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21.
Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)- dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell. 相似文献
22.
The existence and characteristics of bone marrow T-cell progenitors have not yet been established in man. Several pieces of evidence such as the reconstitution of certain immunodeficiencies by bone marrow graft suggest that T-cell precursors are present in the bone marrow. We report the growth of T-cell colonies from bone marrow populations using PHA-stimulated lymphocyte-conditioned medium containing T-cell growth factor (TCGF). Rosetting experiments and complement-dependent cytotoxicity assays with monoclonal antibodies indicate that the bone marrow T colony-forming cells (T-CFC) are E- OKT 3- and la+, i.e., immature progenitors. The colonies derived from these cells have the phenotype of mature T cells: E + OKT 3 + la- with either helper (OKT 4+) and suppressor (OKT 8 +) antigens. These results suggest that a thymic microenvironment may not be necessary for the in vitro proliferation and differentiation of the T-cell lineage in adult humans. These methodologies may permit direct investigation of early phenomena concerning the T-cell lineage, such as the acquisition of self-tolerance, the formation of a repertoire of specificities, and the HLA restriction phenomena that we believe takes place before the thymic maturation. 相似文献
23.
Lineage-restricted regulation of the murine SCL/TAL-1 promoter 总被引:10,自引:2,他引:10
Bockamp EO; McLaughlin F; Murrell AM; Gottgens B; Robb L; Begley CG; Green AR 《Blood》1995,86(4):1502-1514
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26.
Quantification of CD4+ T Cell Alloreactivity and Its Control by Regulatory T Cells Using Time‐Lapse Microscopy and Immune Synapse Detection
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S. C. Juvet S. Sanderson J. Hester K. J. Wood A. Bushell 《American journal of transplantation》2016,16(5):1394-1407
Assays designed to select transplant recipients for immunosuppression withdrawal have met with limited success, perhaps because they measure events downstream of T cell–alloantigen interactions. Using in vitro time‐lapse microscopy in a mouse transplant model, we investigated whether transplant outcome would result in changes in the proportion of CD4+ T cells forming prolonged interactions with donor dendritic cells. By blocking CD4–MHC class II and CD28–B7 interactions, we defined immunologically relevant interactions as those ≥500 s. Using this threshold, T cell–dendritic cell (T‐DC) interactions were examined in rejection, tolerance and T cell control mediated by regulatory T cells. The frequency of T‐DC contacts ≥500 s increased with T cells from mice during acute rejection and decreased with T cells from mice rendered unresponsive to alloantigen. Regulatory T cells reduced prolonged T‐DC contacts. Importantly, this effect was replicated with human polyclonally expanded naturally occurring regulatory T cells, which we have previously shown can control rejection of human tissues in humanized mouse models. Finally, in a proof‐of‐concept translational context, we were able to visualize differential allogeneic immune synapse formation in polyclonal CD4+ T cells using high‐throughput imaging flow cytometry. 相似文献
27.
Aarons CB Bajenova O Andrews C Heydrick S Bushell KN Reed KL Thomas P Becker JM Stucchi AF 《Clinical & experimental metastasis》2007,24(3):201-209
The liver is the most common site for metastasis by colorectal cancer, and numerous studies have shown a relationship between
serum carcinoembryonic antigen (CEA) levels and metastasis to this site. CEA activates hepatic macrophages or Kupffer cells
via binding to the CEA receptor (CEA-R), which results in the production of cytokines and the up-regulation of endothelial
adhesion molecules, both of which are implicated in hepatic metastasis. Since tissue macrophages implicated in the metastatic
process can often be difficult to isolate, the aim of this study was to develop an in vitro model system to study the complex
mechanisms of CEA-induced macrophage activation and metastasis. Undifferentiated, human monocytic THP-1 (U-THP) cells were
differentiated (D-THP) to macrophages by exposure to 200 ng/ml phorbol myristate acetate (PMA) for 18 h. Immunohistochemistry
showed two CEA-R isoforms present in both U- and D-THP cells. The receptors were localized primarily to the nucleus in U-THP
cells, while a significant cell-surface presence was observed following PMA-differentiation. Incubation of D-THP-1 cells with
CEA resulted in a significant increase in tumor necrosis factor-alpha (TNF-α) release over 24 h compared to untreated D-THP-1
or U-THP controls confirming the functionality of these cell surface receptors. U-THP cells were unresponsive to CEA. Attachment
of HT-29 cells to human umbilical vein endothelial cells significantly increased at 1 h after incubation with both recombinant
TNF-α and conditioned media from CEA stimulated D-THP cells by six and eightfold, respectively. This study establishes an
in vitro system utilizing a human macrophage cell line expressing functional CEA-Rs to study activation and signaling mechanisms
of CEA that facilitate tumor cell attachment to activated endothelial cells. Utilization of this in vitro system may lead
to a more complete understanding of the expression and function of CEA-R and facilitate the design of anti-CEA-R therapeutic
modalities that may significantly diminish the metastatic potential of CEA overexpressing colorectal tumors. 相似文献
28.
Temporal artery biopsy is considered the gold standard investigation of giant cell arteritis and is recommended in suspected cases despite a sensitivity of 81–91%. This review highlights the potential risk of facial nerve injury during temporal artery biopsy and introduces recent advances in the emerging role of imaging modalities. When these non-invasive techniques are used in conjunction with American College of Rheumatology scoring, which includes clinical features and biochemical test results, temporal artery biopsy may be avoided in selected cases. 相似文献
29.
DK Bilku AR Dennison TC Hall MS Metcalfe G Garcea 《Annals of the Royal College of Surgeons of England》2014,96(1):15-22
INTRODUCTION
Surgical stress in the presence of fasting worsens the catabolic state, causes insulin resistance and may delay recovery. Carbohydrate rich drinks given preoperatively may ameliorate these deleterious effects. A systematic review was undertaken to analyse the effect of preoperative carbohydrate loading on insulin resistance, gastric emptying, gastric acidity, patient wellbeing, immunity and nutrition following surgery.METHODS
All studies identified through PubMed until September 2011 were included. References were cross-checked to ensure capture of cited pertinent articles.RESULTS
Overall, 17 randomised controlled trials with a total of 1,445 patients who met the inclusion criteria were identified. Preoperative carbohydrate drinks significantly improved insulin resistance and indices of patient comfort following surgery, especially hunger, thirst, malaise, anxiety and nausea. No definite conclusions could be made regarding preservation of muscle mass. Following ingestion of carbohydrate drinks, no adverse events such as apparent or proven aspiration during or after surgery were reported.CONCLUSIONS
Administration of oral carbohydrate drinks before surgery is probably safe and may have a positive influence on a wide range of perioperative markers of clinical outcome. Further studies are required to determine its cost effectiveness. 相似文献30.
J Isherwood G Garcea R Williams M Metcalfe AR Dennison 《Annals of the Royal College of Surgeons of England》2014,96(3):224-228