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991.
Zhuang Z Johnson RE Haracska L Prakash L Prakash S Benkovic SJ 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(14):5361-5366
To ensure efficient and timely replication of genomic DNA, organisms in all three kingdoms of life possess specialized translesion DNA synthesis (TLS) polymerases (Pols) that tolerate various types of DNA lesions. It has been proposed that an exchange between the replicative DNA Pol and the TLS Pol at the site of DNA damage enables lesion bypass to occur. However, to date the molecular mechanism underlying this process is not fully understood. In this study, we demonstrated in a reconstituted system that the exchange of Saccharomyces cerevisiae Poldelta with Poleta requires both the stalling of the holoenzyme and the monoubiquitination of proliferating cell nuclear antigen (PCNA). A moving Poldelta holoenzyme is refractory to the incoming Poleta. Furthermore, we showed that the Poleta C-terminal PCNA-interacting protein motif is required for the exchange process. We also demonstrated that the second exchange step to bring back Poldelta is prohibited when Lys-164 of PCNA is monoubiquitinated. Thus the removal of the ubiquitin moiety from PCNA is likely required for the reverse exchange step after the lesion bypass synthesis by Poleta. 相似文献
992.
993.
Charles E. Brady III M.D. Stephen J. Utts M.D. John R. Hyatt M.D. Jai Dev 《The American journal of gastroenterology》1988,83(2):130-135
Our previous secretin provocation studies in normal volunteers and unoperated duodenal ulcer patients suggested that the gastrin rise in gastrinoma may be an exaggeration of the normal response rather than paradoxical. We report further studies in various clinical settings having normogastrinemia (normal, n = 17; unoperated duodenal ulcer, n = 13; primary hyperparathyroidism, n = 7) and hypergastrinemia (postvagotomy, n = 5; hypochlorhydria, n = 7; achlorhydria, n = 10; chronic renal failure, n = 10; gastrinoma, n = 5). Under all nongastrinoma conditions, there were similar gastrin rises of 9-19% between 2 and 5 min after bolus intravenous GIH secretin (2 CU/kg), which fell to baseline by 8 min, except for chronic renal failure. In chronic renal failure, gastrin remained elevated from 7 to 30 min and was significantly different (p less than 0.05) at 10-30 min compared to all other nongastrinoma conditions except hyperparathyroidism. Peak rises occurred within 5 min in all entities, but only three gastrinoma patients had positive secretin provocation tests by the predefined criterion of a gastrin rise greater than 200 pg/ml. The results of secretin provocation in various clinical entities with and without hypergastrinemia further support the hypothesis that the gastrin rise in gastrinoma is an exaggeration of the normal response. The prolonged gastrin rise seen in chronic renal failure may be due to altered renal clearance, inasmuch as other hypergastrinemic states had responses similar to normal and duodenal ulcer. 相似文献
994.
Stephen J Dresnick MD 《Annals of emergency medicine》1997,30(6):754-756
No specialty better personifies the changes occurring throughout the health care delivery system than emergency medicine. It was just a short 25 years ago that the specialty of emergency medicine, as it is known today, emerged. The full-time staffing of EDs arose out of a need by patients who were presenting in ever-increasing numbers to hospital EDs that were staffed by a nurse or part-time physician. The specialty has continued to be responsive to the changing health care system throughout the past 25 years with innovations such as fast track units, observation units, and chest pain treatment center. To develop a vision for the future of the specialty, it is important to first evaluate the current trends in health care and their influences on the specialty. Three significant areas stand out in the current health care landscape: consolidation of hospital systems, emergence of publicly traded physician practice management companies, and the increasing penetration of managed care. [Dresnick SJ: The future of the private practice of emergency medicine. Ann Emerg Med December 1997;30:754-756.] 相似文献
995.
Aoki J Serruys PW van Beusekom H Ong AT McFadden EP Sianos G van der Giessen WJ Regar E de Feyter PJ Davis HR Rowland S Kutryk MJ 《Journal of the American College of Cardiology》2005,45(10):1574-1579
OBJECTIVES: This study was designed to evaluate whether rapid endothelialization of stainless steel stents with a functional endothelium prevents stent thrombosis and reduces the restenotic process. BACKGROUND: A "pro-healing" approach for prevention of post-stenting restenosis is theoretically favored over the use of cytotoxic or cytostatic local pharmacologic therapies. It is believed that the central role of the vascular endothelium is to maintain quiescence of the underlying media and adventitia. METHODS: Sixteen patients with de novo coronary artery disease were successfully treated with implantation of endothelial progenitor cell (EPC) capture stents. RESULTS: Complete procedural and angiographic success was achieved in all 16 patients. The nine-month composite major adverse cardiac and cerebrovascular events (MACCE) rate was 6.3% as a result of a symptom-driven target vessel revascularization in a single patient. There were no other MACCE despite only one month of clopidogrel treatment. At six-month follow-up, mean angiographic late luminal loss was 0.63 +/- 0.52 mm, and percent stent volume obstruction by intravascular ultrasound analysis was 27.2 +/- 20.9%. CONCLUSIONS: This first human clinical investigation of this technology demonstrates that the EPC capture coronary stent is safe and feasible for the treatment of de novo coronary artery disease. Further developments in this technology are warranted to evaluate the efficacy of this device for the treatment of coronary artery disease. 相似文献
996.
Jan D. Marshall Jean Muller Gayle B. Collin Gabriella Milan Stephen F. Kingsmore Darrell Dinwiddie Emily G. Farrow Neil A. Miller Francesca Favaretto Pietro Maffei Hélène Dollfus Roberto Vettor Jürgen K. Naggert 《Human mutation》2015,36(7):660-668
Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone‐rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world‐wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date. 相似文献
997.
Jacob E. Resch Cathleen N. Brown Stephen N. Macciocchi C. Munro Cullum Damond Blueitt Michael S. Ferrara 《Journal of Athletic Training》2015,50(12):1292-1298
ContextSymptom presentation and recovery after sport concussion (SC) are variable. Empirically based models documenting typical symptom duration would assist health care providers in managing return to play after SC.ObjectiveTo develop a prediction model for SC symptom duration.DesignCross-sectional study.SettingTwo National Collegiate Athletic Association Division I university laboratories.Intervention(s)Participants completed the Revised Head Injury Scale (HIS-r), Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), and Sensory Organization Test within 24 hours of SC diagnosis.ResultsThe final formula consisted of the HIS-r''s self-reported neck pain, drowsiness, tingling, and nervousness duration and ImPACT total symptom severity (R = 0.62, R2 = 39%, R2adj = 34.2%, P < .001). Approximately 29% (R2cv = 29%) of the variance associated with total days symptomatic after SC was explained by our preliminary formula when cross-validated. The current formula correctly identified 76% of participants who recovered within 10 days of injury.ConclusionsOur results suggest that self-reported duration of 4 symptoms during the initial 24 hours after injury along with total symptom severity as measured by ImPACT accounted for a considerable amount of variance associated with days symptomatic after SC in collegiate athletes. Until the formula is cross-validated in a college-aged sample, caution is warranted in using it clinically.Key Words: traumatic brain injuries, prediction, prolonged recovery, symptom severity, symptom duration
Key Points
- A formula to predict symptom resolution after sport concussion primarily consisting of initial symptom duration and severity correctly identified 76% of National Collegiate Athletic Association Division I collegiate athletes who recovered within 10 days.
- Before it can be used clinically, the formula must be cross-validated on larger samples.
998.
999.
Tannistha Nandi Matthew T.G. Holden Xavier Didelot Kurosh Mehershahi Justin A. Boddey Ifor Beacham Ian Peak John Harting Primo Baybayan Yan Guo Susana Wang Lee Chee How Bernice Sim Angela Essex-Lopresti Mitali Sarkar-Tyson Michelle Nelson Sophie Smither Catherine Ong Lay Tin Aw Chua Hui Hoon Stephen Michell David J. Studholme Richard Titball Swaine L. Chen Julian Parkhill Patrick Tan 《Genome research》2015,25(1):129-141
Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a serious infectious disease of humans and animals and a leading cause of community-acquired sepsis and pneumonia in endemic regions (Currie et al. 2010). Initially thought to be confined to Southeast Asia and Northern Australia, the prevalence of Bp appears to be spreading (Wiersinga et al. 2012), and Bp has been designated a biothreat select agent in the United States. Bp can persist in extreme environmental conditions and can infect several plant and animal hosts, including birds, dolphins, and humans (Wuthiekanun et al. 1995; Howard and Inglis 2003; Sprague and Neubauer 2004; Larsen et al. 2013). Treatment of clinical melioidosis is challenging because the bacterium is inherently resistant to many antibiotics, and Bp infections can persist in humans for more than a decade (Hayden et al. 2012; Wiersinga et al. 2012).The Bp genome comprises one of the largest and most complex bacterial genomes sequenced to date. Consisting of two large circular replicons (chromosomes) with a combined 7.2-Mb genome size (Holden et al. 2004), it contains a rich arsenal of genes related to virulence (e.g., Type III and Type VI secretion systems, polysaccharide biosynthesis clusters), metabolic pathways, and environmental adaptation (Wiersinga et al. 2012). Besides conserved regions, accessory genes on mobile elements and genomic islands may also contribute to phenotypic and clinical differences in microbial behavior (Currie et al. 2000; Sim et al. 2008). Analysis of the Bp genome has revealed previously unknown toxins and mechanisms of antibiotic resistance (Chantratita et al. 2011; Cruz-Migoni et al. 2011).Most large-scale studies of Bp genetic diversity to date have analyzed strains using multilocus sequence typing (MLST). These studies have suggested a high degree of genetic variability between Bp strains and related Burkholderia species (Cheng et al. 2008), and have shown that Bp strains belonging to different sequence types (STs) can often coexist in the same locale and sometimes even within the same sample (Pitt et al. 2007; Wuthiekanun et al. 2009). However, due to the limited number of genes analyzed by MLST, these studies cannot comment on the global proportion of genetic material shared between strains of different STs nor on the relative contribution of recombination, mutation, and horizontal gene transfer on intraspecies genetic diversity. Moreover, although previous studies have applied whole-genome sequencing (WGS) to study global patterns of Bp genetic heterogeneity and evolution, earlier Bp WGS reports have been confined to a limited number of isolates (10–12) derived from diverse geographical regions (Nandi et al. 2010), where geophysical barriers likely limit the propensity of the analyzed strains to exchange genetic material. To achieve a comprehensive understanding of genetic variation among closely related Bp strains, WGS analysis of much larger strain panels, ideally performed on strains isolated from a common region and belonging to the same (or closely related) ST groups, is required.In this study, we attempted to fill this important knowledge gap by performing WGS on 106 Bp strains drawn from a restricted Asian locale (Singapore and Malaysia). The WGS data, exceeding previous Bp WGS studies by 10-fold, enabled us to identify specific genomic clades of Bp, molecular features of Bp recombination at the whole-genome level, and accessory genome features contributing to recombination and horizontal gene transfer. We found a consistent pattern of genetic separation correlating with MLST, recombination haplotypes, shared accessory genes, and restriction modification (RM) systems. We provide evidence that restriction modification, beyond its role as defense against foreign DNA invasion, may have also partitioned the Bp species by restricting gene flow, resulting in the other observed correlations. Because RM systems are widely dispersed through the bacterial kingdom, it is possible that similar principles may apply to other bacterial species, implicating a potential role for epigenetic barriers as a driver of early incipient speciation. 相似文献
1000.
Christopher M. Frost Daniel C. Ursu Shane M. Flattery Andrej Nedic Cheryl A. Hassett Jana D. Moon Patrick J. Buchanan R. Brent Gillespie Theodore A. Kung Stephen W. P. Kemp Paul S. Cederna Melanie G. Urbanchek 《Journal of neuroengineering and rehabilitation》2018,15(1):108