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321.
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
322.
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome 总被引:15,自引:0,他引:15
Niihori T Aoki Y Narumi Y Neri G Cavé H Verloes A Okamoto N Hennekam RC Gillessen-Kaesbach G Wieczorek D Kavamura MI Kurosawa K Ohashi H Wilson L Heron D Bonneau D Corona G Kaname T Naritomi K Baumann C Matsumoto N Kato K Kure S Matsubara Y 《Nature genetics》2006,38(3):294-296
Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders. 相似文献
323.
324.
Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for
the majority of cancer-related deaths in women. These cancer types share a number of features, including their association
with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand
break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose)
polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly
active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and
the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients.
In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order
to individualize therapy in breast and ovarian cancer. 相似文献
325.
Schmidt T Ben-Batalla I Schultze A Loges S 《Cellular and molecular life sciences : CMLS》2012,69(9):1391-1414
Ample clinical and preclinical evidence indicates that macrophages interact with tumor cells as well as with virtually all
populations of host cells present in the tumor microenvironment. This crosstalk can strongly promote malignancy, but also
has in principle the potential to inhibit tumor growth. Thus, it is of the utmost importance to improve our understanding
of the mechanisms driving the pro- and antimalignant behavior of tumor-associated macrophages (TAMs) in order to develop better
anticancer therapies. In this review, we discuss the biological consequences of reciprocal interactions between TAMs, cancer
cells, endothelial cells, fibroblasts and other leukocyte subfractions within tumors. It was recently elucidated that tumors
specifically educate macrophages to secrete growth arrest-specific gene 6 (Gas6), the common ligand of the Tyro3, Axl, Mer
receptor (TAMR) family. In turn, Gas6 fosters tumor growth by promoting cancer cell proliferation. Therefore, the Gas6–TAMR
axis might represent a novel target for disrupting tumor–macrophage crosstalk. We summarize here what is known about TAMR
and their ligands in (human) cancer biology. In order to shed more light on the role of macrophages in human cancer, we additionally
provide an overview of what is currently known about the prognostic impact of TAMs in human cancer. 相似文献
326.
Natalia Ramírez Lorea Beloki Miriam Ciaúrriz Mercedes Rodríguez-Calvillo David Escors Cristina Mansilla Eva Bandrés Eduardo Olavarría 《Cellular and molecular life sciences : CMLS》2014,71(7):1211-1224
Chemotherapy and/or radiotherapy regular regimens used for conditioning of recipients of hematopoietic stem cell transplantation (SCT) induce a period of transient profound immunosuppression. The onset of a competent immunological response, such as the appearance of viral-specific T cells, is associated with a lower incidence of viral infections after haematopoietic transplantation. The rapid development of immunodominant peptide virus screening together with advances in the design of genetic and non-genetic viral- and tumoural-specific cellular selection strategies have opened new strategies for cellular immunotherapy in oncologic recipients who are highly sensitive to viral infections. However, the rapid development of cellular immunotherapy in SCT has disclosed the role of the T cell selection method in the modulation of functional cell activity and of in vivo secondary effects triggered following immunotherapy. 相似文献
327.
Weedon MN Lango H Lindgren CM Wallace C Evans DM Mangino M Freathy RM Perry JR Stevens S Hall AS Samani NJ Shields B Prokopenko I Farrall M Dominiczak A;Diabetes Genetics Initiative;Wellcome Trust Case Control Consortium Johnson T Bergmann S Beckmann JS Vollenweider P Waterworth DM Mooser V Palmer CN Morris AD Ouwehand WH;Cambridge GEM Consortium Zhao JH Li S Loos RJ Barroso I Deloukas P Sandhu MS Wheeler E Soranzo N Inouye M Wareham NJ Caulfield M Munroe PB Hattersley AT McCarthy MI Frayling TM 《Nature genetics》2008,40(5):575-583
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. 相似文献
328.
Aragonés J Schneider M Van Geyte K Fraisl P Dresselaers T Mazzone M Dirkx R Zacchigna S Lemieux H Jeoung NH Lambrechts D Bishop T Lafuste P Diez-Juan A Harten SK Van Noten P De Bock K Willam C Tjwa M Grosfeld A Navet R Moons L Vandendriessche T Deroose C Wijeyekoon B Nuyts J Jordan B Silasi-Mansat R Lupu F Dewerchin M Pugh C Salmon P Mortelmans L Gallez B Gorus F Buyse J Sluse F Harris RA Gnaiger E Hespel P Van Hecke P Schuit F Van Veldhoven P Ratcliffe P Baes M Maxwell P Carmeliet P 《Nature genetics》2008,40(2):170-180
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. 相似文献
329.
Hollox EJ Huffmeier U Zeeuwen PL Palla R Lascorz J Rodijk-Olthuis D van de Kerkhof PC Traupe H de Jongh G den Heijer M Reis A Armour JA Schalkwijk J 《Nature genetics》2008,40(1):23-25
Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for beta-defensin genes and risk of psoriasis. 相似文献
330.
In this article we reflect upon an integrated approach to action research. The role of the engaged researcher is empirically
addressed by using longitudinal field experiences. We take a narrative approach and tell three stories from the field. In
analysing the stories we propose a transition of the role of the engaged researcher, from that of a translator of general
theory and contextual practices to one of a literary change agent. The literary change agent inspires practitioners by means
as concepts, metaphors and storytelling. We suggest that the narrative approach can bring a new and critical flavour to the
previously under-explored area of the role of the researcher in action research.
相似文献
Lene FossEmail: |