全文获取类型
收费全文 | 1310篇 |
免费 | 105篇 |
出版年
2023年 | 7篇 |
2022年 | 13篇 |
2021年 | 32篇 |
2020年 | 16篇 |
2019年 | 17篇 |
2018年 | 22篇 |
2017年 | 20篇 |
2016年 | 35篇 |
2015年 | 56篇 |
2014年 | 61篇 |
2013年 | 95篇 |
2012年 | 103篇 |
2011年 | 110篇 |
2010年 | 74篇 |
2009年 | 63篇 |
2008年 | 100篇 |
2007年 | 103篇 |
2006年 | 83篇 |
2005年 | 81篇 |
2004年 | 77篇 |
2003年 | 81篇 |
2002年 | 59篇 |
2001年 | 14篇 |
2000年 | 8篇 |
1999年 | 13篇 |
1998年 | 13篇 |
1997年 | 9篇 |
1996年 | 3篇 |
1995年 | 7篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 2篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1974年 | 6篇 |
1970年 | 3篇 |
1968年 | 1篇 |
1965年 | 1篇 |
1949年 | 1篇 |
排序方式: 共有1415条查询结果,搜索用时 15 毫秒
961.
Zhang X Rueter JK Chen Y Moorjani M Lanier MC Lin E Gross RS Tellew JE Williams JP Lechner SM Markison S Joswig T Malany S Santos M Castro-Palomino JC Crespo MI Prat M Gual S Díaz JL Saunders J Slee DH 《Bioorganic & medicinal chemistry letters》2008,18(6):1778-1783
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease. 相似文献
962.
Guo L Ye Z Ujjainwalla F Sings HL Sebhat IK Huber J Weinberg DH Tang R MacNeil T Tamvakopoulos C Peng Q MacIntyre E van der Ploeg LH Goulet MT Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2008,18(11):3242-3247
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed. 相似文献
963.
Biswas K Aya T Qian W Peterkin TA Chen JJ Human J Hungate RW Kumar G Arik L Lester-Zeiner D Biddlecome G Manning BH Sun H Dong H Huang M Loeloff R Johnson EJ Askew BC 《Bioorganic & medicinal chemistry letters》2008,18(17):4764-4769
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models. 相似文献
964.
Chase CC Braun LJ Leslie-Steen P Graham T Miskimins D Ridpath JF 《Journal of wildlife diseases》2008,44(3):753-759
The susceptibility of wild ruminants, especially cervids, to bovine viral diarrhea virus (BVDV) has remained an enigma. Two white-tailed deer (Odocoileus virginianus) were submitted to the Animal Disease Research and Diagnostic Laboratory (ADRDL) in the fall of 2003 by the South Dakota Game Fish and Parks for chronic wasting disease (CWD) testing. Both animals were CWD negative. The animals were necropsied and histopathology, viral antigen detection, and virus isolation were performed. A noncytopathic (NCP) BVDV was isolated from the lungs and several other tissues of both animals. Formalin-fixed ear notches from both animals were positive for BVDV antigen by immunohistochemistry. The BVDV isolates were typed with the use of polymerase chain reaction in 5' untranslated region (UTR) and one isolate was typed a Type 2a and the other a Type 1b. Future field surveys to determine the incidence of BVDV along with experimental studies to determine if white-tailed deer fawns can be persistently infected with BVDV are needed. 相似文献
965.
Aligning and comparing genomic sequences enables the identification of conserved sequence signatures and can enrich for coding and noncoding functional regions. In vertebrates, the comparison of human and rodent genomes and the comparison of evolutionarily distant genomes, such as human and pufferfish, have identified specific sets of 'ultraconserved' sequence elements associated with the control of early development. However, is this just the tip of a 'conservation iceberg' or do these sequences represent a specific class of regulatory element? Studies on the zebrafish phox2b gene region and the ENCODE project suggest that many regulatory elements are not highly conserved, posing intriguing questions about the relationship between noncoding sequence conservation and function and the evolution of regulatory sequences. 相似文献
966.
Genetic redundancy means that two genes can perform the same function. Using a comprehensive phylogenetic analysis, we show here in both Saccharomyces cerevisiae and Caenorhabditis elegans that genetic redundancy is not just a transient consequence of gene duplication, but is often an evolutionary stable state. In multiple examples, genes have retained redundant functions since the divergence of the animal, plant and fungi kingdoms over a billion years ago. The stable conservation of genetic redundancy contrasts with the more rapid evolution of genetic interactions between unrelated genes and can be explained by theoretical models including a 'piggyback' mechanism in which overlapping redundant functions are co-selected with nonredundant ones. 相似文献
967.
McLean KJ Carroll P Lewis DG Dunford AJ Seward HE Neeli R Cheesman MR Marsollier L Douglas P Smith WE Rosenkrands I Cole ST Leys D Parish T Munro AW 《The Journal of biological chemistry》2008,283(48):33406-33416
Mycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by gene knock-out with complementation. Production of CYP121 protein in Mtb cells is demonstrated. Minimum inhibitory concentration values for azole drugs against Mtb H37Rv were determined, the rank order of which correlated well with Kd values for their binding to CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies and crystal structure determination for a series of CYP121 active site mutants provide further insights into structure and biophysical features of the enzyme. Pro346 was shown to control heme cofactor conformation, whereas Arg386 is a critical determinant of heme potential, with an unprecedented 280-mV increase in heme iron redox potential in a R386L mutant. A homologous Mtb redox partner system was reconstituted and transported electrons faster to CYP121 R386L than to wild type CYP121. Heme potential was not perturbed in a F338H mutant, suggesting that a proposed P450 superfamily-wide role for the phylogenetically conserved phenylalanine in heme thermodynamic regulation is unlikely. Collectively, data point to an important cellular role for CYP121 and highlight its potential as a novel Mtb drug target. 相似文献
968.
The spike glycoprotein of murine coronavirus MHV-JHM mediates receptor-independent infection and spread in the central nervous systems of Ceacam1a-/- Mice 下载免费PDF全文
Miura TA Travanty EA Oko L Bielefeldt-Ohmann H Weiss SR Beauchemin N Holmes KV 《Journal of virology》2008,82(2):755-763
The MHV-JHM strain of the murine coronavirus mouse hepatitis virus is much more neurovirulent than the MHV-A59 strain, although both strains use murine CEACAM1a (mCEACAM1a) as the receptor to infect murine cells. We previously showed that Ceacam1a−/− mice are completely resistant to MHV-A59 infection (E. Hemmila et al., J. Virol. 78:10156-10165, 2004). In vitro, MHV-JHM, but not MHV-A59, can spread from infected murine cells to cells that lack mCEACAM1a, a phenomenon called receptor-independent spread. To determine whether MHV-JHM could infect and spread in the brain independent of mCEACAM1a, we inoculated Ceacam1a−/− mice. Although Ceacam1a−/− mice were completely resistant to i.c. inoculation with 106 PFU of recombinant wild-type MHV-A59 (RA59) virus, these mice were killed by recombinant MHV-JHM (RJHM) and a chimeric virus containing the spike of MHV-JHM in the MHV-A59 genome (SJHM/RA59). Immunohistochemistry showed that RJHM and SJHM/RA59 infected all neural cell types and induced severe microgliosis in both Ceacam1a−/− and wild-type mice. For RJHM, the 50% lethal dose (LD50) is <101.3 in wild-type mice and 103.1 in Ceacam1a−/− mice. For SJHM/RA59, the LD50 is <101.3 in wild-type mice and 103.6 in Ceacam1a−/− mice. This study shows that infection and spread of MHV-JHM in the brain are dependent upon the viral spike glycoprotein. RJHM can initiate infection in the brains of Ceacam1a−/− mice, but expression of mCEACAM1a increases susceptibility to infection. The spread of infection in the brain is mCEACAM1a independent. Thus, the ability of the MHV-JHM spike to mediate mCEACAM1a-independent spread in the brain is likely an important factor in the severe neurovirulence of MHV-JHM in wild-type mice. 相似文献
969.
Densely Packed Random Quarterpolymers Containing Two Donor and Two Acceptor Units: Controlling Absorption Ability and Molecular Interaction to Enable Enhanced Polymer Photovoltaic Devices 下载免费PDF全文
So‐Huei Kang Tanya Kumari Sang Myeon Lee Mingyu Jeong Changduk Yang 《Liver Transplantation》2017,7(15)
Dithienyldiketopyrrolopyrrole (DPP2T) and thieno[3,2‐b]thiophene (TT) building blocks, enabling a large intermolecular overlap through π–π stacking, into an amorphous‐like polymer composed of benzo(1,2‐b:4,5‐b′)dithiophene (BDT) and fluorinated thieno[3,4‐b]thiophene (QTT), are introduced. Herein, through the variation of relative compositions of DPP2T‐TT and BDT‐QTT in the polymer backbone, the synthesis and characterization of a series of condensed random 2D‐2A “quarterpolymers” with two reference alternating copolymers are reported. The best power conversion efficiency (PCE) of 9.45% is achieved for the optimum composition due to the synergistic effects such as improved photon absorption and reduced recombination loss, and optimized blend morphology via a change in the crystallinity and orientation of the blend films compared to the alternating copolymers. Moreover, by isolating higher molecular weight and narrower polydispersity fractions of the quarterpolymer via a marginal solvent‐soaking technique, the PCE is further boosted to 10.30%, which is among the highest PCE reported to date for random polymer‐based PSCs. Therefore, this simple 2D‐2A strategy, reported for the first time, should be extended to numerous quaterpolymer systems, greatly accelerating random polymer systems toward further improving PSCs. 相似文献
970.
McLarren KW Severson TM du Souich C Stockton DW Kratz LE Cunningham D Hendson G Morin RD Wu D Paul JE An J Nelson TN Chou A DeBarber AE Merkens LS Michaud JL Waters PJ Yin J McGillivray B Demos M Rouleau GA Grzeschik KH Smith R Tarpey PS Shears D Schwartz CE Gecz J Stratton MR Arbour L Hurlburt J Van Allen MI Herman GE Zhao Y Moore R Kelley RI Jones SJ Steiner RD Raymond FL Marra MA Boerkoel CF 《American journal of human genetics》2010,87(6):905-914
CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. 相似文献