全文获取类型
收费全文 | 707篇 |
免费 | 65篇 |
专业分类
耳鼻咽喉 | 6篇 |
儿科学 | 1篇 |
妇产科学 | 3篇 |
基础医学 | 110篇 |
口腔科学 | 11篇 |
临床医学 | 28篇 |
内科学 | 225篇 |
皮肤病学 | 2篇 |
神经病学 | 43篇 |
特种医学 | 75篇 |
外科学 | 27篇 |
综合类 | 8篇 |
预防医学 | 67篇 |
眼科学 | 5篇 |
药学 | 140篇 |
中国医学 | 2篇 |
肿瘤学 | 19篇 |
出版年
2024年 | 2篇 |
2023年 | 16篇 |
2022年 | 54篇 |
2021年 | 72篇 |
2020年 | 35篇 |
2019年 | 25篇 |
2018年 | 17篇 |
2017年 | 22篇 |
2016年 | 24篇 |
2015年 | 31篇 |
2014年 | 54篇 |
2013年 | 57篇 |
2012年 | 41篇 |
2011年 | 27篇 |
2010年 | 29篇 |
2009年 | 29篇 |
2008年 | 34篇 |
2007年 | 23篇 |
2006年 | 15篇 |
2005年 | 18篇 |
2004年 | 13篇 |
2003年 | 18篇 |
2002年 | 5篇 |
2001年 | 10篇 |
2000年 | 7篇 |
1999年 | 6篇 |
1998年 | 10篇 |
1997年 | 11篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 9篇 |
1991年 | 4篇 |
1990年 | 11篇 |
1989年 | 7篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
排序方式: 共有772条查询结果,搜索用时 15 毫秒
751.
The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant evolution of SARS-CoV-2 generates new mutations across its genome including the coding region for the RBD in the spike protein. In addition to the well-known single mutation in the RBD, the recent new mutation strains with an RBD “double mutation” are causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of double-mutated strains could be attributed to the altered interaction between the RBD and ACE2 receptor, the molecular details remain to be elucidated. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation, and antibody escaping, we investigated the relationship between the ACE2 receptor and the RBD double mutants of L452R/T478K (delta), L452R/E484Q (kappa), and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered the RBD structure and enhanced the binding of the mutated RBD to ACE2 receptor. Together with the mutations in other parts of the virus genome, the double mutations increase the transmissibility of SARS-CoV-2 to host cells. 相似文献
752.
Thijmen W. Hokken MD Hendrik Wienemann MD James Dargan BMBS Dirk-Jan van Ginkel MD Cameron Dowling MBBS PhD Axel Unbehaun MD Johan Bosmans MD PhD Andreas Bader-Wolfe MD PhD Robert Gooley MBBS PhD MBA Martin Swaans MD Stephen J. Brecker MD Matti Adam MD Nicolas M. Van Mieghem MD PhD 《Catheterization and cardiovascular interventions》2023,102(6):1140-1148
Background
Preprocedural computed tomography planning improves procedural safety and efficacy of transcatheter aortic valve implantation (TAVI). However, contemporary imaging modalities do not account for device-host interactions.Aims
This study evaluates the value of preprocedural computer simulation with FEops HEARTguideTM on overall device success in patients with challenging anatomies undergoing TAVI with a contemporary self-expanding supra-annular transcatheter heart valve.Methods
This prospective multicenter observational study included patients with a challenging anatomy defined as bicuspid aortic valve, small annulus or severely calcified aortic valve. We compared the heart team's transcatheter heart valve (THV) planning decision based on (1) conventional multislice computed tomography (MSCT) and (2) MSCT imaging with FEops HEARTguideTM simulations. Clinical outcomes and THV performance were followed up to 30 days.Results
A total of 77 patients were included (median age 79.9 years (IQR 74.2–83.8), 42% male). In 35% of the patients, preprocedural planning changed after FEops HEARTguideTM simulations (change in valve size selection [12%] or target implantation height [23%]). A new permanent pacemaker implantation (PPI) was implanted in 13% and >trace paravalvular leakage (PVL) occurred in 28.5%. The contact pressure index (i.e., simulation output indicating the risk of conduction abnormalities) was significantly higher in patients with a new PPI, compared to those without (16.0% [25th–75th percentile 12.0–21.0] vs. 3.5% [25th–75th percentile 0–11.3], p < 0.01) The predicted PVL was 5.7 mL/s (25th–75th percentile 1.3–11.1) in patients with none-trace PVL, 12.7 (25th–75th percentile 5.5–19.1) in mild PVL and 17.7 (25th–75th percentile 3.6–19.4) in moderate PVL (p = 0.04).Conclusion
FEops HEARTguideTM simulations may provide enhanced insights in the risk for PVL or PPI after TAVI with a self-expanding supra-annular THV in complex anatomies. 相似文献753.
Stagg L Zhang SQ Cheung MS Wittung-Stafshede P 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(48):18976-18981
To investigate the consequences of macromolecular crowding on the behavior of a globular protein, we performed a combined experimental and computational study on the 148-residue single-domain alpha/beta protein, Desulfovibrio desulfuricans apoflavodoxin. In vitro thermal unfolding experiments, as well as assessment of native and denatured structures, were probed by using far-UV CD in the presence of various amounts of Ficoll 70, an inert spherical crowding agent. Ficoll 70 has a concentration-dependent effect on the thermal stability of apoflavodoxin (DeltaT(m) of 20 degrees C at 400 mg/ml; pH 7). As judged by CD, addition of Ficoll 70 causes an increase in the amount of secondary structure in the native-state ensemble (pH 7, 20 degrees C) but only minor effects on the denatured state. Theoretical calculations, based on an off-lattice model and hard-sphere particles, are in good agreement with the in vitro data. The simulations demonstrate that, in the presence of 25% volume occupancy of spheres, native flavodoxin is thermally stabilized, and the free energy landscape shifts to favor more compact structures in both native and denatured states. The difference contact map reveals that the native-state compaction originates in stronger interactions between the helices and the central beta-sheet, as well as by less fraying in the terminal helices. This study demonstrates that macromolecular crowding has structural effects on the folded ensemble of polypeptides. 相似文献
754.
755.
Amino acids with an intermolecular proton bond as proton storage site in bacteriorhodopsin 下载免费PDF全文
Prasad Phatak Nilanjan Ghosh Haibo Yu Qiang Cui Marcus Elstner 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(50):19672-19677
The positions of protons are not available in most high-resolution structural data of biomolecules, thus the identity of proton storage sites in biomolecules that transport proton is generally difficult to determine unambiguously. Using combined quantum mechanical/molecular mechanical computations, we demonstrate that a pair of conserved glutamate residues (Glu 194/204) bonded by a delocalized proton is the proton release group that has been long sought in the proton pump, bacteriorhodopsin. This model is consistent with all available experimental structural and infrared data for both the wild-type bacteriorhodopsin and several mutants. In particular, the continuum infrared band in the 1,800- to 2,000-cm−1 region is shown to arise due to the partially delocalized nature of the proton between the glutamates in the wild-type bacteriorhodopsin; alternations in the flexibility of the glutamates and electrostatic nature of nearby residues in various mutants modulate the degree of proton delocalization and therefore intensity of the continuum band. The strong hydrogen bond between Glu 194/204 also significantly shifts the carboxylate stretches of these residues well <1,700 cm−1, which explains why carboxylate spectral shift was not observed experimentally in the typical >1,700-cm−1 region upon proton release. By contrast, simulations with the proton restrained on the nearby water cluster, as proposed by several recent studies [see, for example, Garezarek K, Gerwert K (2006) Functional waters in intraprotein proton transfer monitored by FTIR difference spectroscopy. Nature 439:109], led to significant structural deviations from available X-ray structures. This study establishes a biological function for strong, low-barrier hydrogen bonds. 相似文献
756.
Valdiosera CE García-Garitagoitia JL Garcia N Doadrio I Thomas MG Hänni C Arsuaga JL Barnes I Hofreiter M Orlando L Götherström A 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(13):5123-5128
The endangered brown bear populations (Ursus arctos) in Iberia have been suggested to be the last fragments of the brown bear population that served as recolonization stock for large parts of Europe during the Pleistocene. Conservation efforts are intense, and results are closely monitored. However, the efforts are based on the assumption that the Iberian bears are a unique unit that has evolved locally for an extended period. We have sequenced mitochondrial DNA (mtDNA) from ancient Iberian bear remains and analyzed them as a serial dataset, monitoring changes in diversity and occurrence of European haplogroups over time. Using these data, we show that the Iberian bear population has experienced a dynamic, recent evolutionary history. Not only has the population undergone mitochondrial gene flow from other European brown bears, but the effective population size also has fluctuated substantially. We conclude that the Iberian bear population has been a fluid evolutionary unit, developed by gene flow from other populations and population bottlenecks, far from being in genetic equilibrium or isolated from other brown bear populations. Thus, the current situation is highly unusual and the population may in fact be isolated for the first time in its history. 相似文献
757.
Dietmar Paschek Sascha Hempel Angel E. García 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(46):17754-17759
We report molecular dynamics simulations of the equilibrium folding/unfolding thermodynamics of an all-atom model of the Trp-cage miniprotein in explicit solvent. Simulations are used to sample the folding/unfolding free energy difference and its derivatives along 2 isochores. We model the ΔGu(P,T) landscape using the simulation data and propose a stablility diagram model for Trp-cage. We find the proposed diagram to exhibit features similar to globular proteins with increasing hydrostatic pressure destabilizing the native fold. The observed energy differences ΔEu are roughly linearly temperature-dependent and approach ΔEu = 0 with decreasing temperature, suggesting that the system approached the region of cold denaturation. In the low-temperature denatured state, the native helical secondary structure elements are largely preserved, whereas the protein conformation changes to an “open-clamp” configuration. A tighter packing of water around nonpolar sites, accompanied by an increasing solvent-accessible surface area of the unfolded ensemble, seems to stabilize the unfolded state at elevated pressures. 相似文献
758.
759.
Sheng Wu Juan Pablo Acevedo Manfred T. Reetz 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(7):2775-2780
The molecular basis of allosteric effects, known to be caused by an effector docking to an enzyme at a site distal from the binding pocket, has been studied recently by applying directed evolution. Here, we utilize laboratory evolution in a different way, namely to induce allostery by introducing appropriate distal mutations that cause domain movements with concomitant reshaping of the binding pocket in the absence of an effector. To test this concept, the thermostable Baeyer–Villiger monooxygenase, phenylacetone monooxygenase (PAMO), was chosen as the enzyme to be employed in asymmetric Baeyer–Villiger reactions of substrates that are not accepted by the wild type. By using the known X-ray structure of PAMO, a decision was made regarding an appropriate site at which saturation mutagenesis is most likely to generate mutants capable of inducing allostery without any effector compound being present. After screening only 400 transformants, a double mutant was discovered that catalyzes the asymmetric oxidative kinetic resolution of a set of structurally different 2-substituted cyclohexanone derivatives as well as the desymmetrization of three different 4-substituted cyclohexanones, all with high enantioselectivity. Molecular dynamics (MD) simulations and covariance maps unveiled the origin of increased substrate scope as being due to allostery. Large domain movements occur that expose and reshape the binding pocket. This type of focused library production, aimed at inducing significant allosteric effects, is a viable alternative to traditional approaches to “designed” directed evolution that address the binding site directly. 相似文献
760.