全文获取类型
收费全文 | 236篇 |
免费 | 13篇 |
出版年
2022年 | 2篇 |
2021年 | 6篇 |
2020年 | 7篇 |
2019年 | 2篇 |
2018年 | 3篇 |
2017年 | 2篇 |
2016年 | 8篇 |
2015年 | 8篇 |
2014年 | 11篇 |
2013年 | 19篇 |
2012年 | 12篇 |
2011年 | 27篇 |
2010年 | 9篇 |
2009年 | 5篇 |
2008年 | 12篇 |
2007年 | 14篇 |
2006年 | 10篇 |
2005年 | 11篇 |
2004年 | 10篇 |
2003年 | 9篇 |
2002年 | 14篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1973年 | 2篇 |
1965年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有249条查询结果,搜索用时 824 毫秒
201.
Alexander S. Taylor Jacqueline J. Glascock Ferrill F. Rose Jr. Cathleen Lutz Christian L. Lorson 《Transgenic research》2013,22(5):1029-1036
Spinal Muscular Atrophy (SMA), an autosomal recessive neuromuscular disorder, is a leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). However, low, but essential, levels of SMN protein are produced by a nearly identical copy gene called SMN2. Detailed analysis of neuromuscular junctions in SMA mice has revealed a selective vulnerability in a subset of muscle targets, suggesting that while SMN is reduced uniformly, the functional deficits manifest sporadically. Additionally, in severe SMA models, it is becoming increasing apparent that SMA is not restricted solely to motor neurons. Rather, additional tissues including the heart, vasculature, and the pancreas contribute to the complete SMA-associated pathology. Recently, transgenic models have been utilized to examine the tissue-specific requirements of SMN, including selective depletion and restoration of SMN in motor neurons. To determine whether the cortical neuronal populations expressing the Emx-1 promoter are involved in SMA pathology, we generated a novel SMA mouse model in which SMN expression was specifically induced in Emx-1 expressing cortical neurons utilizing an Emx-1-Cre transgene. While SMN expression was robust in the central nervous system as expected, SMA mice did not live longer. Weight and time-to-right motor function were not significantly improved. 相似文献
202.
Nicholas L. Cianciola Diane J. Greene Richard E. Morton Cathleen R. Carlin 《Molecular biology of the cell》2013,24(21):3309-3325
Niemann–Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2, which coordinate egress of low-density-lipoprotein (LDL)-cholesterol from late endosomes. We previously reported that the adenovirus-encoded protein RIDα rescues the cholesterol storage phenotype in NPC1-mutant fibroblasts. We show here that RIDα reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified by acyl-CoA:cholesterol acyltransferase and stored in lipid droplets (LDs) in NPC1-deficient cells. Furthermore, the RIDα pathway is regulated by the oxysterol-binding protein ORP1L. Studies have classified ORP1L as a sterol sensor involved in LE positioning downstream of GTP-Rab7. Our data, however, suggest that ORP1L may play a role in transport of LDL-cholesterol to a specific ER pool designated for LD formation. In contrast to NPC1, which is dispensable, the RIDα/ORP1L-dependent route requires functional NPC2. Although NPC1/NPC2 constitutes the major pathway, therapies that amplify minor egress routes for LDL-cholesterol could significantly improve clinical management of patients with loss-of-function NPC1 mutations. The molecular identity of putative alternative pathways, however, is poorly characterized. We propose RIDα as a model system for understanding physiological egress routes that use ORP1L to activate ER feedback responses involved in LD formation. 相似文献
203.
Yiru Chen Yordan S. Yordanov Cathleen Ma Steven Strauss Victor B. Busov 《Plant cell reports》2013,32(3):453-463
Key message
Auxin responsive promoter DR5 reporter system is functional in Populus to monitor auxin response in tissues including leaves, roots, and stems.Abstract
We described the behavior of the DR5::GUS reporter system in stably transformed Populus plants. We found several similarities with Arabidopsis, including sensitivity to native and synthetic auxins, rapid induction after treatment in a variety of tissues, and maximal responses in root tissues. There were also several important differences from Arabidopsis, including slower time to maximum response and lower induction amplitude. Young leaves and stem sections below the apex showed much higher DR5 activity than did older leaves and stems undergoing secondary growth. DR5 activity was highest in cortex, suggesting high levels of auxin concentration and/or sensitivity in this tissue. Our study shows that the DR5 reporter system is a sensitive and facile system for monitoring auxin responses and distribution at cellular resolution in poplar. 相似文献204.
Marcel Lindemann Sonja Hinz Winnie Deuther-Conrad Vigneshwaran Namasivayam Sladjana Dukic-Stefanovic Rodrigo Teodoro Magali Toussaint Mathias Kranz Cathleen Juhl Jörg Steinbach Peter Brust Christa E. Müller Barbara Wenzel 《Bioorganic & medicinal chemistry》2018,26(16):4650-4663
On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B)?=?4.24?nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5?min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood–brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo. 相似文献
205.
206.
The POLO kinase is a key regulator of the release of sister chromatid cohesion at the onset of mitotic anaphase, as well as of other features of the mitotic and meiotic processes. In this issue of Developmental Cell, Clarke et al. show that POLO also regulates the function of the MEI-S332 protein, which plays a critical role in the maintenance of sister chromatid cohesion at the centromere during meiosis. 相似文献
207.
Shi Q Canada EJ Xu Y Warshawsky AM Etgen GJ Broderick CL Clutinger CK Irwin LA Laurila ME Montrose-Rafizadeh C Oldham BA Wang M Winneroski LL Xie C York JS Yumibe NP Zink RW Mantlo N 《Bioorganic & medicinal chemistry letters》2007,17(24):6744-6749
A series of potent amide linked PPARγ/δ dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARγ agonist rosiglitazone with less weight gain. 相似文献
208.
Satish P. RamachandraRao Michael A. Matthias Chanthel Kokoy-Mondrogon Eamon Aghania Cathleen Park Casey Kong Michelle Ishaya Assael Madrigal Jennifer Horng Roni Khoshaba Anousone Bounkhoun Fabrizio Basilico Antonella De Palma Anna Maria Agresta Linda Awdishu Robert K. Naviaux Joseph M. Vinetz Pierluigi Mauri 《PLoS neglected tropical diseases》2015,9(4)
209.
Sachiko Koyama Helena A. Soini James Wager-Miller William R. Alley Matthew J. Pizzo Cathleen Rodda Jeffrey Alberts Jonathon D. Crystal Cary Lai John Foley Milos V. Novotny 《Proceedings. Biological sciences / The Royal Society》2015,282(1811)
The current understanding of the activity of mammalian pheromones is that endocrine and behavioural effects are limited to the exposed individuals. Here, we demonstrate that the nasal exposure of female mice to a male murine pheromone stimulates expansion of mammary glands, leading to prolonged nursing of pups. Subsequent behavioural testing of the pups from pheromone-exposed dams exhibited enhanced learning. Sialic acid components in the milk are known to be involved in brain development. We hypothesized that the offspring might have received more of this key nutrient that promotes brain development. The mRNA for polysialyltransferase, which produces polysialylated neural cell adhesion molecules related to brain development, was increased in the brain of offspring of pheromone-exposed dams at post-natal day 10, while it was not different at embryonic stages, indicating possible differential brain development during early post-natal life. 相似文献