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A significant portion of ubiquitin (Ub)-dependent cellular protein quality control takes place at the endoplasmic reticulum (ER) in a process termed “ER-associated degradation” (ERAD). Yeast ERAD employs two integral ER membrane E3 Ub ligases: Hrd1 (also termed “Der3”) and Doa10, which recognize a distinct set of substrates. However, both E3s bind to and activate a common E2-conjugating enzyme, Ubc7. Here we describe a novel feature of the ERAD system that entails differential activation of Ubc7 by its cognate E3s. We found that residues within helix α2 of Ubc7 that interact with donor Ub were essential for polyUb conjugation. Mutagenesis of these residues inhibited the in vitro activity of Ubc7 by preventing the conjugation of donor Ub to the acceptor. Unexpectedly, Ub chain formation by mutant Ubc7 was restored selectively by the Hrd1 RING domain but not by the Doa10 RING domain. In agreement with the in vitro data, Ubc7 α2 helix mutations selectively impaired the in vivo degradation of Doa10 substrates but had no apparent effect on the degradation of Hrd1 substrates. To our knowledge, this is the first example of distinct activation requirements of a single E2 by two E3s. We propose a model in which the RING domain activates Ub transfer by stabilizing a transition state determined by noncovalent interactions between the α2 helix of Ubc7 and Ub and that this transition state may be stabilized further by some E3 ligases, such as Hrd1, through additional interactions outside the RING domain.The ubiquitin (Ub) conjugation machinery employs three basic enzymatic activities, E1, E2, and E3, that work in concert to transfer Ub to client substrates and to form polyUb chains (1). Initially, an E1 Ub-activating enzyme forms a high-energy thioester bond with the C terminus of Ub, after which the Ub molecule is transferred to the active-site Cys of an E2 Ub-conjugating (Ubc) enzyme. The Ub-charged E2 binds to an E3 ligase and catalyzes the transfer of Ub to the ε-amino group of a Lys side chain within the substrate. Additional Ubs then can be ligated to the initial Ub molecule through sequential ubiquitylation cycles, ultimately forming a polyUb chain. Ub can be conjugated to itself via specific Lys residues, resulting in diverse types of chain linkages. Linkage through Lys48 is linked primarily to substrate degradation. Consequently, protein substrates carrying Lys48-linked polyUb chains bind to and are degraded by 26S proteasome.Although it is well established that E3 ligases activate Ub ligation by E2s via their RING domains, very little is actually known about the underlying regulatory mechanism. Several recent studies determined the structure of RING domain complexes with Ub-charged UbcH5 (24). In one of these studies, the structure in solution of Ub-charged UbcH5c together with the mouse E3 ligase E4B U-box domain revealed that Ub can adopt an array of “open” and “closed” conformations (2). The productive closed conformation promotes a nucleophilic attack on the Ub∼E2 thioester by an incoming Lys (acceptor) residue (2). A similar closed conformation was identified in the structures of UbcH5a and UbcH5b, together with their cognate RING domains (3, 4). Taken together, these structural studies suggest that RING domains can catalyze Ub transfer by stabilizing a transition state of a closed conformation of the E2-bound (donor) Ub (5).Among the fundamental intracellular functions of the Ub–proteasome system is maintenance of cellular protein quality control (PQC) by targeting a diverse array of transiently or permanently misfolded substrates for proteolysis. A central branch of PQC degradation takes place in the endoplasmic reticulum (ER) in a process termed “ER-associated degradation” (ERAD) (6). Despite the multitude of misfolded substrates, ERAD employs only a few E3–ligase complexes (7). In fact, the bakers'' yeast S. cerevisiae ERAD system employs only two Ub-ligation complexes, specified by their E3 ligase components, Hrd1 and Doa10 (812). Importantly, each of the two E3 ligase complexes recognizes a distinct set of substrates, with minor overlaps (13).Degradation by the yeast ERAD Ub-ligation system entails the combined activity of two E2 enzymes: Ubc6 and Ubc7 for the Doa10 pathway and Ubc1 and Ubc7 for the Hrd1 pathway (14, 15). The shared E2 enzyme, Ubc7, is a soluble cytosolic protein whose binding to either of the E3–ligase complexes at the ER membrane is mediated by the auxiliary ER membrane protein Cue1. Binding to Cue1 not only mediates the interaction with the E3–ligase complex but also protects Ubc7 from degradation and stimulates its Ub-transfer activity (1620). Ubc7 is highly conserved in evolution, as evident from substantial sequence and structure similarities with its orthologs from other species (21). The human Ubc7 ortholog, Ube2g2 (21), functions together with several ER membrane-embedded E3 ligases, the best characterized of which is the tumor autocrine motility factor receptor, gp78 (22). Ubc7 and Ube2g2 are subjected to similar regulatory mechanisms: They bind to and are activated by the RING domains of their cognate E3s as well as by the E2-binding regions and CUE domains within Cue1 and gp78 (19, 20, 2326). The evolutionarily conserved sequence, structure, and regulatory mechanisms of the Ubc7 E2s imply an essential physiological function.In this study we explored the role of helix α2 of Ubc7 in enzyme activation. Based on our in vivo and in vitro observations and on the available structural information, we propose a mechanism whereby activation of Ubc7, mediated by noncovalent interaction with Ub at helix α2, is differentially affected by the RING domains of its cognate E3 ligases Hrd1 and Doa10.  相似文献   
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Individuals with Prader–Willi syndrome (PWS), a genetic disorder caused by mutations to the q11‐13 region on chromosome 15, commonly show severe skin‐picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanisms underlying these behaviors. Seventeen individuals with PWS, aged 6–25 years, who showed severe skin‐picking behaviors, were recruited and scanned on a 3T scanner. We used functional magnetic resonance imaging (fMRI) while episodes of skin picking were recorded on an MRI‐safe video camera. Three participants displayed skin picking continuously throughout the scan, three participants did not display skin picking, and the data for one participant evidenced significant B0 inhomogeneity that could not be corrected. The data for the remaining 10 participants (six male, four female) who displayed a sufficient number of picking and nonpicking episodes were subjected to fMRI analysis. Results showed that regions involved in interoceptive, motor, attention, and somatosensory processing were activated during episodes of skin‐picking behavior compared with nonpicking episodes. Scores obtained on the Self‐Injury Trauma scale were significantly negatively correlated with mean activation within the right insula and left precentral gyrus. These data indicate that itch and pain processes appear to underlie skin‐picking behaviors in PWS, suggesting that interoceptive disturbance may contribute to the severity and maintenance of abnormal skin‐picking behaviors in PWS. Implications for treatments are discussed. Hum Brain Mapp 36:4135–4143, 2015. © 2015 Wiley Periodicals, Inc.  相似文献   
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We set out to clone Bax-specific CD8+ T cells from peripheral blood samples of patients with primary chronic lymphocytic leukaemia. A number of clones were generated using a Bax peptide pool and their T-cell epitope was mapped to two peptides sharing a common 9-amino-acid sequence (LLSYFGTPT), restricted by HLA-A*0201. However, when these T-cell clones were tested against highly purified syntheses (> 95%) of the same peptide sequence, there was no functional response. Subsequent mass spectrometric analysis and HPLC fractionation suggested that the active component in the original crude peptide preparations (77% pure) was a peptide with a tert-butyl (tBu) modification of the tyrosine residue. This was confirmed by modification of the inactive wild-type sequence to generate functionally active peptides. Computer modelling of peptide:HLA-A*0201 structures predicted that the tBu modification would not affect interactions between peptide residues and the HLA binding site. However, these models did predict that the tBu modification of tyrosine would result in an extension of the side chain out of the peptide-binding groove up towards the T-cell receptor. This modified product formed < 1% of the original P603 crude peptide preparation and < 0·05% of the original 23-peptide mixture used for T-cell stimulation. The data presented here, illustrate the potential for chemical modifications to change the immunogenicity of synthetic peptides, and highlight the exquisite capacity of T-cell receptors to discriminate between structurally similar peptide sequences. Furthermore, this study highlights potential pitfalls associated with the use of synthetic peptides for the monitoring and modulating of human immune responses.  相似文献   
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Unicystic Ameloblastoma (UA) is a rare variant of ameloblastoma which is an odontogenic epithelial neoplasm, typically affecting mandibular ramus. Maxillary ameloblastoma is a rare entity with a more disastrous consequence. Although extremely rare, their highly recurrent and locally aggressive behavior can lead to invasion of vital structures surrounding maxilla (orbit, cranium) even after several years of conservative surgical management (limited resection, curettage). We report a case of 16-year-old girl presenting with proptosis of left eye, UA left maxilla, who was treated initially with limited resection (enucleation) and curettage and the lesion recurred after two years with a more aggressive behavior, causing destruction floor of orbit. To this date there are only 23 documented cases of orbital invasion and only three of the reports are in ophthalmic literature. The ophthalmologists need to be aware of this type of rare lesion presenting as proptosis.  相似文献   
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Ellen C. Caniglia  James M. Robins  Lauren E. Cain  Caroline Sabin  Roger Logan  Sophie Abgrall  Michael J. Mugavero  Sonia Hernández-Díaz  Laurence Meyer  Remonie Seng  Daniel R. Drozd  George R. Seage III  Fabrice Bonnet  Fabien Le Marec  Richard D. Moore  Peter Reiss  Ard van Sighem  William C. Mathews  Inma Jarrín  Belén Alejos  Steven G. Deeks  Roberto Muga  Stephen L. Boswell  Elena Ferrer  Joseph J. Eron  John Gill  Antonio Pacheco  Beatriz Grinsztejn  Sonia Napravnik  Sophie Jose  Andrew Phillips  Amy Justice  Janet Tate  Heiner C. Bucher  Matthias Egger  Hansjakob Furrer  Jose M. Miro  Jordi Casabona  Kholoud Porter  Giota Touloumi  Heidi Crane  Dominique Costagliola  Michael Saag  Miguel A. Hernán 《Statistics in medicine》2019,38(13):2428-2446
Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the “no direct effect” assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The “no direct effect” assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.  相似文献   
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We report an index case of a male patient who presented with all clinical manifestations of Pacak‐Zhuang syndrome, including early‐age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings. Sequencing analysis detected an EPAS1 mutation in all tumors tested, but not in the germline.  相似文献   
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Journal of Autism and Developmental Disorders - Previous studies have suggested that girls with Turner syndrome (TS) exhibit symptoms of social anxiety during interactions with others. However, few...  相似文献   
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