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91.
Fleming JN Nash RA McLeod DO Fiorentino DF Shulman HM Connolly MK Molitor JA Henstorf G Lafyatis R Pritchard DK Adams LD Furst DE Schwartz SM 《PloS one》2008,3(1):e1452
Background
Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.Methodology/Principal Findings
We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon α (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon α and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.Conclusion/Significance
These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation. 相似文献92.
Cooley G Etheridge RD Boehlke C Bundy B Weatherly DB Minning T Haney M Postan M Laucella S Tarleton RL 《PLoS neglected tropical diseases》2008,2(10):e316
Background
Diagnosis of Trypanosoma cruzi infection by direct pathogen detection is complicated by the low parasite burden in subjects persistently infected with this agent of human Chagas disease. Determination of infection status by serological analysis has also been faulty, largely due to the lack of well-characterized parasite reagents for the detection of anti-parasite antibodies.Methods
In this study, we screened more than 400 recombinant proteins of T. cruzi, including randomly selected and those known to be highly expressed in the parasite stages present in mammalian hosts, for the ability to detect anti-parasite antibodies in the sera of subjects with confirmed or suspected T. cruzi infection.Findings
A set of 16 protein groups were identified and incorporated into a multiplex bead array format which detected 100% of >100 confirmed positive sera and also documented consistent, strong and broad responses in samples undetected or discordant using conventional serologic tests. Each serum had a distinct but highly stable reaction pattern. This diagnostic panel was also useful for monitoring drug treatment efficacy in chronic Chagas disease.Conclusions
These results substantially extend the variety and quality of diagnostic targets for Chagas disease and offer a useful tool for determining treatment success or failure. 相似文献93.
94.
Coastal estuaries are useful model systems to study the ecological and evolutionary responses of organisms to highly variable, discontinuous habitats. For this study, the molecular population genetic diversity of the planktonic calanoid copepod Acartia tonsa (Dana, 1849) was described based on DNA sequence variation for a 183 base-pair region of the mitochondrial 16S rRNA gene. Samples of A. tonsa were collected from four estuaries on the Atlantic coast of the USA during 1993 and 1994, one estuary on the Gulf of Mexico coast in 1994, and one site on the Pacific coast of the USA in 1994. Dispersal of A. tonsa was shown to be restricted, with significant population genetic structuring between different estuaries. For all but the closely-adjacent MA and RI samples, frequencies of haplotypes and/or length polymorphisms within one haplotype (caused by insertion/deletion mutations) revealed highly significant genetic differentiation and geographic isolation. Mt16S haplotypes of A. tonsa from Atlantic and Gulf of Mexico estuaries were assorted among four deeply-diverged clades. Haplotypes within each clade differed by <2%, while differences among clades of 10% to 14% approached those between described Acartia species (e.g., 19% to 28% among A. clausi, A. hudsonica, and A. longiremis). Atlantic and Pacific coast samples identified as A. tonsa had no haplotypes in common and genetic differences between haplotypes ranged from 18% to 29%; phylogenetic analysis supported the separation of Pacific coast A. tonsa as a distinct species. We hypothesize that the observed patterns of molecular genetic diversity and structure of A. tonsa resulted from responses to historical climatic variation, including episodic range compression and displacement, and alteration of NW Atlantic coastal and estuarine environments. 相似文献
95.
Gretchen A Murphy Suzanne M Graham Staeci Morita Sarah E Reks Kelley Rogers-Graham Anne Vojtek Grant G Kelley Channing J Der 《The Journal of biological chemistry》2002,277(12):9966-9975
Oncogenic Ras and activated forms of the Ras-related protein TC21/R-Ras2 share similar abilities to alter cell proliferation. However, in contrast to Ras, we found previously that TC21 fails to activate the Raf-1 serine/threonine kinase. Thus, TC21 must utilize non-Raf effectors to regulate cell function. In this study, we determined that TC21 interacts strongly with some (RalGDS, RGL, RGL2/Rlf, AF6, and the phosphatidylinositol 3-kinase (PI3K) catalytic subunit p110delta), and weakly with other Ras small middle dotGTP-binding proteins. In addition, library screening identified novel TC21-interacting proteins. We also determined that TC21, similar to Ras, mediates activation of phospholipase Cepsilon. We then examined if RalGDS, a RalA guanine nucleotide exchange factor, or PI3K are effectors for TC21-mediated signaling and cell proliferation in murine fibroblasts. We found that overexpression of full-length RalGDS reduced the focus forming activity of activated TC21. Furthermore, expression of activated Ras, but not TC21, enhanced GTP loading on RalA. In fact, TC21 attenuated insulin-stimulated RalA small middle dotGTP formation. In contrast, like Ras, expression of activated TC21 resulted in membrane translocation and an increase in the PI3K-dependent phosphorylation of Akt, and inhibition of PI3K activity interfered with TC21 focus formation. Finally, unlike Ras, TC21 did not activate the Rac small GTPase, indicating that Ras may not activate Rac by PI3K. Taken together, these results suggest that PI3K, but not RalGDS, is an important mediator of cell proliferation by TC21. 相似文献
96.
Gretchen Dollar Eric Struckhoff Jason Michaud Robert S Cohen 《Development (Cambridge, England)》2002,129(2):517-526
The Drosophila embryonic body plan is specified by asymmetries that arise in the oocyte during oogenesis. These asymmetries are apparent in the subcellular distribution of key mRNAs and proteins and in the organization of the microtubule cytoskeleton. We present evidence that the Drosophila oocyte also contains important asymmetries in its membrane trafficking pathways. Specifically, we show that alpha-adaptin and Rab11, which function critically in the endocytic pathways of all previously examined animal cells, are localized to neighboring compartments at the posterior pole of stage 8-10 oocytes. Rab11 and alpha-adaptin localization occurs in the absence of a polarized microtubule cytoskeleton, i.e. in grk null mutants, but is later reinforced and/or refined by Osk, the localization of which is microtubule dependent. Analyses of germline clones of a rab11 partial loss-of-function mutation reveal a requirement for Rab11 in endocytic recycling and in the organization of posterior membrane compartments. Such analyses also reveal a requirement for Rab11 in the organization of microtubule plus ends and osk mRNA localization and translation. We propose that microtubule plus ends and, possibly, translation factors for osk mRNA are anchored to posterior membrane compartments that are defined by Rab11-mediated trafficking and reinforced by Rab11-Osk interactions. 相似文献
97.
98.
P. A. Rodriguez R. Takigiku L. D. Lehman-McKeeman M. L. Fey C. L. Eddy D. Caudill 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1991,563(2)
A Perkin Elmer 3920 gas chromatograph, equipped with a versatile inlet system (i.e. an injector/trap), was interfaced to a radioactivity detector and a mass-selective detector (H/P 5970B) to identify 14C-labeled compounds. The use of a pre-trap as a demountable, programmable-temperature injector, in conjunction with the injector/trap, allowed the introduction of 0.5-ml samples of rat kidney cytosol extracts to 0.32 mm I.D. capillary columns. The instrumentation greatly facilitated the identification of the major radiolabeled metabolite of d-limonene associated with the male rat-specific protein α2u-globulin as 1,2-cis-d-limonene oxide. 相似文献
99.
100.
Gretchen Roedde 《CMAJ》2010,182(12):E593-E594