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141.
Zoe Barclay Louise Dickson Derek Robertson Melanie Johnson Pamela Holland Roberta Rosie Liting Sun Helen Jerina Eve Lutz Sue Fleetwood-Walker Rory Mitchell 《Cellular signalling》2013,25(4):814-821
The 5-HT2A receptor (5-HT2AR) is implicated in psychotropic changes within the central nervous system (CNS). A number of polymorphisms have been reported in the 5-HT2AR gene; one of these results in a non-synonymous change, H452Y, in the carboxy-terminal tail of the receptor protein. The minor allele (9% occurrence) has been statistically associated with CNS dysfunction such as impaired memory processing and resistance to neuroleptic treatment in schizophrenic patients. We investigated the impact of H452Y mutation of the 5-HT2AR expressed in COS7 cells on distinctly coupled intracellular signalling pathways from the receptor, focusing on the heterotrimeric G protein-independent phospholipase D (PLD) pathway, compared to the conventional Gq/11-linked phospholipase C (PLC) pathway. The H452Y mutation selectively attenuated PLD signalling, which as in the wild-type receptor, was mediated by a molecular complex involving PLD1 docked to the receptor's carboxy-terminal tail domain. Co-immunoprecipitation and GST-fusion protein experiments revealed that the H452Y mutation selectively reduced PLD1 binding to the receptor. Experiments with blocking peptides to mimic short sections of the 5-HT2AR tail sequence revealed that the peptide spanning residue 452 strongly reduced PLD but not PLC responses of the receptor. Similar observations were made when assessing both PLD responses and PLD-dependent cellular proliferation elicited by activation of 5-HT2ARs natively expressed in MCF-7 cells. Overall these findings indicate that the H452Y polymorphic variant of the 5-HT2AR displays selective disruption of its PLD signalling pathway. This may potentially play a role in the CNS dysfunction associated with the H452Y allele of the 5-HT2AR. 相似文献
142.
Katie E. Olson Pranesh Narayanaswami Pamela D. Vise David F. Lowry Marc S. Wold Gary W. Daughdrill 《Journal of biomolecular structure & dynamics》2013,31(2):113-124
Abstract The transient secondary structure and dynamics of an intrinsically unstructured linker domain from the 70 kDa subunit of human replication protein A was investigated using solution state NMR. Stable secondary structure, inferred from large secondary chemical shifts, was observed for a segment of the intrinsically unstructured linker domain when it is attached to an N-terminal protein interaction domain. Results from NMR relaxation experiments showed the rotational diffusion for this segment of the intrinsically unstructured linker domain to be correlated with the N-terminal protein interaction domain. When the N-terminal domain is removed, the stable secondary structure is lost and faster rotational diffusion is observed. The large secondary chemical shifts were used to calculate phi and psidihedral angles and these dihedral angles were used to build a backbone structural model. Restrained molecular dynamics were performed on this new structure using the chemical shift based dihedral angles and a single NOE distance as restraints. In the resulting family of structures a large, solvent exposed loop was observed for the segment of the intrinsically unstructured linker domain that had large secondary chemical shifts. 相似文献
143.
144.
Edward T. Pryor Gustave J. Goldmann Michael J. Sheridan Pamela M. White 《Ethnic and racial studies》2013,36(2):214-235
Measuring ethnicity in any society is a challenge. Given world immigration patterns, many countries face a growing dilemma in determining the cultural antecedents of their populations. A further complication is the reality that such determination occurs within the political and nationalistic settings where ethnic‐cultural groups may be potent forces in their own right. As societies mature and evolve, there is an increasing tendency for populations, especially those with many generations of residence in the country, to see themselves as ‘indigenous’ to the society in which they live. Canada is not alone in having to deal with the fluidity of the concept, ‘Canadian’, ‘American’, ‘Australian’, ‘Yugoslav’, and ‘Soviet’ are parallel concepts in other countries of multiple ethnic composition. Using 1991 National Census Test results, the article explores some of the parameters of the indigenous category ‘Canadian’. In particular, the location in Canada and mother tongue of respondents reporting ‘Canadian’ as the ethnic origin of their parents and grandparents or as their own ethnic identity are important indicators for this emerging ethnic category. 相似文献
145.
146.
Xunjun Xiao Michael R. Ferguson Kelsey E. Magee Pamela D. Hale Yan Wang Mark E. Lowe 《Journal of lipid research》2013,54(2):514-521
Colipase is essential for efficient fat digestion. An arginine-to-cysteine polymorphism at
position 92 of colipase (Arg92Cys) associates with an increased risk for developing type-2 diabetes
through an undefined mechanism. To test our hypothesis that the extra cysteine increases colipase
misfolding, thereby altering its intracellular trafficking and function, we expressed Cys92 colipase
in HEK293T cells. Less Cys92 colipase is secreted and more is retained intracellularly in an
insoluble form compared with Arg92 colipase. Nonreducing gel electrophoresis suggests the folding of
secreted Cys92 colipase differs from Arg92 colipase. Cys92 colipase misfolding does not trigger the
unfolded protein response (UPR) or endoplasmic reticulum (ER) stress. The ability of secreted Cys92
colipase to stimulate pancreatic triglyceride lipase (PTL) is reduced with all substrates tested,
particularly long-chain triglycerides. The reaction of Cys92 colipase with triolein and Intralipid
has a much longer lag time, reflecting decreased ability to anchor PTL on those substrates. Our data
predicts that humans with the Arg92Cys substitution will secrete less functional colipase into the
duodenum and have less efficient fat digestion. Whether inefficient fat digestion or another
property of colipase contributes to the risk for developing diabetes remains to be clarified. 相似文献
147.
Jean-Baptiste Ramond Pamela J. Welz Marla I. Tuffin Stephanie G. Burton Don A. Cowan 《Microbial ecology》2013,66(3):563-570
Agri effluents such as winery or olive mill wastewaters are characterized by high phenolic concentrations. These compounds are highly toxic and generally refractory to biodegradation. Biological sand filters (BSFs) represent inexpensive, environmentally friendly, and sustainable wastewater treatment systems which rely vastly on microbial catabolic processes. Using denaturing gradient gel electrophoresis and terminal-restriction fragment length polymorphism, this study aimed to assess the impact of increasing concentrations of synthetic phenolic-rich wastewater, ranging from 96 mg L?1 gallic acid and 138 mg L?1 vanillin (i.e., a total chemical oxygen demand (COD) of 234 mg L?1) to 2,400 mg L?1 gallic acid and 3,442 mg L?1 vanillin (5,842 mg COD L?1), on bacterial communities and the specific functional diazotrophic community from BSF mesocosms. This amendment procedure instigated efficient BSF phenolic removal, significant modifications of the bacterial communities, and notably led to the selection of a phenolic-resistant and less diverse diazotrophic community. This suggests that bioavailable N is crucial in the functioning of biological treatment processes involving microbial communities, and thus that functional alterations in the bacterial communities in BSFs ensure provision of sufficient bioavailable nitrogen for the degradation of wastewater with a high C/N ratio. 相似文献
148.
149.
Kevin Anderson Yi Chen Zhi Chen Romyr Dominique Kelli Glenn Yang He Cheryl Janson Kin-Chun Luk Christine Lukacs Ann Polonskaia Qi Qiao Aruna Railkar Pamela Rossman Hongmao Sun Qing Xiang Masha Vilenchik Peter Wovkulich Xiaolei Zhang 《Bioorganic & medicinal chemistry letters》2013,23(24):6610-6615
DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented. 相似文献
150.
Lisa Dalla Via Aída N. García-Argáez Arianna Adami Silvia Grancara Pamela Martinis Antonio Toninello Daniela Belli Dell’Amico Luca Labella Simona Samaritani 《Bioorganic & medicinal chemistry》2013,21(22):6965-6972
A convenient synthetic route and the characterization of complexes trans-[PtCl2(L)(PPh3)] (L = Et2NH (2), (PhCH2)2NH (3), (HOCH2CH2)2NH) (4) are reported. The antiproliferative activity was evaluated on three human tumor cell lines. The investigation on the mechanism of action highlighted for the most active complex 4 the capacity to affect mitochondrial functions. In particular, both the induction of the mitochondrial permeability transition phenomenon and an aspecific membrane damage occurred, depending on concentration. 相似文献