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Dušan Garić Shao Tao Eisha Ahmed Mina Youssef Cynthia Kanagaratham Juhi Shah Bruce Mazer Danuta Radzioch 《Journal of cystic fibrosis》2019,18(3):349-356
BackgroundCystic fibrosis (CF) is a genetic disease characterized by chronic inflammation of the lungs that is ineffective at clearing pathogens. B-cell activating factor (BAFF), a cytokine involved in the development of B-cells, is known to be elevated in CF patients with subclinical infections. We postulate that the elevated BAFF levels in CF patients might be triggered by Pseudomonas aeruginosa infection and it might play a protective role in the regulation of lung responses to infection.MethodsTo address this hypothesis, we used a well characterized model of CFTR.KO mice infected with a clinical strain of P. aeruginosa (PA508). We quantified cell types with flow cytometry, concentration of cytokines by ELISA tests, bacterial load by colony counting and lung physiology by metacholine-induced lung resistance.ResultsOur data demonstrates that BAFF is not elevated in uninfected CF mice, and infection with Pseudomonas leads to significant induction of this regulatory cytokine. We also demonstrate that the maintenance of BAFF levels and its induction during the infection is important for clearance of Pseudomonas infection as its depletion during the course of infection leads to decrease in the resolution of infection both in WT and CFTR-KO mice. Interestingly, the depletion of BAFF not only results in a depletion of B cells numbers but also to a significant decrease in the number of regulatory T cells in the non-infected lungs.ConclusionsOverall, our data demonstrate for the first time that BAFF is an important regulatory molecule helping to maintain the immunological response to infection and clearance of lung infection. 相似文献
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Acute systemic MK‐801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex
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The hippocampus and retrosplenial cortex are integrated within a higher‐order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate‐early genes (IEGs) Arc and Homer1a in spatial context‐specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non‐competitive NMDAR antagonists such as MK‐801 is used to model psychosis in animals and humans. Acute systemic MK‐801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate‐early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK‐801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK‐801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK‐801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK‐801‐induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganization in psychosis. © 2016 Wiley Periodicals, Inc. 相似文献
955.
Spinal Cord MR Diffusion Properties in Patients with Degenerative Cervical Cord Compression
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Toma Keser Ivan Gornik Frano Vučković Najda Selak Tamara Pavić Edita Lukić Ivan Gudelj Hrvoje Gašparović Bojan Biočina Therese Tilin Annika Wennerström Satu Männistö Veikko Salomaa Aki Havulinna Wei Wang James F. Wilson Nishi Charutvedi Markus Perola Harry Campbell Gordan Lauc Olga Gornik 《Diabetologia》2017,60(12):2352-2360
Aims/hypothesis
Better understanding of type 2 diabetes and its prevention is a pressing need. Changes in human plasma N-glycome are associated with many diseases and represent promising diagnostic and prognostic biomarkers. Variations in glucose metabolism directly affect glycosylation through the hexosamine pathway but studies of plasma glycome in type 2 diabetes are scarce. The aim of this study was to determine whether plasma protein N-glycome is changed in individuals who are at greater risk of developing type 2 diabetes.Methods
Using a chromatographic approach, we analysed N-linked glycans from plasma proteins in two populations comprising individuals with registered hyperglycaemia during critical illness (increased risk for development of type 2 diabetes) and individuals who stayed normoglycaemic during the same condition: AcuteInflammation (59 cases vs 49 controls) and AcuteInflammation Replication (52 cases vs 14 controls) populations. N-glycome was also studied in individuals from FinRisk (37 incident cases of type 2 diabetes collected at baseline vs 37 controls), Orkney Complex Disease Study (ORCADES; 94 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 658 controls) and Southall and Brent Revisited (SABRE) cohort studies (307 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 307 controls).Results
Individuals with increased risk for diabetes type 2 development (AcuteInflammation and AcuteInflammation Replication populations), incident cases of type 2 diabetes collected at baseline (FinRisk population) and individuals with elevated HbA1c (ORCADES and SABRE populations) all presented with increased branching, galactosylation and sialylation of plasma protein N-glycans and these changes were of similar magnitude.Conclusions/interpretation
Increased complexity of plasma N-glycan structures is associated with higher risk of developing type 2 diabetes and poorer regulation of blood glucose levels. Although further research is needed, this finding could offer a potential new approach for improvement in prevention of diabetes and its complications.958.
959.
Plechanovová A Byun Y Alquicer G Skultétyová L Mlčochová P Němcová A Kim HJ Navrátil M Mease R Lubkowski J Pomper M Konvalinka J Rulíšek L Bařinka C 《Journal of medicinal chemistry》2011,54(21):7535-7546
Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII. 相似文献
960.