全文获取类型
收费全文 | 752篇 |
免费 | 79篇 |
专业分类
831篇 |
出版年
2021年 | 13篇 |
2020年 | 5篇 |
2016年 | 16篇 |
2015年 | 30篇 |
2014年 | 18篇 |
2013年 | 25篇 |
2012年 | 36篇 |
2011年 | 33篇 |
2010年 | 22篇 |
2009年 | 24篇 |
2008年 | 28篇 |
2007年 | 35篇 |
2006年 | 30篇 |
2005年 | 29篇 |
2004年 | 24篇 |
2003年 | 35篇 |
2002年 | 23篇 |
2001年 | 20篇 |
2000年 | 24篇 |
1999年 | 18篇 |
1998年 | 10篇 |
1997年 | 17篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1994年 | 15篇 |
1993年 | 5篇 |
1992年 | 12篇 |
1991年 | 17篇 |
1990年 | 13篇 |
1989年 | 9篇 |
1988年 | 12篇 |
1987年 | 10篇 |
1986年 | 9篇 |
1985年 | 8篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 7篇 |
1980年 | 8篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1977年 | 6篇 |
1976年 | 8篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1969年 | 5篇 |
1968年 | 4篇 |
1952年 | 5篇 |
1945年 | 5篇 |
1927年 | 4篇 |
排序方式: 共有831条查询结果,搜索用时 0 毫秒
91.
Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease 总被引:9,自引:0,他引:9
Lee JP Jeyakumar M Gonzalez R Takahashi H Lee PJ Baek RC Clark D Rose H Fu G Clarke J McKercher S Meerloo J Muller FJ Park KI Butters TD Dwek RA Schwartz P Tong G Wenger D Lipton SA Seyfried TN Platt FM Snyder EY 《Nature medicine》2007,13(4):439-447
Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases. 相似文献
92.
93.
Expression of Ca2+-permeable two-pore channels rescues NAADP signalling in TPC-deficient cells 下载免费PDF全文
Margarida Ruas Lianne C Davis Cheng-Chang Chen Anthony J Morgan Kai-Ting Chuang Timothy F Walseth Christian Grimm Clive Garnham Trevor Powell Nick Platt Frances M Platt Martin Biel Christian Wahl-Schott John Parrington Antony Galione 《The EMBO journal》2015,34(13):1743-1758
The second messenger NAADP triggers Ca2+ release from endo-lysosomes. Although two-pore channels (TPCs) have been proposed to be regulated by NAADP, recent studies have challenged this. By generating the first mouse line with demonstrable absence of both Tpcn1 and Tpcn2 expression (Tpcn1/2−/−), we show that the loss of endogenous TPCs abolished NAADP-dependent Ca2+ responses as assessed by single-cell Ca2+ imaging or patch-clamp of single endo-lysosomes. In contrast, currents stimulated by PI(3,5)P2 were only partially dependent on TPCs. In Tpcn1/2−/− cells, NAADP sensitivity was restored by re-expressing wild-type TPCs, but not by mutant versions with impaired Ca2+-permeability, nor by TRPML1. Another mouse line formerly reported as TPC-null likely expresses truncated TPCs, but we now show that these truncated proteins still support NAADP-induced Ca2+ release. High-affinity [32P]NAADP binding still occurs in Tpcn1/2−/− tissue, suggesting that NAADP regulation is conferred by an accessory protein. Altogether, our data establish TPCs as Ca2+-permeable channels indispensable for NAADP signalling. 相似文献
94.
95.
Karsdal MA Woodworth T Henriksen K Maksymowych WP Genant H Vergnaud P Christiansen C Schubert T Qvist P Schett G Platt A Bay-Jensen AC 《Arthritis research & therapy》2011,13(2):215-20
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond. 相似文献
96.
Woods LA Platt GW Hellewell AL Hewitt EW Homans SW Ashcroft AE Radford SE 《Nature chemical biology》2011,7(10):730-739
Although small molecules that modulate amyloid formation in vitro have been identified, significant challenges remain in determining precisely how these species act. Here we describe the identification of rifamycin SV as a potent inhibitor of β(2) microglobulin (β(2)m) fibrillogenesis when added during the lag time of assembly or early during fibril elongation. Biochemical experiments demonstrate that the small molecule does not act by a colloidal mechanism. Exploiting the ability of electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) to resolve intermediates of amyloid assembly, we show instead that rifamycin SV inhibits β(2)m fibrillation by binding distinct monomeric conformers, disfavoring oligomer formation and diverting the course of assembly to the formation of spherical aggregates. The results demonstrate the power of ESI-IMS-MS to identify specific protein conformers as targets for intervention in fibrillogenesis using small molecules and reveal a mechanism of action in which ligand binding diverts unfolded protein monomers toward alternative assembly pathways. 相似文献
97.
Background
Many studies have evaluated methicillin-resistant Staphylococcus aureus (MRSA) infections during single hospitalizations and subsequent readmissions to the same institution. None have assessed the comprehensive burden of MRSA infection in the period after hospital discharge while accounting for healthcare utilization across institutions.Methodology/Principal Findings
We conducted a retrospective cohort study of adult patients insured by Harvard Pilgrim Health Care who were newly-detected to harbor MRSA between January 1991 and December 2003 at a tertiary care medical center. We evaluated all MRSA-attributable infections associated with hospitalization in the year following new detection, regardless of hospital location. Data were collected on comorbidities, healthcare utilization, mortality and MRSA outcomes. Of 591 newly-detected MRSA carriers, 23% were colonized and 77% were infected upon detection. In the year following detection, 196 (33%) patients developed 317 discrete and unrelated MRSA infections. The most common infections were pneumonia (34%), soft tissue (27%), and primary bloodstream (18%) infections. Infections occurred a median of 56 days post-detection. Of all infections, 26% involved bacteremia, and 17% caused MRSA-attributable death. During the admission where MRSA was newly-detected, 14% (82/576) developed subsequent infection. Of those surviving to discharge, 24% (114/482) developed post-discharge infections in the year following detection. Half (99/185, 54%) of post-discharge infections caused readmission, and most (104/185, 55%) occurred over 90 days post-discharge.Conclusions/Significance
In high-risk tertiary care patients, newly-detected MRSA carriage confers large risks of infection and substantial attributable mortality in the year following acquisition. Most infections occur post-discharge, and 18% of infections associated with readmission occurred in hospitals other than the one where MRSA was newly-detected. Despite gains in reducing MRSA infections during hospitalization, the risk of MRSA infection among critically and chronically ill carriers persists after discharge and warrants targeted prevention strategies. 相似文献98.
99.
Genome‐wide signature of local adaptation linked to variable CpG methylation in oak populations 下载免费PDF全文
Alexander Platt Paul F. Gugger Matteo Pellegrini Victoria L. Sork 《Molecular ecology》2015,24(15):3823-3830
It has long been known that adaptive evolution can occur through genetic mutations in DNA sequence, but it is unclear whether adaptive evolution can occur through analogous epigenetic mechanisms, such as through DNA methylation. If epigenetic variation contributes directly to evolution, species under threat of disease, invasive competition, climate change or other stresses would have greater stores of variation from which to draw. We looked for evidence of natural selection acting on variably methylated DNA sites using population genomic analysis across three climatologically distinct populations of valley oaks. We found patterns of genetic and epigenetic differentiations that indicate local adaptation is operating on large portions of the oak genome. While CHG methyl polymorphisms are not playing a significant role and would make poor targets for natural selection, our findings suggest that CpG methyl polymorphisms as a whole are involved in local adaptation, either directly or through linkage to regions under selection. 相似文献
100.
Annemarie MM Vlaar Angela EP Bouwmans Marinus JPG van Kroonenburgh Werner H Mess Selma C Tromp Piet GWM Wuisman Alfons GH Kessels Ania Winogrodzka Wim EJ Weber 《BMC neurology》2007,7(1):28