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141.
Siu Wai Tsang Hongjie Zhang Chengyuan Lin Haitao Xiao Michael Wong Hongcai Shang Zhi-Jun Yang Aiping Lu Ken Kin-Lam Yung Zhaoxiang Bian 《PloS one》2013,8(12)
Pancreatic fibrosis, a prominent histopathological feature of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma, is essentially a dynamic process that leads to irreversible scarring of parenchymal tissues of the pancreas. Though the exact mechanisms of its initiation and development are poorly understood, recent studies suggested that the activation of pancreatic stellate cells (PSCs) plays a critical role in eliciting such active course of fibrogenesis. Anthraquinone compounds possess anti-inflammatory bioactivities whereas its natural derivative rhein has been shown to effectively reduce tissue edema and free-radical production in rat models of inflammatory conditions. Apart from its anti-inflammatory properties, rhein actually exerts strong anti-fibrotic effects in our current in-vivo and in-vitro experiments. In the mouse model of cerulein-induced CP, prolonged administration of rhein at 50 mg/kg/day significantly decreased immunoreactivities of the principal fibrotic activators alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) on pancreatic sections implicating the activation of PSCs, which is the central tread to fibrogenesis, was attenuated. Consequently, the overwhelmed deposition of extracellular matrix proteins fibronectin 1 (FN1) and type I collagen (COL I-α1) in exocrine parenchyma was found accordingly reduced. In addition, the expression levels of sonic hedgehog (SHH), which plays important roles in molecular modulation of various fibrotic processes, and its immediate effector GLI1 in pancreatic tissues were positively correlated to the degree of cerulein-induced fibrosis. Such up-regulation of SHH signaling was restrained in rhein-treated CP mice. In cultured PSCs, we demonstrated that the expression levels of TGF-β-stimulated fibrogenic markers including α-SMA, FN1 and COL I-α1 as well as SHH were all notably suppressed by the application of rhein at 10 μM. The present study firstly reported that rhein attenuates PSC activation and suppresses SHH/GLI1 signaling in pancreatic fibrosis. With strong anti-fibrotic effects provided, rhein can be a potential remedy for fibrotic and/or PSC-related pathologies in the pancreas. 相似文献
142.
Gabriel Fung Chen Seng Ng Jingchun Zhang Junyan Shi Jerry Wong Paulina Piesik Lillian Han Fanny Chu Julienne Jagdeo Eric Jan Takashi Fujita Honglin Luo 《PloS one》2013,8(11)
Stress granules (SGs) are dynamic cytosolic aggregates containing messenger ribonucleoproteins and target poly-adenylated (A)-mRNA. A key component of SGs is Ras-GAP SH3 domain binding protein-1 (G3BP1), which in part mediates protein-protein and protein-RNA interactions. SGs are modulated during infection by several viruses, however, the function and significance of this process remains poorly understood. In this study, we investigated the interplay between SGs and Coxsackievirus type B3 (CVB3), a member of the Picornaviridae family. Our studies demonstrated that SGs were formed early during CVB3 infection; however, G3BP1-positive SGs were actively disassembled at 5 hrs post-infection, while poly(A)-positive RNA granules persisted. Furthermore, we confirmed G3BP1 cleavage by 3Cpro at Q325. We also demonstrated that overexpression of G3BP1-SGs negatively impacted viral replication at the RNA, protein, and viral progeny levels. Using electron microscopy techniques, we showed that G3BP1-positive SGs localized near mitochondrial surfaces. Finally, we provided evidence that the C-terminal cleavage product of G3BP1 inhibited SG formation and promoted CVB3 replication. Taken together, we conclude that CVB3 infection selectively targets G3BP1-SGs by cleaving G3BP1 to produce a dominant-negative fragment that further inhibits G3BP1-SG formation and facilitates viral replication. 相似文献
143.
Hui-Chen Ko Tien-Chen Liu Li-Ang Lee Wei-Chieh Chao Yung-Ting Tsou Shu-Hang Ng Che-Ming Wu 《PloS one》2013,8(11)
Objectives
(1) To report the speech perception and intelligibility results of Mandarin-speaking patients with large vestibular aqueduct syndrome (LVAS) after cochlear implantation (CI); (2) to compare their performance with a group of CI users without LVAS; (3) to understand the effects of age at implantation and duration of implant use on the CI outcomes. The obtained data may be used to guide decisions about CI candidacy and surgical timing.Methods
Forty-two patients with LVAS participating in this study were divided into two groups: the early group received CI before 5 years of age and the late group after 5. Open-set speech perception tests (on Mandarin tones, words and sentences) were administered one year after implantation and at the most recent follow-up visit. Categories of auditory perception (CAP) and Speech Intelligibility Rating (SIR) scale scores were also obtained.Results
The patients with LVAS with more than 5 years of implant use (18 cases) achieved a mean score higher than 80% on the most recent speech perception tests and reached the highest level on the CAP/SIR scales. The early group developed speech perception and intelligibility steadily over time, while the late group had a rapid improvement during the first year after implantation. The two groups, regardless of their age at implantation, reached a similar performance level at the most recent follow-up visit.Conclusion
High levels of speech performance are reached after 5 years of implant use in patients with LVAS. These patients do not necessarily need to wait until their hearing thresholds are higher than 90 dB HL or PB word score lower than 40% to receive CI. They can do it “earlier” when their speech perception and/or speech intelligibility do not reach the performance level suggested in this study. 相似文献144.
Seung Mi Lee Jeong Woo Park Byoung Jae Kim Chan-Wook Park Joong Shin Park Jong Kwan Jun Bo Hyun Yoon 《PloS one》2013,8(12)
Background
The objective of this study was to determine whether acute histologic chorioamnionitis is associated with adverse neonatal outcomes in late preterm infants who were born after preterm PROM.Methodology/Principal Findings
The relationship between the presence of acute histologic chorioamnionitis and adverse neonatal outcome was examined in patients with preterm PROM who delivered singleton preterm newborns between 34 weeks and 36 6/7 weeks of gestation. Nonparametric statistics were used for data analysis. The frequency of acute histologic chorioamnionitis was 24% in patients with preterm PROM who delivered preterm newborns between 34 weeks and 36 6/7 weeks of gestation. Newborns born to mothers with histologic chorioamnionitis had significantly higher rates of adverse neonatal outcome (74% vs 51%; p<0.005) than those without histologic chorioamnionitis. This relationship remained significant after adjustment for gestational age at preterm PROM, gestational age at delivery, and exposure to antenatal corticosteroids.Conclusions/Significance
The presence of acute histologic chorioamnionitis is associated with adverse neonatal outcome in late preterm infants born to mothers with preterm PROM. 相似文献145.
Xiangdan Wang Valerie Quarmby Carl Ng Anan Chuntharapai Theresa Shek Charles Eigenbrot Robert F. Kelley Steven Shia Krista M McCutcheon John Lowe Cecilia Leddy Kyle Coachman Gary Cain Felix Chu Isidro Hotzel Mauricio Maia Eric Wakshull Jihong Yang 《MABS-AUSTIN》2013,5(4):540-554
Pharmacokinetic (PK) and immunohistochemistry (IHC) assays are essential to the evaluation of the safety and efficacy of therapeutic monoclonal antibodies (mAb) during drug development. These methods require reagents with a high degree of specificity because low concentrations of therapeutic antibody need to be detected in samples containing high concentrations of endogenous human immunoglobulins. Current assay reagent generation practices are labor-intensive and time-consuming. Moreover, these practices are molecule-specific and so only support one assay for one program at a time. Here, we describe a strategy to generate a unique assay reagent, 10C4, that preferentially recognizes a panel of recombinant human mAbs over endogenous human immunoglobulins. This “panel-specific” feature enables the reagent to be used in PK and IHC assays for multiple structurally-related therapeutic mAbs. Characterization revealed that the 10C4 epitope is conformational, extensive and mainly composed of non-CDR residues. Most key contact residues were conserved among structurally-related therapeutic mAbs, but the combination of these residues exists at low prevalence in endogenous human immunoglobulins. Interestingly, an indirect contact residue on the heavy chain of the therapeutic appears to play a critical role in determining whether or not it can bind to 10C4, but has no affect on target binding. This may allow us to improve the binding of therapeutic mAbs to 10C4 for assay development in the future. Here, for the first time, we present a strategy to develop a panel-specific reagent that can expedite the development of multiple clinical assays for structurally-related therapeutic mAbs. 相似文献
146.
Yang Shen Lin Zeng Aiping Zhu Tim Blanc Dipa Patel Anthony Pennello Amtul Bari Stanley Ng Kris Persaud Yun Kang Paul Balderes David Surguladze Sagit Hindi Qinwei Zhou Dale L. Ludwig Marshall Snavely 《MABS-AUSTIN》2013,5(3):418-431
Optimization of biophysical properties is a critical success factor for the developability of monoclonal antibodies with potential therapeutic applications. The inter-domain disulfide bond between light chain (Lc) and heavy chain (Hc) in human IgG1 lends structural support for antibody scaffold stability, optimal antigen binding, and normal Fc function. Recently, human IgG1λ has been suggested to exhibit significantly greater susceptibility to reduction of the inter Lc-Hc disulfide bond relative to the same disulfide bond in human IgG1κ. To understand the molecular basis for this observed difference in stability, the sequence and structure of human IgG1λ and human IgG1κ were compared. Based on this Lc comparison, three single mutations were made in the λ Lc proximal to the cysteine residue, which forms a disulfide bond with the Hc. We determined that deletion of S214 (dS) improved resistance of the association between Lc and Hc to thermal stress. In addition, deletion of this terminal serine from the Lc of IgG1λ provided further benefit, including an increase in stability at elevated pH, increased yield from transient transfection, and improved in vitro antibody dependent cell-mediated cytotoxicity (ADCC). These observations support the conclusion that the presence of the terminal serine of the λ Lc creates a weaker inter-chain disulfide bond between the Lc and Hc, leading to slightly reduced stability and a potential compromise in IgG1λ function. Our data from a human IgG1λ provide a basis for further investigation of the effects of deleting terminal serine from λLc on the stability and function of other human IgG1λ antibodies. 相似文献
147.
Emily H. M. Wong Chun-Laam Ng Vincent Chi-Hang Lui Man-ting So Stacey S. Cherny Pak-Chung Sham Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló 《PloS one》2013,8(8)
Anorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known to govern the development of the anorectal region. We have linked 11 candidate genes to the WNT signalling pathway and 17 genes to the cytoskeletal network. Interestingly, candidate genes with similar functions are disrupted by the same type of CNV. The gene network we discovered provides evidence that rare mutations in different interrelated genes may lead to similar phenotypes, accounting for genetic heterogeneity in ARMs. Classification of patients according to the affected pathway and lesion type should eventually improve the diagnosis and the identification of common genes/molecules as therapeutic targets. 相似文献
148.
In plants, salicylic acid (SA) is a signaling molecule that regulates disease resistance responses, such as systemic acquired resistance (SAR) and hypertensive response (HR). SA has been implicated as participating in various biotic and abiotic stresses. This study was conducted to investigate the role of SA in adventitious root formation (ARF) in mung bean (Phaseolus radiatus L) hypocotyl cuttings. We observed that hypocotyl treatment with SA could significantly promote the adventitious root formation, and its effects were dose and time dependent. Explants treated with SA displayed a 130% increase in adventitious root number compared with control seedlings. The role of SA in mung bean hypocotyl ARF as well as its interaction with hydrogen peroxide (H2O2) were also elucidated. Pretreatment of mung bean explants with N, N’-dimethylthiourea (DMTU), a scavenger for H2O2, resulted in a significant reduction of SA-induced ARF. Diphenyleneiodonium (DPI), a specific inhibitor of membrane-linked NADPH oxidase, also inhibited the effect of adventitious rooting triggered by SA treatment. The determination of the endogenous H2O2 level indicated that the seedlings treated with SA could induce H2O2 accumulation compared with the control treatment. Our results revealed a distinctive role of SA in the promotion of adventitious rooting via the process of H2O2 accumulation. This conclusion was further supported by antioxidant enzyme activity assays. Based on these results, we conclude that the accumulation of free H2O2 might be a downstream event in response to SA-triggered adventitious root formation in mung bean seedlings. 相似文献
149.
Yoke-Leng Ng Borut Klopcic Frances Lloyd Cynthia Forrest Wayne Greene Ian C. Lawrance 《PloS one》2013,8(10)
Background
Secreted Protein Acidic and Rich in Cysteine (SPARC) is expressed during tissue repair and regulates cellular proliferation, migration and cytokine expression. The aim was to determine if SPARC modifies intestinal inflammation.Methods
Wild-type (WT) and SPARC-null (KO) mice received 3% dextran sodium sulphate (DSS) for 7 days. Inflammation was assessed endoscopically, clinically and histologically. IL-1β, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-12/IL23p40, TNF-α, IFN-γ, RANTES, MCP-1, MIP-1α, MIP-1β, MIG and TGF-β1 levels were measured by ELISA and cytometric bead array. Inflammatory cells were characterised by CD68, Ly6G, F4/80 and CD11b immunofluorescence staining and regulatory T cells from spleen and mesenteric lymph nodes were assessed by flow cytometry.Results
KO mice had less weight loss and diarrhoea with less endoscopic and histological inflammation than WT animals. By day 35, all (n = 13) KO animals completely resolved the inflammation compared to 7 of 14 WT mice (p<0.01). Compared to WTs, KO animals at day 7 had less IL1β (p = 0.025) and MIG (p = 0.031) with higher TGFβ1 (p = 0.017) expression and a greater percentage of FoxP3+ regulatory T cells in the spleen and draining lymph nodes of KO animals (p<0.01). KO mice also had fewer CD68+ and F4/80+ macrophages, Ly6G+ neutrophils and CD11b+ cells infiltrating the inflamed colon.Conclusions
Compared to WT, SPARC KO mice had less inflammation with fewer inflammatory cells and more regulatory T cells. Together, with increased TGF-β1 levels, this could aid in the more rapid resolution of inflammation and restoration of the intestinal mucosa suggesting that the presence of SPARC increases intestinal inflammation. 相似文献150.
Cynthia Chen Nasheen Naidoo Benjamin Er Angela Cheong Ngan Phoon Fong Choo Yian Tay Kin Ming Chan Boon Yeow Tan Edward Menon Chye Hua Ee Kok Keng Lee Yee Sien Ng Yik Ying Teo Gerald C. H. Koh 《PloS one》2013,8(12)