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91.
Wilson WA Skurat AV Probst B de Paoli-Roach A Roach PJ Rutter J 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(46):16596-16601
The regulation of glycogen metabolism is critical for the maintenance of glucose and energy homeostasis in mammals. Glycogen synthase, the enzyme responsible for glycogen production, is regulated by multisite phosphorylation in yeast and mammals. We have previously identified PAS kinase as a physiological regulator of glycogen synthase in Saccharomyces cerevisiae. We provide evidence here that PAS kinase is an important regulator of mammalian glycogen synthase. Glycogen synthase is efficiently phosphorylated by PAS kinase in vitro at Ser-640, a known regulatory phosphosite. Efficient phosphorylation requires a region of PAS kinase outside the catalytic domain. This region appears to mediate a direct interaction between glycogen synthase and PAS kinase, thereby targeting kinase activity to this substrate specifically. This interaction is regulated by the PAS kinase PAS domain, raising the possibility that this interaction (and phosphorylation event) is modulated by the cellular metabolic state. This mode of regulation provides a mechanism for metabolic status to impinge directly on the cellular decision of whether to store or use available energy. 相似文献
92.
93.
Brandon P. Verdoorn MD Tamara K. Evans BS Gregory J. Hanson MD Yi Zhu PhD Larissa G. P. Langhi Prata PhD Robert J. Pignolo MD PhD Elizabeth J. Atkinson MS Erin O. Wissler-Gerdes MA George A. Kuchel MD Joan B. Mannick MD Stephen B. Kritchevsky PhD Sundeep Khosla MD Stacey A. Rizza MD Jeremy D. Walston MD Nicolas Musi MD Lewis A. Lipsitz MD Douglas P. Kiel MD Raymond Yung MB ChB Nathan K. LeBrasseur PhD Ravinder J. Singh PhD Teresa McCarthy MD MS Michael A. Puskarich MD Laura J. Niedernhofer MD PhD Paul D. Robbins PhD Matthew Sorenson JD MA Tamara Tchkonia PhD James L. Kirkland MD PhD 《Journal of the American Geriatrics Society》2021,69(11):3023-3033
The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials. 相似文献
94.
95.
Brandon N. Nicolay Paul S. Danielian Filippos Kottakis John D. Lapek Jr Ioannis Sanidas Wayne O. Miles Mantre Dehnad Katrin Tsch?p Jessica J. Gierut Amity L. Manning Robert Morris Kevin Haigis Nabeel Bardeesy Jacqueline A. Lees Wilhelm Haas Nicholas J. Dyson 《Genes & development》2015,29(17):1875-1889
96.
Arthritis in Lewis rats induced by the non-immunogenic adjuvant CP20961: an immunohistochemical analysis of the developing disease. 下载免费PDF全文
OBJECTIVES--The role of lymphocytes and macrophages in developing adjuvant arthritis induced by an injection of CP20961 in inbred Lewis rats was studied over a 32 day period using a novel biotin-avidin immunoperoxidase histochemical technique. METHODS--Fresh frozen sections of hind paws and spleens, as well as lymph nodes draining the site of the injected adjuvant were immunostained using a panel of monoclonal antibodies specific for subsets of lymphocytes and macrophages and for MHC Class II antigen. RESULTS--An increase in the numbers of activated T-lymphocytes was detected early in the draining lymph nodes before hind paw swelling had begun. The presence of these cells in significant numbers was only observed in the vicinity of the joint after joint swelling and damage had begun. Macrophages were among the first cells to invade the swollen paws and later were found with T-lymphocytes and cells bearing the MHC class II antigen at the face of eroding and re-organising bone. CONCLUSIONS--The activity of T-lymphocytes in initiating arthritis appeared to occur early in lymph nodes. Joint destruction was more closely associated with the arrival of macrophages but later arrival of T-lymphocytes may have contributed to the maintenance of chronic inflammation. 相似文献
97.
98.
Biomaterial characterization of off‐the‐shelf decellularized porcine pericardial tissue for use in prosthetic valvular applications 下载免费PDF全文
Joshua A. Choe Soumen Jana Brandon J. Tefft Ryan S. Hennessy Jason Go David Morse Amir Lerman Melissa D. Young 《Journal of tissue engineering and regenerative medicine》2018,12(7):1608-1620
Fixed pericardial tissue is commonly used for commercially available xenograft valve implants, and has proven durability, but lacks the capability to remodel and grow. Decellularized porcine pericardial tissue has the promise to outperform fixed tissue and remodel, but the decellularization process has been shown to damage the collagen structure and reduce mechanical integrity of the tissue. Therefore, a comparison of uniaxial tensile properties was performed on decellularized, decellularized‐sterilized, fixed, and native porcine pericardial tissue versus native valve leaflet cusps. The results of non‐parametric analysis showed statistically significant differences (p < .05) between the stiffness of decellularized versus native pericardium and native cusps as well as fixed tissue, respectively; however, decellularized tissue showed large increases in elastic properties. Porosity testing of the tissues showed no statistical difference between decellularized and decell‐sterilized tissue compared with native cusps (p > .05). Scanning electron microscopy confirmed that valvular endothelial and interstitial cells colonized the decellularized pericardial surface when seeded and grown for 30 days in static culture. Collagen assays and transmission electron microscopy analysis showed limited reductions in collagen with processing; yet glycosaminoglycan assays showed great reductions in the processed pericardium relative to native cusps. Decellularized pericardium had comparatively low mechanical properties among the groups studied; yet the stiffness was comparatively similar to the native cusps and demonstrated a lack of cytotoxicity. Suture retention, accelerated wear, and hydrodynamic testing of prototype decellularized and decell‐sterilized valves showed positive functionality. Sterilized tissue could mimic valvular mechanical environment in vitro, therefore making it a viable potential candidate for off‐the‐shelf tissue‐engineered valvular applications. 相似文献
99.
Joseph N. Liu Grant H. Garcia Anirudh K. Gowd Brandon C. Cabarcas Michael D. Charles Anthony A. Romeo Nikhil N. Verma 《Current reviews in musculoskeletal medicine》2018,11(1):55-62
Purpose of Review
To review the etiology, classification, presentation, evaluation, treatment strategy, and outcomes in overhead athletes with partial thickness rotator cuff tears.Recent Findings
Despite advances in surgical repair techniques, return to play following surgical repair of partial rotator cuff tears remains modest at best.Summary
Overhead athletes may be particularly prone to rotator cuff pathology due to the supraphysiological strains within the tendon during the throwing motion, as well as mechanical stress with contact between the undersurface of the rotator cuff and the glenoid. The true prevalence of partial tears may be underestimated given the high incidence of asymptomatic tears. Both dynamic ultrasound and enhanced contrast MRI have improved our understanding of this pathology. For most overhead athletes, nonoperative management is the most common course. Despite advances in imaging, diagnosis, and surgical techniques, our ability to return these patients to their elite level is modest at best when nonoperative management fails and surgical treatment is performed. If a surgical route is needed, debridement alone is the most frequent procedure given concerns of over constraint and poor return to play with surgical repair of the partial thickness rotator cuff tear.100.
Govind Pandompatam Daniel A. Sweeney Jose L. Diaz-Gomez Brandon M. Wiley 《Current cardiovascular imaging reports》2018,11(9):23