相似文献
843.
Tinto N Zagari A Capuano M De Simone A Capobianco V Daniele G Giugliano M Spadaro R Franzese A Sacchetti L 《PloS one》2008,3(4):e1870
Background
Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK).Methodology/Principal Findings
We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients'' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: ∼59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04).Conclusions
The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation. 相似文献844.
Kiryluk K Li Y Sanna-Cherchi S Rohanizadegan M Suzuki H Eitner F Snyder HJ Choi M Hou P Scolari F Izzi C Gigante M Gesualdo L Savoldi S Amoroso A Cusi D Zamboli P Julian BA Novak J Wyatt RJ Mucha K Perola M Kristiansson K Viktorin A Magnusson PK Thorleifsson G Thorsteinsdottir U Stefansson K Boland A Metzger M Thibaudin L Wanner C Jager KJ Goto S Maixnerova D Karnib HH Nagy J Panzer U Xie J Chen N Tesar V Narita I Berthoux F Floege J Stengel B Zhang H Lifton RP Gharavi AG 《PLoS genetics》2012,8(6):e1002765
IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10−32–3×10−10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10−4). A seven–SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10−128). This model paralleled the known East–West gradient in disease risk. Moreover, the prediction of a South–North axis was confirmed by registry data showing that the prevalence of IgAN–attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN. 相似文献
845.
846.
Joaquim Jesus Maria Clara P. Amorim Paulo J. Fonseca Amílcar Teixeira Silvestre Natário João Carrola Simone Varandas Luís Torres Pereira Rui M. V. Cortes 《Journal of fish biology》2019,95(1):247-255
This study focused on the use of sound playbacks as acoustic deterrents to direct native potamodromous migratory species away from all kind of traps. The effects of two acoustic treatments, a repeated sine sweep up to 2 kHz (sweep-up stimulus) and an intermittent 140 Hz tone, were tested in three fish species native to Iberia: Salmo trutta, Pseudochondrostoma duriense and Luciobarbus bocagei. In contrast with S. trutta, the endemic cyprinids P. duriense and L. bocagei exhibited a strong repulse reaction to the frequency sweep-up sound. The 140 Hz stimulus did not seem to alter significantly the behaviour of any of the studied species. These results highlight the potential of acoustic stimuli as fish behavioural barriers and their application to in situ conservation measures of native Iberian fish populations, to protect them from hydropower dams. In addition, this study shows that acoustic deterrents can be used selectively on target species. 相似文献
847.
Sayantani Chatterjee Ling Y. Lee Rebeca Kawahara Jodie L. Abrahams Barbara Adamczyk Merrina Anugraham Christopher Ashwood Zeynep Sumer‐Bayraktar Matthew T. Briggs Jenny H. L. Chik Arun Everest‐Dass Sarah Frster Hannes Hinneburg Katia R. M. Leite Ian Loke Uwe Mginger Edward S. X. Moh Miyako Nakano Saulo Recuero Manveen K. Sethi Miguel Srougi Kathrin Stavenhagen Vignesh Venkatakrishnan Katherine Wongtrakul‐Kish Simone Diestel Peter Hoffmann Niclas G. Karlsson Daniel Kolarich Mark P. Molloy Michael H. Muders Martin K. Oehler Nicolle H. Packer Giuseppe Palmisano Morten Thaysen‐Andersen 《Proteomics》2019,19(21-22)
While aberrant protein glycosylation is a recognized characteristic of human cancers, advances in glycoanalytics continue to discover new associations between glycoproteins and tumorigenesis. This glycomics‐centric study investigates a possible link between protein paucimannosylation, an under‐studied class of human N‐glycosylation [Man1‐3GlcNAc2Fuc0‐1], and cancer. The paucimannosidic glycans (PMGs) of 34 cancer cell lines and 133 tissue samples spanning 11 cancer types and matching non‐cancerous specimens are profiled from 467 published and unpublished PGC‐LC‐MS/MS N‐glycome datasets collected over a decade. PMGs, particularly Man2‐3GlcNAc2Fuc1, are prominent features of 29 cancer cell lines, but the PMG level varies dramatically across and within the cancer types (1.0–50.2%). Analyses of paired (tumor/non‐tumor) and stage‐stratified tissues demonstrate that PMGs are significantly enriched in tumor tissues from several cancer types including liver cancer (p = 0.0033) and colorectal cancer (p = 0.0017) and is elevated as a result of prostate cancer and chronic lymphocytic leukaemia progression (p < 0.05). Surface expression of paucimannosidic epitopes is demonstrated on human glioblastoma cells using immunofluorescence while biosynthetic involvement of N‐acetyl‐β‐hexosaminidase is indicated by quantitative proteomics. This intriguing association between protein paucimannosylation and human cancers warrants further exploration to detail the biosynthesis, cellular location(s), protein carriers, and functions of paucimannosylation in tumorigenesis and metastasis. 相似文献
848.
Laura K. Weber Awale Isse Simone Rentschler Richard E. Kneusel Andrea Palermo Jürgen Hubbuch Alexander Nesterov‐Mueller Frank Breitling Felix F. Loeffler 《Engineering in Life Science》2017,17(10):1078-1087
Lyme disease is the most common tick‐borne infectious disease in Europe and North America. Previous studies discovered the immunogenic role of a surface‐exposed lipoprotein (VlsE) of Borreliella burgdorferi. We employed high density peptide arrays to investigate the antibody response to the VlsE protein in VlsE‐positive patients by mapping the protein as overlapping peptides and subsequent in‐depth epitope substitution analyses. These investigations led to the identification of antibody fingerprints represented by a number of key residues that are indispensable for the binding of the respective antibody. This approach allows us to compare the antibody specificities of different patients to the resolution of single amino acids. Our study revealed that the sera of VlsE‐positive patients recognize different epitopes on the protein. Remarkably, in those cases where the same epitope is targeted, the antibody fingerprint is almost identical. Furthermore, we could correlate two fingerprints with human autoantigens and an Epstein‐Barr virus epitope; yet, the link to autoimmune disorders seems unlikely and must be investigated in further studies. The other three fingerprints are much more specific for B. burgdorferi. Since antibody fingerprints of longer sequences have proven to be highly disease specific, our findings suggest that the fingerprints could function as diagnostic markers that can reduce false positive test results. 相似文献
849.
Franco Chimenti Daniela Secci Adriana Bolasco Paola Chimenti Arianna Granese Simone Carradori Elias Maccioni M. Cristina Cardia Matilde Yáñez Francisco Orallo Stefano Alcaro Francesco Ortuso Roberto Cirilli Rosella Ferretti Simona Distinto Johannes Kirchmair Thierry Langer 《Bioorganic & medicinal chemistry》2010,18(14):5063-5070
The present study reports on synthesis in high yields (70–99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1–45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds. 相似文献
850.
Ryon Graf Simone Barbero Nadine Keller Lauren Chen Sean Uryu David Schlaepfer Dwayne Stupack 《Cell Adhesion & Migration》2013,7(4):362-369
Procaspase-8, the zymogen form of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell attachment to an extracellular matrix substrate. Concordant with cell attachment to fibronectin, a population of procaspase-8 becomes associated with a peripheral insoluble compartment that includes focal complexes and lamellar microfilaments. Phosphorylation of procaspase-8 both impairs its maturation to the proapoptotic form and can promote cell migration. Here we show that the cytoskeletal adaptor protein CrkL promotes caspase-8 recruitment to the peripheral spreading edge of cells, and that the catalytic domain of caspase-8 directly interacts with the SH2 domain of CrkL. We show that the interaction is abolished by shRNA-mediated silencing of Src, in Src-deficient MEFs, and by pharmacologic inhibitors of the kinase. The results provide insight into how tyrosine kinases may act to coordinate the suppression caspase-8 mediated apoptosis, while promoting cell invasion. 相似文献