全文获取类型
收费全文 | 1907篇 |
免费 | 109篇 |
专业分类
2016篇 |
出版年
2023年 | 12篇 |
2022年 | 28篇 |
2021年 | 58篇 |
2020年 | 28篇 |
2019年 | 27篇 |
2018年 | 52篇 |
2017年 | 33篇 |
2016年 | 81篇 |
2015年 | 94篇 |
2014年 | 109篇 |
2013年 | 177篇 |
2012年 | 170篇 |
2011年 | 157篇 |
2010年 | 96篇 |
2009年 | 87篇 |
2008年 | 118篇 |
2007年 | 101篇 |
2006年 | 85篇 |
2005年 | 94篇 |
2004年 | 88篇 |
2003年 | 69篇 |
2002年 | 59篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 7篇 |
1998年 | 8篇 |
1997年 | 13篇 |
1996年 | 12篇 |
1995年 | 8篇 |
1994年 | 13篇 |
1993年 | 7篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 8篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 5篇 |
1982年 | 6篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1977年 | 3篇 |
1973年 | 7篇 |
1967年 | 3篇 |
1966年 | 2篇 |
1964年 | 2篇 |
排序方式: 共有2016条查询结果,搜索用时 15 毫秒
51.
Yasuhito Hamaguchi Manabu Fujimoto Takashi Matsushita Kenzo Kaji Kazuhiro Komura Minoru Hasegawa Masanari Kodera Eiji Muroi Keita Fujikawa Mariko Seishima Hidehiro Yamada Ryo Yamada Shinichi Sato Kazuhiko Takehara Masataka Kuwana 《PloS one》2013,8(4)
Objective
To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).Methods
This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009.Results
Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset.Conclusion
Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.” 相似文献52.
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with X-linked mental retardation and autism spectrum disorder. We found that IL1RAPL1 regulates synapse formation of cortical neurons. To investigate how IL1RAPL1 controls synapse formation, we here screened IL1RAPL1-interacting proteins by affinity chromatography and mass spectroscopy. IL1RAPL1 interacted with Mcf2-like (Mcf2l), a Rho guanine nucleotide exchange factor, through the cytoplasmic Toll/IL-1 receptor domain. Knockdown of endogenous Mcf2l and treatment with an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of RhoA, suppressed IL1RAPL1-induced excitatory synapse formation of cortical neurons. Furthermore, we found that the expression of IL1RAPL1 affected the turnover of AMPA receptor subunits. Insertion of GluA1-containing AMPA receptors to the cell surface was decreased, whereas that of AMPA receptors composed of GluA2/3 was enhanced. Mcf2l knockdown and ROCK inhibitor treatment diminished the IL1RAPL1-induced changes of AMPA receptor subunit insertions. Our results suggest that Mcf2l-RhoA-ROCK signaling pathway mediates IL1RAPL1-dependent formation and stabilization of glutamatergic synapses of cortical neurons. 相似文献
53.
54.
55.
Hiroaki Tobimatsu Antoine Paragon Yosuke Okamura Shinji Takeoka Ryo Sudo Yasuo Ikeda Kazuo Tanishita 《Journal of Biorheology》2013,26(1-2):11-20
Recombinant glycoprotein Ibα latex beads (rGPIbα-LB) are a potential solution to overcoming platelet transfusion problems with artificial platelets. To understand the transport process of artificial platelets and to estimate the particle motion when adhering to the wall surface, we evaluated the lateral motion of rGPIbα-LB in terms of drift and random motion, because the lateral motion is an important factor for transport and adhesion. We observed the lateral motion of rGPIbα-LB flowing with red blood cells toward the immobilized von Willebrand factor (vWf) surface in a model arteriole at wall shear rates of 200–1000 s?1 and 0–40% Hct. At 40% Hct, wall shear rate dependence was observed for the drift motion, i.e. the lateral velocity of rGPIbα-LB toward the wall. In the near-wall region, the drift motion of contacting particles differed substantially from that of non-contacting particles. Additionally, the trajectories of contacting particles on the vWf surface had specific motion that was not observed on the BSA surface. These results suggest that the adhesion force between rGPIbα and vWf is highly associated with the motion of particles near the wall. These features are desirable for artificial platelets, particularly for the adhesion process. 相似文献
56.
Takuya Matsushita Takahisa Tateishi Noriko Isobe Tomomi Yonekawa Ryo Yamasaki Dai Matsuse Hiroyuki Murai Jun-ichi Kira 《PloS one》2013,8(4)
Background
Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis.Methods/Principal Findings
We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients.Conclusions
Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse. 相似文献57.
Vincent Daien Isabelle Carriere Ryo Kawasaki Jean-Paul Cristol Max Villain Pierre Fesler Karen Ritchie Cecile Delcourt 《PloS one》2013,8(7)
Purpose
Retinal vascular caliber has been linked with increased cardiovascular risk and is predictive of cardiovascular pathology, including stroke and coronary heart disease. Oxidative stress, as well as inflammatory mechanisms, plays a major role in the pathogenesis and progression of atherosclerosis, plaque rupture and vascular thrombotic propensity. The purpose of this study is to explore the relationship between retinal vascular calibers and biomarkers of oxidative stress and inflammation, in subjects free of cardiovascular pathology.Patients and Methods
Cross-sectional analysis from a community-dwelling cohort comprising 1224 individuals aged 60 years and over, without a history of coronary or peripheral artery disease or stroke. Retinal vascular caliber was measured from fundus photographs using semi-automated standardized imaging software. Oxidative stress was evaluated using plasma superoxide dismutase 2 and glutathione peroxidase (GPx-3) activities, and inflammatory state was assessed using plasma high sensitivity C-reactive protein (hsCRP) and orosomucoid.Results
In a multivariate model controlling for cardiovascular risk factors, larger retinal arteriolar caliber was independently related to higher level of GPx-3 activity (p = 0.003) whereas larger venular caliber was associated with higher levels of hsCRP (p = 0.0001) and orosomucoid (p = 0.01).Conclusion
In the present study, biomarkers of oxidative stress regulation and inflammation were independently associated with retinal vascular calibers. This suggests that an assessment of retinal vessels may offer early and non-invasive detection of subclinical vascular pathology. 相似文献58.
59.
Akira Ainai Elly van Riet Ryo Ito Kazuyuki Ikeda Kyosuke Senchi Tadaki Suzuki Shin-ichi Tamura Hideki Asanuma Takato Odagiri Masato Tashiro Takeshi Kurata Pretty Multihartina Vivi Setiawaty Krisna Nur Andriana Pangesti Hideki Hasegawa 《Microbiology and immunology》2020,64(4):313-325
Intranasally administered influenza vaccines could be more effective than injected vaccines, because intranasal vaccination can induce virus-specific immunoglobulin A (IgA) antibodies in the upper respiratory tract, which is the initial site of infection. In this study, immune responses elicited by an intranasal inactivated vaccine of influenza A(H5N1) virus were evaluated in healthy individuals naive for influenza A(H5N1) virus. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy vinyl polymer, had a notable impact on the induction of nasal IgA antibody responses but not on serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific Th cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against influenza A(H5N1) viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses. 相似文献
60.
Structural characterization of alternatively folded and partially disordered protein conformations remains challenging. Outer surface protein A (OspA) is a pivotal protein in Borrelia infection, which is the etiological agent of Lyme disease. OspA exists in equilibrium with intermediate conformations, in which the central and the C-terminal regions of the protein have lower stabilities than the N-terminal. Here, we characterize pressure- and temperature-stabilized intermediates of OspA by nuclear magnetic resonance spectroscopy combined with paramagnetic relaxation enhancement (PRE). We found that although the C-terminal region of the intermediate was partially disordered, it retains weak specific contact with the N-terminal region, owing to a twist of the central β-sheet and increased flexibility in the polypeptide chain. The disordered C-terminal region of the pressure-stabilized intermediate was more compact than that of the temperature-stabilized form. Further, molecular dynamics simulation demonstrated that temperature-induced disordering of the β-sheet was initiated at the C-terminal region and continued through to the central region. An ensemble of simulation snapshots qualitatively described the PRE data from the intermediate and indicated that the intermediate structures of OspA may expose tick receptor-binding sites more readily than does the basic folded conformation. 相似文献