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Jyothi Mahadevan Johannes Rudolph Asmita Jha Jian Wei Tay Joseph Dragavon Erik M. Grumstrup Karolin Luger 《Biophysical journal》2019,116(11):2224-2233
The repair of DNA damage requires the ordered recruitment of many different proteins that are responsible for signaling and subsequent repair. A powerful and widely used tool for studying the orchestrated accumulation of these proteins at damage sites is laser microirradiation in live cells, followed by monitoring the accumulation of the fluorescently labeled protein in question. Despite the widespread use of this approach, there exists no rigorous method for characterizing the recruitment process quantitatively. Here, we introduce a diffusion model that explicitly accounts for the unique sizes and shapes of individual nuclei and uses two variables: Deff, the effective coefficient of diffusion, and F, the fraction of mobile protein that accumulates at sites of DNA damage. Our model quantitatively describes the accumulation of three test proteins, poly-ADP-ribose polymerases 1 and 2 (PARP1/2) and histone PARylation factor 1. Deff for PARP1, as derived by our approach, is 6× greater than for PARP2 and in agreement with previous literature reports using fluorescence correlation spectroscopy and fluorescence recovery after photobleaching. Our data indicate that histone PARylation factor 1 arrives at sites of DNA damage independently of either PARP. Importantly, our model, which can be applied to existing data, allows for the direct comparison of the coefficient of diffusion for any DNA repair protein between different cell types, obtained in different laboratories and by different methods, and also allows for the interrogation of cell-to-cell variability. 相似文献
33.
Anu Manhas Dhaval Patel Mohsin Y. Lone Prakash C. Jha 《Journal of cellular biochemistry》2019,120(9):14531-14543
In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D -xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors. 相似文献
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The development of resistance to different drugs remains a major problem for a wide range of infections. In particular, combinations of specific mutations, which individually demonstrate no effect, exhibit significant cooperativity. Here we show that changes to the energy of ligand binding in different resistant HIV-1 proteases are correlated with the creation of water binding sites in the active site. This correlation is conserved across two drugs (ritonavir and lopinavir). We propose that individual mutations induce changes in flap packing that are insufficient to allow water binding but in combination allow access, leading to the observed cooperative resistance. 相似文献
36.
Background
The Indian Sample Registration System (SRS) with verbal autopsy methods provides estimations of cause specific mortality for maternal deaths, where the majority of deaths occur at home, unregistered. We aim to examine factors that influence physician agreement and coding choices in assigning causes of death from verbal autopsies.Methodology/Principal Findings
Among adult deaths identified in the SRS, pregnancy-related deaths recorded in 2001–2003 were assigned ICD-10 codes by two independent physicians. Inter-rater reliability was estimated using Landis Koch Kappa classification – poor to fair agreement; > – moderate agreement; > – substantial agreement; >– high agreement. We identified factors associated with physician agreement using multivariate logistic regression. A central consensus panel reviewed cases for errors and reclassified as needed based on 2011 ICD-10 coding guidelines. Of 1130 pregnancy-related deaths, 1040 were assigned ICD-10 codes by two physicians. We found substantial agreement regardless of the woman''s residence, whether the death was registered, religion, respondent''s or deceased''s education, age, hospital admission or gestational age. Physician agreement was not influenced by the above variables, with the exception of greater agreement in cases where the respondent did not live with the deceased, or early gestational age at the time of death. A central consensus panel reviewed all cases and recoded 10% of cases due to insufficient use of information in the verbal autopsy by the coding physicians and rationale for this reclassification are discussed.Conclusion
In the absence of complete vital registration and universal healthcare services, physician coded verbal autopsies continues to be heavily relied upon to ascertain pregnancy-related death. From this study, two independent physicians had good inter-rater reliability for assigning pregnancy-related causes of death in a nationally-represented sample, and physician coding does not appear to be heavily influenced by case characteristics or demographics. 相似文献37.
Complexes of Co(II), Ni(lI), Cu(II), Zn(II) and Pt(II) with 1-formylisoquinoline thiosemicarbazone (1-iqtsc-H) were prepared and characterized by elemental analyses, conductance measurement and spectral studies. On the basis of these studies a distorted octahedral structure for [Co(1-iqtsc)2]·2H2O, a distorted trigonal-bipyramidal structure for [Ni- (1-iqtsc-H)Cl2], [Cu(1-iqtsc-H)Cl2] and [Zn(1-iqtsc- H)(OAc)2]·H2O and a square-planar structure for [Pt(1-iqtsc)Cl] are suggested. All these metal(II) complexes were screened for their antitumour activity in the P388 lymphocytic leukaemia test system in mice. Except for Pt(Il), the complexes were found to possess significant activity; the Ni(II) complex showed a T/C value of 161 at the optimum dosage. 相似文献
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Polyacrylamide grafted Agar (Ag-g-PAM) has been successfully synthesized by conventional method and microwave assisted method. The former method employs ceric ammonium nitrate (CAN) as the free radical initiator while the latter uses the combination of ceric ammonium nitrate (CAN) and microwave irradiation. The synthesized graft copolymers have been characterized by elemental analysis (C, H, N, O and S), FTIR spectroscopy, intrinsic viscosity measurement and scanning electron micrograph (SEM); taking agar as a reference. Flocculation efficacy of synthesized graft copolymers was studied in kaolin suspension and in waste water through 'Jar test' procedure. In the present investigation, we have observed that polyacrylamide grafted agar synthesized by microwave assisted technique shows superior properties than conventional technique. These properties are reported in terms of intrinsic viscosity, flocculation efficacy and pollutant load reduction of waste water. 相似文献
40.
Vivek Kumar Mukesh M. Mudgal Nidhi Rani Amrita Jha Manu Jaggi Anu T. Singh 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):763-770
A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC50 = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC50 = 6.1 μm) and oral (IC50 = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents. 相似文献