全文获取类型
收费全文 | 179篇 |
免费 | 18篇 |
专业分类
197篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2019年 | 4篇 |
2018年 | 3篇 |
2017年 | 6篇 |
2016年 | 6篇 |
2015年 | 11篇 |
2014年 | 12篇 |
2013年 | 13篇 |
2012年 | 9篇 |
2011年 | 7篇 |
2010年 | 7篇 |
2009年 | 9篇 |
2008年 | 12篇 |
2007年 | 10篇 |
2006年 | 10篇 |
2005年 | 8篇 |
2004年 | 9篇 |
2003年 | 10篇 |
2002年 | 4篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 1篇 |
1998年 | 9篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 3篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1975年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有197条查询结果,搜索用时 15 毫秒
71.
Valentina C Sladky Katja Knapp Tamas G Szabo Vincent Z Braun Laura Bongiovanni Hilda van den Bos Diana CJ Spierings Bart Westendorp Ana Curinha Tatjana Stojakovic Hubert Scharnagl Gerald Timelthaler Kaoru Tsuchia Matthias Pinter Georg Semmler Floris Foijer Alain de Bruin Thomas Reiberger Nataliya RohrUdilova Andreas Villunger 《EMBO reports》2020,21(12)
Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro‐tumorigenic effect of PIDDosome‐mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence‐free survival in HCC patients. 相似文献
72.
Sonja Melman Ellen NC Schoorel Carmen Dirksen Anneke Kwee Luc Smits Froukje de Boer Madelaine Jonkers Mallory D Woiski Ben Willem J Mol Johannes PR Doornbos Harry Visser Anjoke JM Huisjes Martina M Porath Friso MC Delemarre Simone MI Kuppens Robert Aardenburg Ivo MA Van Dooren Francis PJM Vrouenraets Frans TH Lim Gunilla Kleiverda Paulien CM van der Salm Karin de Boer Marko J Sikkema Jan G Nijhuis Rosella PMG Hermens Hubertina CJ Scheepers 《Implementation science : IS》2013,8(1):1-8
Background
Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently. Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).Methods
An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.Discussion
This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.Trial registration
http://www.clinicaltrials.gov: NCT01261676 相似文献73.
Ellen F. VieuxDoug Barrick 《Biophysical chemistry》2011,159(1):152-161
Mapping the stability distributions of proteins in their native folded states provides a critical link between structure, thermodynamics, and function. Linear repeat proteins have proven more amenable to this kind of mapping than globular proteins. C-terminal deletion studies of YopM, a large, linear leucine-rich repeat (LRR) protein, show that stability is distributed quite heterogeneously, yet a high level of cooperativity is maintained [1]. Key components of this distribution are three interfaces that strongly stabilize adjacent sequences, thereby maintaining structural integrity and promoting cooperativity.To better understand the distribution of interaction energy around these critical interfaces, we studied internal (rather than terminal) deletions of three LRRs in this region, including one of these stabilizing interfaces. Contrary to our expectation that deletion of structured repeats should be destabilizing, we find that internal deletion of folded repeats can actually stabilize the native state, suggesting that these repeats are destabilizing, although paradoxically, they are folded in the native state. We identified two residues within this destabilizing segment that deviate from the consensus sequence at a position that normally forms a stacked leucine ladder in the hydrophobic core. Replacement of these nonconsensus residues with leucine is stabilizing. This stability enhancement can be reproduced in the context of nonnative interfaces, but it requires an extended hydrophobic core. Our results demonstrate that different LRRs vary widely in their contribution to stability, and that this variation is context-dependent. These two factors are likely to determine the types of rearrangements that lead to folded, functional proteins, and in turn, are likely to restrict the pathways available for the evolution of linear repeat proteins. 相似文献
74.
Cooperativity is a defining feature of protein folding, but its thermodynamic and structural origins are not completely understood. By constructing consensus ankyrin repeat protein arrays that have nearly identical sequences, we quantify cooperativity by resolving stability into intrinsic and interfacial components. Heteronuclear NMR and CD spectroscopy show that these constructs adopt ankyrin repeat structures. Applying a one-dimensional Ising model to a series of constructs chosen to maximize information content in unfolding transitions, we quantify stabilities of the terminal capping repeats, and resolve the effects of denaturant into intrinsic and interfacial components. Reversible thermal denaturation resolves interfacial and intrinsic free energies into enthalpic, entropic, and heat capacity terms. Intrinsic folding is entropically disfavored, whereas interfacial interaction is entropically favored and attends a decrease in heat capacity. These results suggest that helix formation and backbone ordering occurs upon intrinsic folding, whereas hydrophobic desolvation occurs upon interfacial interaction, contributing to cooperativity. 相似文献
75.
Puverel S Barrick C Dolci S Coppola V Tessarollo L 《Development (Cambridge, England)》2011,138(12):2511-2521
RanBPM is a recently identified scaffold protein that links and modulates interactions between cell surface receptors and their intracellular signaling pathways. RanBPM has been shown to interact with a variety of functionally unrelated proteins; however, its function remains unclear. Here, we show that RanBPM is essential for normal gonad development as both male and female RanBPM(-/-) mice are sterile. In the mutant testis there was a marked decrease in spermatogonia proliferation during postnatal development. Strikingly, the first wave of spermatogenesis was totally compromised, as seminiferous tubules of homozygous mutant animals were devoid of post-meiotic germ cells. We determined that spermatogenesis was arrested around the late pachytene-diplotene stages of prophase I; surprisingly, without any obvious defect in chromosome synapsis. Interestingly, RanBPM deletion led to a remarkably quick disappearance of all germ cell types at around one month of age, suggesting that spermatogonia stem cells are also affected by the mutation. Moreover, in chimeric mice generated with RanBPM(-/-) embryonic stem cells all mutant germ cells disappeared by 3 weeks of age suggesting that RanBPM is acting in a cell-autonomous way in germ cells. RanBPM homozygous mutant females displayed a premature ovarian failure due to a depletion of the germ cell pool at the end of prophase I, as in males. Taken together, our results highlight a crucial role for RanBPM in mammalian gametogenesis in both genders. 相似文献
76.
Evidence for a second class of S-adenosylmethionine riboswitches and other regulatory RNA motifs in alpha-proteobacteria 下载免费PDF全文
Corbino KA Barrick JE Lim J Welz R Tucker BJ Puskarz I Mandal M Rudnick ND Breaker RR 《Genome biology》2005,6(8):R70-10
Background
Riboswitches are RNA elements in the 5' untranslated leaders of bacterial mRNAs that directly sense the levels of specific metabolites with a structurally conserved aptamer domain to regulate expression of downstream genes. Riboswitches are most common in the genomes of low GC Gram-positive bacteria (for example, Bacillus subtilis contains examples of all known riboswitches), and some riboswitch classes seem to be restricted to this group.Results
We used comparative sequence analysis and structural probing to identify five RNA elements (serC, speF, suhB, ybhL, and metA) that reside in the intergenic regions of Agrobacterium tumefaciens and many other α-proteobacteria. One of these, the metA motif, is found upstream of methionine biosynthesis genes and binds S-adenosylmethionine (SAM). This natural aptamer most likely functions as a SAM riboswitch (SAM-II) with a consensus sequence and structure that is distinct from the class of SAM riboswitches (SAM-I) predominantly found in Gram-positive bacteria. The minimal functional SAM-II aptamer consists of fewer than 70 nucleotides, which form a single stem and a pseudoknot. Despite its simple architecture and lower affinity for SAM, the SAM-II aptamer strongly discriminates against related compounds.Conclusion
SAM-II is the only metabolite-binding riboswitch class identified so far that is not found in Gram-positive bacteria, and its existence demonstrates that biological systems can use multiple RNA structures to sense a single chemical compound. The two SAM riboswitches might be 'RNA World' relics that were selectively retained in certain bacterial lineages or new motifs that have emerged since the divergence of the major bacterial groups. 相似文献77.
Lonneke Smeding Jan Willem Kuiper Frans B Pl?tz Martin CJ Kneyber AB Johan Groeneveld 《Respiratory research》2013,14(1):92
Background
Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism.Materials and methods
N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level.Results
Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses.Conclusions
Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity. 相似文献78.
79.
F Yang A Dong P Mueller J Caicedo AM Sutton J Odetunde CJ Barrick YM Klyachkin A Abdel-Latif SS Smyth 《PloS one》2012,7(8):e40196
Left ventricular hypertrophy (LVH) is usually accompanied by intensive interstitial and perivascular fibrosis, which may contribute to arrhythmogenic sudden cardiac death. The mechanisms underlying the development of cardiac fibrosis are incompletely understood. To investigate the role of perivascular inflammation in coronary artery remodeling and cardiac fibrosis during hypertrophic ventricular remodeling, we used a well-established mouse model of LVH (transverse aortic constriction [TAC]). Three days after pressure overload, macrophages and T lymphocytes accumulated around and along left coronary arteries in association with luminal platelet deposition. Consistent with these histological findings, cardiac expression of IL-10 was upregulated and in the systemic circulation, platelet white blood cell aggregates tended to be higher in TAC animals compared to sham controls. Since platelets can dynamically modulate perivascular inflammation, we investigated the impact of thrombocytopenia on the response to TAC. Immunodepletion of platelets decreased early perivascular T lymphocytes' accumulation and altered subsequent coronary artery remodeling. The contribution of lymphocytes were examined in Rag1(-/-) mice, which displayed significantly more intimal hyperplasia and perivascular fibrosis compared to wild-type mice following TAC. Collectively, our studies support a role of early perivascular accumulation of platelets and T lymphocytes in pressure overload-induced inflammation. 相似文献
80.