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61.
Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice 下载免费PDF全文
Yang YH Hall P Milenkovski G Sharma L Hutchinson P Melis E Carmeliet P Tipping P Morand E 《The American journal of pathology》2004,164(1):109-117
Tissue factor (TF), a transmembrane receptor for plasma factor VII(a), is the main initiator of the coagulation cascade. It has also been implicated in noncoagulant processes, including inflammation. The function of the TF cytoplasmic domain was studied in mice in which 18 of the 20 cytoplasmic amino acids were deleted. This mutation (TF(deltaCT/deltaCT)) is not associated with alterations in blood coagulation. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in mice preimmunized with mBSA. Arthritis severity was significantly reduced in TF(deltaCT/deltaCT) mice compared to wild-type mice, including reductions in synovitis, synovial exudate, cartilage degradation, and bone damage. A marked reduction in synovial interleukin (IL)-1beta and IL-6 mRNA was also observed. Serum anti-mBSA IgG1, but not IgG2a, was increased in mutant mice. Cutaneous delayed-type hypersensitivity and antigen-induced T-cell proliferation were reduced in TF(deltaCT/deltaCT) compared to wild-type mice. A significant down-regulation of lipopolysaccharide-induced IL-1, tumor necrosis factor, IL-6, macrophage migration inhibitory factor, and matrix metalloproteinase-13 mRNA was observed in immunized, but not in naive TF(deltaCT/deltaCT) macrophages ex vivo. These data suggest a significant role for the cytoplasmic domain of TF in the regulation of the immunoinflammatory responses, a murine arthritis model, and macrophage function. 相似文献
62.
Ringrose JH Meiring HD Speijer D Feltkamp TE van Els CA de Jong AP Dankert J 《Infection and immunity》2004,72(9):5097-5105
Reactive arthritis (ReA) induced by infection with several gram-negative bacteria is strongly associated with expression of the major histocompatibility complex class I molecule HLA-B27. It is thought that due to the intracellular lifestyle of ReA-inducing bacteria, bacterial fragments can be presented by HLA-B27. Cytotoxic T cells recognizing such bacterial peptides or other induced host peptides could cross-react with self peptides presented in the joints, giving rise to disease. Studies to analyze the B27 peptide repertoire in relation to infection were severely hampered, as complex peptide profiles obtained from separate infected and noninfected cell preparations had to be compared. For this study, we applied a new approach to examine the effect of Salmonella enterica serovar Typhimurium infection on the B27 peptide repertoire presented by the HLA-B*2704 subtype associated with disease. Firstly, we showed that both host cell and S. enterica serovar Typhimurium proteins can be tagged metabolically with stable-isotope-labeled arginine. We then designed experiments so that either the tagged endogenous or tagged bacterial B*2704-presented peptide repertoires from infected cells could be analyzed by mass spectrometry from single peptide preparations that included uninfected controls. Using this new approach, we found no evidence for significant changes in endogenous B*2704 peptide presentation after infection or for any S. enterica serovar Typhimurium-derived B27-bound peptide. In conclusion, the hypothesis that S. enterica serovar Typhimurium induces changes in B27 peptide presentation could not be supported. 相似文献
63.
The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia 下载免费PDF全文
Sharma L Melis E Hickey MJ Clyne CD Erlich J Khachigian LM Davenport P Morand E Carmeliet P Tipping PG 《The American journal of pathology》2004,165(1):331-340
Tissue factor (TF) is an integral membrane protein that binds factor VIIa and initiates coagulation. The extracellular domain of TF is responsible for its hemostatic function and by implication in the dysregulation of coagulation, which contributes to death in endotoxemia. The role of the cytoplasmic domain of tissue factor in endotoxemia was studied in mice, which lack the cytoplasmic domain of TF (TF(deltaCT/deltaCT)). These mice develop normally and have normal coagulant function. Following i.p injection with 0.5 mg of lipopolysaccharide (LPS), TF(deltaCT/deltaCT) mice showed significantly greater survival at 24 hours compared to the wt mice (TF(+/+)). The serum levels of TNF-alpha and IL-1beta were significantly lower at 1 hour after LPS injection and IL-6 levels were significantly lower at 24 hours in TF(deltaCT/deltaCT) mice compared to TF(+/+)mice. Neutrophil recruitment into the lung was also significantly reduced in TF(deltaCT/deltaCT) mice. Nuclear extracts from tissues of endotoxemic TF(deltaCT/deltaCT) mice also showed reduced NFkappaB activation. LPS induced leukocyte rolling, adhesion, and transmigration in post-capillary venules assessed by intravital microscopy was also significantly reduced in TF(deltaCT/deltaCT) mice. These results indicate that deletion of the cytoplasmic domain of TF impairs the recruitment and activation of leukocytes and increases survival following endotoxin challenge. 相似文献
64.
Donor‐specific alloreactive T cells can be quantified from whole blood,and may predict cellular rejection after renal transplantation 下载免费PDF全文
Michaela Fischer Sarah Leyking Marco Schäfer Julia Elsäßer Martin Janssen Janine Mihm Danilo Fliser Martina Sester Urban Sester 《European journal of immunology》2017,47(7):1220-1231
Preformed cellular alloreactivity can exist prior to transplantation and may contribute to rejection. Here, we used a rapid flow‐cytometric whole‐blood assay to characterize the extent of alloreactive T cells among 1491 stimulatory reactions from 61 renal transplant candidates and 75 controls. The role of preformed donor‐specific alloreactive T cells in cellular rejection was prospectively analyzed in 21 renal transplant recipients. Alloreactive CD8+ T cells were more frequent than respective CD4+ T cells, and these levels were stable over time. CD8+ T cells were effector‐memory T cells largely negative for expression of CD27, CD62L, and CCR7, and were susceptible to steroid and calcineurin inhibitor inhibition. Alloreactivity was more frequent in samples with higher number of HLA mismatches. Moreover, the percentage of individuals with alloreactive T cells was higher in transplant candidates than in controls. Among transplant candidates, 5/61 exhibited alloreactive CD8+ T cells against most stimulators, 23/61 toward a limited number of stimulators, and 33/61 did not show any alloreactivity. Among 21 renal transplant recipients followed prospectively, one had donor‐specific preformed T‐cell alloreactivity. She was the only patient who developed cellular rejection posttransplantation. In conclusion, donor‐specific alloreactive T cells may be rapidly quantified from whole blood, and may predict cellular rejection after transplantation. 相似文献
65.
Geelen E Van Hoyweghen I Doevendans PA Marcelis CL Horstman K 《American journal of medical genetics. Part A》2011,155(8):1930-1938
Professional guidelines on genetic testing of children have recently shifted their focus from protecting the child's autonomous choice to professionals, together with parents, striving to work in the child's “best interest.” This notion of “best interest” allows room for therapeutical as well as psychological and social considerations, and gives rise to the question how parents and professionals weigh up the child's best interest in practice. In this qualitative study, we followed six extended families involved in genetic testing for hypertrophic cardiomyopathy in the Netherlands for 3½ years. In total 57 members of these families were interviewed in depth; many of them more than once. Our empirical analysis shows that the best interest of a child is constructed via long‐term processes in the broader context of family and kin. In this context, “best interests” are considered and reconsidered. We conclude that a child's best interest should not be framed as the result of an instantaneous agreement between parents and professionals. In dealing with genetic testing of children, parents as well as professionals reflect on and learn from the processes of generating new meanings of “best interest.” To enable professionals to deal with the variety in family life, these learning processes should be documented closely. © 2011 Wiley‐Liss, Inc. 相似文献
66.
Huyghe JR Fransen E Hannula S Van Laer L Van Eyken E Mäki-Torkko E Aikio P Sorri M Huentelman MJ Van Camp G 《European journal of human genetics : EJHG》2011,19(3):347-352
The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations. 相似文献
67.
Alex D. Sheftel Oliver Stehling Antonio J. Pierik Hans-Peter Els?sser Ulrich Mühlenhoff Holger Webert Anna Hobler Frank Hannemann Rita Bernhardt Roland Lill 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(26):11775-11780
Mammalian adrenodoxin (ferredoxin 1; Fdx1) is essential for the synthesis of various steroid hormones in adrenal glands. As a member of the [2Fe-2S] cluster-containing ferredoxin family, Fdx1 reduces mitochondrial cytochrome P450 enzymes, which then catalyze; e.g., the conversion of cholesterol to pregnenolone, aldosterone, and cortisol. The high protein sequence similarity between Fdx1 and its yeast adrenodoxin homologue (Yah1) suggested that Fdx1, like Yah1, may be involved in the biosynthesis of heme A and Fe/S clusters, two versatile and essential protein cofactors. Our study, employing RNAi technology to deplete human Fdx1, did not confirm this expectation. Instead, we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis. Unlike Fdx1, Fdx2 was unable to efficiently reduce mitochondrial cytochromes P450 and convert steroids, indicating that the two ferredoxin isoforms are highly specific for their substrates in distinct biochemical pathways. Moreover, Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria. We conclude that mammals depend on two distinct mitochondrial ferredoxins for the specific production of either steroid hormones or heme A and Fe/S proteins. 相似文献
68.
Rachel M. Stenger Martien C. M. Poelen Ed E. Moret Betsy Kuipers Sven C. M. Bruijns Peter Hoogerhout Marcel Hijnen Audrey J. King Frits R. Mooi Claire J. P. Boog Ccile A. C. M. van Els 《Infection and immunity》2009,77(2):896-903
P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis, Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+ T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restricted B. pertussis conserved CD4+ T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination and B. pertussis infection, and it was capable of evoking a Th1/Th17-type cytokine response. B. pertussis P.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present in Bordetella parapertussis and Bordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+ T cells in an HLA-DQ-restricted manner. During B. pertussis infection, the epitope was associated with a Th1-type CD4+ T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+ T-cell immunity after B. pertussis vaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance of B. pertussis-specific CD4+ T-cell mechanisms in preclinical and clinical vaccine studies. 相似文献
69.
BongKyoo Choi Jakob Blue Bjorner Per-Olof Ostergren Els Clays Irene Houtman Laura Punnett Annika Rosengren Dirk De Bacquer Marco Ferrario Maaike Bilau Robert Karasek 《International journal of behavioral medicine》2009,16(2):136-147
Background Little is known about cross-language measurement equivalence of the job content questionnaire (JCQ)
Purpose The purposes of this study were to assess the extent of cross-language differential item functioning (DIF) of the 27 JCQ items
in six languages (French, Dutch, Belgian-French, Belgian-Dutch (Flemish), Italian, and Swedish) from six European research
centers and to test whether its effects on the scale-level mean comparisons among the centers were substantial or not.
Method A partial gamma coefficient method was used for statistical DIF analyses where the Flemish JCQ was the reference for other
language versions. Additionally, equivalence between the Flemish and Dutch translations was subjected to a judgmental review.
Results On average, 36% to 39% of the total tested items appeared to be cross-language DIF items in the statistical analyses. The
judgmental review indicated that half of the DIF items may be associated with translation difference. The impacts of the DIF
items on the mean comparisons of the JCQ scales between the centers were non-trivial: underestimated skill discretion (Milan),
underestimated decision authority (Leiden), underestimated psychological demands (Milan women), and incomparable coworker
support (Gothenburg 95).
Conclusion Cross-language DIF of the JCQ among European countries should be considered in international comparative studies on psychosocial
job hazards using JCQ scales.
相似文献
BongKyoo ChoiEmail: |
70.
Inoubli A De Cuypere G Rubens R Heylens G Elaut E Van Caenegem E Menten B T'Sjoen G 《The journal of sexual medicine》2011,8(2):475-478
IntroductionKaryotyping is often performed in transsexual individuals.AimQuantification and characterization of karyotype findings and abnormalities in transsexual persons.Main Outcome MeasuresKaryotypes were listed both in male‐to‐female and in female‐to‐male transsexual persons.MethodsThe data were collected through a retrospective study.ResultsKaryotypes of 368 transsexual individuals (251 male‐to‐female, 117 female‐to‐male) are described. Normal findings were found in 97.55%. Prevalence of abnormal karyotypes was 3.19% among male‐to‐female, and 0.85% among female‐to‐male transsexuals. Nine karyotypes showed variations; Klinefelter syndrome was confirmed in three persons, whereas others displayed autosomal aberrations.ConclusionKaryotyping is only of very limited information in the transsexual population. Inoubli A, De Cuypere G, Rubens R, Heylens G, Elaut E, Van Caenegem E, Menten B, and T'Sjoen G. Karyotyping, is it worthwhile in transsexualism? 相似文献