全文获取类型
收费全文 | 2041篇 |
免费 | 97篇 |
国内免费 | 2篇 |
出版年
2023年 | 11篇 |
2022年 | 24篇 |
2021年 | 57篇 |
2020年 | 41篇 |
2019年 | 24篇 |
2018年 | 31篇 |
2017年 | 29篇 |
2016年 | 65篇 |
2015年 | 90篇 |
2014年 | 105篇 |
2013年 | 134篇 |
2012年 | 179篇 |
2011年 | 163篇 |
2010年 | 114篇 |
2009年 | 69篇 |
2008年 | 100篇 |
2007年 | 121篇 |
2006年 | 99篇 |
2005年 | 97篇 |
2004年 | 83篇 |
2003年 | 87篇 |
2002年 | 60篇 |
2001年 | 24篇 |
2000年 | 22篇 |
1999年 | 18篇 |
1998年 | 21篇 |
1997年 | 16篇 |
1996年 | 17篇 |
1995年 | 15篇 |
1994年 | 15篇 |
1993年 | 12篇 |
1992年 | 22篇 |
1991年 | 11篇 |
1990年 | 14篇 |
1989年 | 8篇 |
1988年 | 15篇 |
1987年 | 13篇 |
1986年 | 9篇 |
1985年 | 8篇 |
1984年 | 10篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1980年 | 7篇 |
1979年 | 8篇 |
1978年 | 4篇 |
1976年 | 12篇 |
1975年 | 5篇 |
1973年 | 6篇 |
1970年 | 4篇 |
1963年 | 3篇 |
排序方式: 共有2140条查询结果,搜索用时 15 毫秒
81.
Prerana Gogoi Prerana Mordina Shankar Prasad Kanaujia 《Journal of structural biology》2019,205(1):67-77
5-Methylthioribose 1-phosphate isomerase (M1Pi) is a crucial enzyme involved in the universally conserved methionine salvage pathway (MSP) where it is known to catalyze the conversion of 5-methylthioribose 1-phosphate (MTR-1-P) to 5-methylthioribulose 1-phosphate (MTRu-1-P) via a mechanism which remains unspecified till date. Furthermore, although M1Pi has a discrete function, it surprisingly shares high structural similarity with two functionally non-related proteins such as ribose-1,5-bisphosphate isomerase (R15Pi) and the regulatory subunits of eukaryotic translation initiation factor 2B (eIF2B). To identify the distinct structural features that lead to divergent functional obligations of M1Pi as well as to understand the mechanism of enzyme catalysis, the crystal structure of M1Pi from a hyperthermophilic archaeon Pyrococcus horikoshii OT3 was determined. A meticulous structural investigation of the dimeric M1Pi revealed the presence of an N-terminal extension and a hydrophobic patch absent in R15Pi and the regulatory α-subunit of eIF2B. Furthermore, unlike R15Pi in which a kink formation is observed in one of the helices, the domain movement of M1Pi is distinguished by a forward shift in a loop covering the active-site pocket. All these structural attributes contribute towards a hydrophobic microenvironment in the vicinity of the active site of the enzyme making it favorable for the reaction mechanism to commence. Thus, a hydrophobic active-site microenvironment in addition to the availability of optimal amino-acid residues surrounding the catalytic residues in M1Pi led us to propose its probable reaction mechanism via a cis-phosphoenolate intermediate formation. 相似文献
82.
Cheung N Saw SM Islam FM Rogers SL Shankar A de Haseth K Mitchell P Wong TY 《Obesity (Silver Spring, Md.)》2007,15(1):209-215
Objective: In adult populations, changes in retinal vascular caliber have been linked with obesity and metabolic syndrome. We examined the association of BMI and weight with retinal vascular caliber in children. Research Methods and Procedures: This was a school‐based, cross‐sectional study of 768 children, 7 to 9 years old, randomly sampled from the Singapore Cohort Study of the Risk Factors for Myopia. Participants had digital retinal photographs. Retinal vascular caliber was measured using a computer‐based program and combined to provide average calibers of arterioles and venules in that eye. Weight and height were measured using standardized protocol. These data were used to calculate BMI. Results: In this population, the mean retinal arteriolar and venular calibers were 156.40 μm [95% confidence interval (CI), 155.44 to 157.36] and 225.43 μm (95% CI, 224.10 to 226.74) respectively. After controlling for age, gender, race, parental monthly income, axial length, birth weight, and birth length, each 3.1 kg/m2 (standard deviation) increase in BMI was associated with a 2.55‐μm (95% CI, 1.21 to 3.89; p < 0.001) larger retinal venular caliber. In multivariable analysis, greater weight was also significantly associated with larger retinal venular caliber. BMI and weight were not associated with retinal arteriolar caliber. Height was not significantly associated with retinal arteriolar or venular caliber. Discussion: Greater BMI and weight are associated with larger retinal venular caliber in healthy children. 相似文献
83.
84.
Density functional theory (DFT) calculations and molecular dynamics (MD) simulations on the atomic level were performed on
three different substituted banana-shaped compounds derived from 1,3-phenylene bis[4-(4-n-hexyloxyphenyliminomethyl)benzoate]
(P-6-O-PIMB). The DFT studies were carried out on the isolated molecules, and in the MD simulations clusters were treated
with up to 64 monomers. The effect of polar substituents, such as chlorine and the nitro group, on the central 1,3-phenylene
unit of banana-shaped compounds was investigated. In particular, flexibility, polarity, electrostatic potential (ESP) group
charge distributions, B-factors, bending angles and molecular lengths were considered. The MD results were analysed by trajectories
of significant torsion angles as well as order parameters such as radial atom pair distribution functions g(r), orientational
correlation functions g(o), diffusion coefficients (D) and root mean square deviations (RMSD) values. The g(r) and g(o) values
show that a certain long range order is generated by the introduction of a NO2 group in the 2-position of the central 1,3-phenylene ring. In contrast, the chlorination at the 4 and 6 positions of the
central 1,3-phenylene unit decreases the long range order tendency by its perturbation effect on the conformations in such
molecules. Moreover, g(r) and g(o) values, as well as diffusion coefficients, show that in the NO2 substituted compound the formation of microphase areas is preferred. Finally, the aggregation effect in such compounds was
studied in a systematic way by a comparison of the conformational properties of the isolated molecules and the monomers in
the clusters.
Figure Molecular dynamics (MD) simulations on the aggregation behaviour of substituted banana-shaped compounds
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
85.
86.
Tanuj Joshi Amit Kumar Singh Pouya Haratipour Archana Negi Sah Abhay K. Pandey Rozita Naseri Vijay Juyal Mohammad H. Farzaei 《Journal of cellular physiology》2019,234(10):17212-17231
Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications. 相似文献
87.
The emergence of multi-drug resistant pathogens in infectious disease conditions accentuates the need for the design of new classes of antimicrobial agents that could defeat the multidrug resistance problems. As a new class of molecules, the Heterocyclic Schiff base is of considerable interest, owing to their preparative accessibility, structural flexibilities, versatile metal chelating properties, and inherent biological activities. In the present study, CAM-B3LYP/LANL2DZ and M062X/DEF2-TZVP level of density functional method is used to explore the complexation of chalcone based Schiff base derivatives by Co2+, Ni2+, Cu2+, and Zn2+ metal ions. The HL(1-3)-Co2+, HL(1-3)-Ni2+ and HL(1-3)-Zn2+ complexes formed the distorted tetrahedral geometry. Whereas, the HL(1-3)-Cu2+ complexes prefers distorted square-planar geometry. The BSSE corrected interaction energies of the studied complexes reveals that Cu2+ ion forms the most stable complexes with all three chalcone based Schiff bases. Of the three Schiff bases studied, the HL2 Schiff base acts as a potent chelating agent and forms the active metal complexes than the HL1 and HL3 Schiff bases. Further, the strength of the interaction follows the order as Cu2+?>?Ni2+?>?Co2+?>?Zn2+. The QTAIM analysis reveals that the interaction between the metal ions and coordinating ligand atoms are electrostatic dominant. The metal interaction increases the π-delocalisation of electrons over the entire chelate. Hence, the antimicrobial activity of the metal complexes is more effective than the free Schiff bases. Moreover, the HL(1-3)-Cu2+ complexes shows higher antimicrobial activities than the other complexes studied. 相似文献
88.
89.
Modeling thrombus growth in pathological flows allows evaluation of risk under patient-specific pharmacological, hematological, and hemodynamical conditions. We have developed a 3D multiscale framework for the prediction of thrombus growth under flow on a spatially resolved surface presenting collagen and tissue factor (TF). The multiscale framework is composed of four coupled modules: a Neural Network (NN) that accounts for platelet signaling, a Lattice Kinetic Monte Carlo (LKMC) simulation for tracking platelet positions, a Finite Volume Method (FVM) simulator for solving convection-diffusion-reaction equations describing agonist release and transport, and a Lattice Boltzmann (LB) flow solver for computing the blood flow field over the growing thrombus. A reduced model of the coagulation cascade was embedded into the framework to account for TF-driven thrombin production. The 3D model was first tested against in vitro microfluidics experiments of whole blood perfusion with various antiplatelet agents targeting COX-1, P2Y1, or the IP receptor. The model was able to accurately capture the evolution and morphology of the growing thrombus. Certain problems of 2D models for thrombus growth (artifactual dendritic growth) were naturally avoided with realistic trajectories of platelets in 3D flow. The generalizability of the 3D multiscale solver enabled simulations of important clinical situations, such as cylindrical blood vessels and acute flow narrowing (stenosis). Enhanced platelet-platelet bonding at pathologically high shear rates (e.g., von Willebrand factor unfolding) was required for accurately describing thrombus growth in stenotic flows. Overall, the approach allows consideration of patient-specific platelet signaling and vascular geometry for the prediction of thrombotic episodes. 相似文献
90.
Vasudha Tandon Ruturajsinh
M. Vala Albert Chen Robert
L. Sah Hitendra
M. Patel Michael
C. Pirrung Sourav Banerjee 《Bioscience reports》2022,42(2)
Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics. 相似文献