全文获取类型
收费全文 | 774篇 |
免费 | 55篇 |
国内免费 | 1篇 |
专业分类
830篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 9篇 |
2021年 | 20篇 |
2020年 | 11篇 |
2019年 | 6篇 |
2018年 | 16篇 |
2017年 | 11篇 |
2016年 | 18篇 |
2015年 | 42篇 |
2014年 | 58篇 |
2013年 | 55篇 |
2012年 | 65篇 |
2011年 | 71篇 |
2010年 | 37篇 |
2009年 | 30篇 |
2008年 | 45篇 |
2007年 | 59篇 |
2006年 | 35篇 |
2005年 | 31篇 |
2004年 | 27篇 |
2003年 | 30篇 |
2002年 | 22篇 |
2001年 | 22篇 |
2000年 | 21篇 |
1999年 | 16篇 |
1998年 | 8篇 |
1997年 | 10篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1968年 | 2篇 |
1966年 | 3篇 |
排序方式: 共有830条查询结果,搜索用时 0 毫秒
31.
Sanaz Gabery Nellie Georgiou-Karistianis Sofia Hult Lundh Rachel Y. Cheong Andrew Churchyard Phyllis Chua Julie C. Stout Gary F. Egan Deniz Kirik ?sa Petersén 《PloS one》2015,10(2)
Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism. Neuropathological and imaging studies using both voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) as well as positron emission tomography (PET) have demonstrated pathological changes in the hypothalamic region during early stages in symptomatic HD. In this investigation, we aimed to establish a robust method for measurements of the hypothalamic volume in MRI in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. Using T1-weighted imaging, we describe a reproducible delineation procedure to estimate the hypothalamic volume which was based on the same landmarks used in histologically processed postmortem hypothalamic tissue. Participants included 36 prodromal HD (pre-HD), 33 symptomatic HD (symp-HD) and 33 control participants who underwent MRI scanning at baseline and 18 months follow-up as part of the IMAGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume. Our results suggest that hypothalamic pathology in HD is not associated with volume changes. 相似文献
32.
Jennifer B. Nagashima Skylar R. Sylvester Jacquelyn L. Nelson Soon Hon Cheong Chinatsu Mukai Colleen Lambo James A. Flanders Vicki N. Meyers-Wallen Nucharin Songsasen Alexander J. Travis 《PloS one》2015,10(12)
Development of assisted reproductive technologies (ART) in the dog has resisted progress for decades, due to their unique reproductive physiology. This lack of progress is remarkable given the critical role ART could play in conserving endangered canid species or eradicating heritable disease through gene-editing technologies—an approach that would also advance the dog as a biomedical model. Over 350 heritable disorders/traits in dogs are homologous with human conditions, almost twice the number of any other species. Here we report the first live births from in vitro fertilized embryos in the dog. Adding to the practical significance, these embryos had also been cryopreserved. Changes in handling of both gametes enabled this progress. The medium previously used to capacitate sperm excluded magnesium because it delayed spontaneous acrosome exocytosis. We found that magnesium significantly enhanced sperm hyperactivation and ability to undergo physiologically-induced acrosome exocytosis, two functions essential to fertilize an egg. Unlike other mammals, dogs ovulate a primary oocyte, which reaches metaphase II on Days 4–5 after the luteinizing hormone (LH) surge. We found that only on Day 6 are oocytes consistently able to be fertilized. In vitro fertilization of Day 6 oocytes with sperm capacitated in medium supplemented with magnesium resulted in high rates of embryo development (78.8%, n = 146). Intra-oviductal transfer of nineteen cryopreserved, in vitro fertilization (IVF)-derived embryos resulted in seven live, healthy puppies. Development of IVF enables modern genetic approaches to be applied more efficiently in dogs, and for gamete rescue to conserve endangered canid species. 相似文献
33.
Hepatitis B virus X protein is a major factor in the HBV-induced disease developments. Stromal cell-derived factor-1 is a small cytokine that is strongly chemotactic for lymphocytes. We explored the role of HBx on recruitment of HBV-induced virus-nonspecific immune cells into liver. Immune cell recruitment and SDF-1 expression level significantly increased in livers of HBx-transgenic mice and X-box binding protein-1 significantly increased SDF-1 gene expression. Finally, we confirmed that immune cell recruitment into liver tissues of HBx-TG mice was diminished by a chemokine receptor antagonist. Therefore, HBx increases ER stress-dependent SDF-1 expression and induces HBV-induced immune cell recruitment into liver. 相似文献
34.
Sachin K Kim EM Cheong SJ Jeong HJ Lim ST Sohn MH Kim DW 《Bioconjugate chemistry》2010,21(12):2282-2288
Syntheses and evaluation of fluoroalkylated ciprofloxacin analogues are described. Among these analogues, N?'-3-fluoropropylciprofloxacin (16) showed the most efficient antibacterial activity against E. coli strains (DH5α and TOP10) and a high binding affinity for DNA gyrase of bacteria. To develop bacteria-specific infection imaging agents for positron emission tomography (PET), no-carrier-added N?-3-[1?F]fluoropropylciprofloxacin ([1?F]16) was prepared in two steps from N?-3-methanesufonyloxypropylciprofloxacin, resulting in a 40% radiochemical yield (decay corrected for 100 min) via the tert-alcohol media radiofluorination protocol with high radiochemical purity (> 99%) as well as high specific activity (149 ± 75 GBq/μmol). The agent was stable (> 90%), as shown by an in vitro human serum stability assay. A bacterial uptake and blocking study of [1?F]16 using authentic compound 16 in TOP10 cells demonstrated its high specific bacterial uptake. The results suggest that this radiotracer holds promise as a useful bacterial infection radiopharmaceutical for PET imaging. 相似文献
35.
Nguyen PH Na M Dao TT Ndinteh DT Mbafor JT Park J Cheong H Oh WK 《Bioorganic & medicinal chemistry letters》2010,20(22):6430-6434
Influenza occurs with seasonal variations and reaches the peak prevalence in winter causing the death of many people worldwide. A few inhibitors of viral neuraminidase, including amantadine, rimantadine, zanamivir, and oseltamivir, have been used as influenza therapy. However, as drug-resistant influenza viruses are generated rapidly, there is a need to identify new agents for chemotherapy against influenza. Therefore, research on more effective drugs has been given high priority. During the course of an anti-influenza screening program on natural products, two new compounds (1 and 2) along with seven known flavonoid derivatives (3-9) were isolated as active principles from an EtOAc-soluble extract of the root bark of Erythrina addisoniae. The stilbenoid (2) and chalcone (3, 4, and 6) compounds of the isolates exhibited stronger activity than the isoflavone ones. Compound 2, which is a formylated stilbenoid derivative, exhibited strong inhibition of both influenza H1N1 and H9N2 neuraminidases with IC(50) values of 8.80±0.34 μg/mL and 7.19±0.40 μg/mL, respectively. 相似文献
36.
Fui Chin Chong Beng Ti Tey Zanariah Mohd Dom Kok Hing Cheong Budiatman Satiawihardja Mohd Nordin Ibrahim Russly Abdul Rahman Dayang Radiah Awang Biak Tau Chuan Ling 《Biotechnology and Bioprocess Engineering》2007,12(3):250-256
Rice bran lipase (RBL) was delipidated to enhance its stability in organic solvent and its esterification activity at elevated
temperature. The esterification activity of delipidated RBL increased as temperature was increased from 45 to 65°C. The esterification
activity of delipidated RBL at 65°C was about 14 times greater than that of the non-delipidated RBL. As temperature was further
increased to 75°C, the non-delipidated RBL lost all esterification activity, whereas the delipidated RBL retained approximately
48% of its esterilication activity. The delipidated RBL maintained a relative esterification activity greater than 80% after
16 h of incubation in hexane, whereas the non-delipidated RBL maintained a relative esterification activity of only 50%. A
method for production of acylglycerol using delipidated RBL to esterify palm oil fatty acid distillate (PFAD) with glycerol
in hexane was successfully developed. The effects of reaction temperatures and type of water removal agents (silica gel and
molecular sieve) on the degree of esterification were also examined. A 4 h reaction at 65°C, catalyzed by delipidated RBL
and using silica gel as the water removal agent resulted in 53.8% esterification. Thin layer chromatography analysis suggested
that the esterified product was primarily comprised of mono-and di-acylglycerols. 相似文献
37.
Meizhi Irene Li Diyar Mailepessov Indra Vythilingam Vernon Lee Patrick Lam Lee Ching Ng Cheong Huat Tan 《PLoS neglected tropical diseases》2021,15(1)
Plasmodium knowlesi is a simian malaria parasite currently recognized as the fifth causative agent of human malaria. Recently, naturally acquired P. cynomolgi infection in humans was also detected in Southeast Asia. The main reservoir of both parasites is the long-tailed and pig-tailed macaques, which are indigenous in this region. Due to increased urbanization and changes in land use, there has been greater proximity and interaction between the long-tailed macaques and the general population in Singapore. As such, this study aims to determine the prevalence of simian malaria parasites in local macaques to assess the risk of zoonosis to the general human population. Screening for the presence of malaria parasites was conducted on blood samples from 660 peridomestic macaques collected between Jan 2008 and Mar 2017, and 379 wild macaques collected between Mar 2009 and Mar 2017, using a Pan-Plasmodium-genus specific PCR. Positive samples were then screened using a simian Plasmodium species-specific nested PCR assay to identify the species of parasites (P. knowlesi, P. coatneyi, P. fieldi, P. cynomolgi, and P. inui) present. All the peridomestic macaques sampled were tested negative for malaria, while 80.5% of the 379 wild macaques were infected. All five simian Plasmodium species were detected; P. cynomolgi being the most prevalent (71.5%), followed by P. knowlesi (47.5%), P. inui (42.0%), P. fieldi (32.5%), and P. coatneyi (28.5%). Co-infection with multiple species of Plasmodium parasites was also observed. The study revealed that Singapore’s wild long-tailed macaques are natural hosts of the five simian malaria parasite species, while no malaria was detected in all peridomestic macaques tested. Therefore, the risk of simian malaria transmission to the general human population is concluded to be low. However, this can be better demonstrated with the incrimination of the vectors of simian malaria parasites in Singapore. 相似文献
38.
Regulation of the dual specificity protein phosphatase, DsPTP1, through interactions with calmodulin
Yoo JH Cheong MS Park CY Moon BC Kim MC Kang YH Park HC Choi MS Lee JH Jung WY Yoon HW Chung WS Lim CO Lee SY Cho MJ 《The Journal of biological chemistry》2004,279(2):848-858
Reversible phosphorylation is a key mechanism for the control of intercellular events in eukaryotic cells. In animal cells, Ca2+/CaM-dependent protein phosphorylation and dephosphorylation are implicated in the regulation of a number of cellular processes. However, little is known on the functions of Ca2+/CaM-dependent protein kinases and phosphatases in Ca2+ signaling in plants. From an Arabidopsis expression library, we isolated cDNA encoding a dual specificity protein phosphatase 1, which is capable of hydrolyzing both phosphoserine/threonine and phosphotyrosine residues of the substrates. Using a gel overlay assay, we identified two Ca2+-dependent CaM binding domains (CaMBDI in the N terminus and CaMBDII in the C terminus). Specific binding of CaM to two CaMBD was confirmed by site-directed mutagenesis, a gel mobility shift assay, and a competition assay using a Ca2+/CaM-dependent enzyme. At increasing concentrations of CaM, the biochemical activity of dual specificity protein phosphatase 1 on the p-nitrophenyl phosphate (pNPP) substrate was increased, whereas activity on the phosphotyrosine of myelin basic protein (MBP) was inhibited. Our results collectively indicate that calmodulin differentially regulates the activity of protein phosphatase, dependent on the substrate. Based on these findings, we propose that the Ca2+ signaling pathway is mediated by CaM cross-talks with a protein phosphorylation signal pathway in plants via protein dephosphorylation. 相似文献
39.
40.
Binding dynamics of hepatitis C virus' NS5A amphipathic peptide to cell and model membranes 下载免费PDF全文
Membrane association of the hepatitis C virus NS5A protein is required for viral replication. This association is dependent on an N-terminal amphipathic helix (AH) within NS5A and is restricted to a subset of host cell intracellular membranes. The mechanism underlying this specificity is not known, but it may suggest a novel strategy for developing specific antiviral therapy. Here we have probed the mechanistic details of NS5A AH-mediated binding to both cell-derived and model membranes by use of biochemical membrane flotation and quartz crystal microbalance (QCM) with dissipation. With both assays, we observed AH-mediated binding to model lipid bilayers. When cell-derived membranes were coated on the quartz nanosensor, however, significantly more binding was detected, and the QCM-derived kinetic measurements suggested the existence of an interacting receptor in the target membranes. Biochemical flotation assays performed with trypsin-treated cell-derived membranes exhibited reduced AH-mediated membrane binding, while membrane binding of control cytochrome b5 remained unaffected. Similarly, trypsin treatment of the nanosensor coated with cellular membranes abolished AH peptide binding to the cellular membranes but did not affect the binding of a control lipid-binding peptide. These results therefore suggest that a protein plays a critical role in mediating and stabilizing the binding of NS5A's AH to its target membrane. These results also demonstrate the successful development of a new nanosensor technology ideal both for studying the interaction between a protein and its target membrane and for developing inhibitors of that interaction. 相似文献