全文获取类型
收费全文 | 436篇 |
免费 | 38篇 |
出版年
2024年 | 3篇 |
2023年 | 2篇 |
2022年 | 12篇 |
2021年 | 16篇 |
2020年 | 7篇 |
2019年 | 7篇 |
2018年 | 6篇 |
2017年 | 7篇 |
2016年 | 29篇 |
2015年 | 23篇 |
2014年 | 21篇 |
2013年 | 26篇 |
2012年 | 23篇 |
2011年 | 23篇 |
2010年 | 24篇 |
2009年 | 15篇 |
2008年 | 24篇 |
2007年 | 20篇 |
2006年 | 19篇 |
2005年 | 18篇 |
2004年 | 15篇 |
2003年 | 7篇 |
2002年 | 6篇 |
2001年 | 8篇 |
2000年 | 4篇 |
1999年 | 7篇 |
1998年 | 5篇 |
1996年 | 3篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1988年 | 2篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1982年 | 4篇 |
1981年 | 6篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1975年 | 8篇 |
1974年 | 6篇 |
1973年 | 4篇 |
1969年 | 2篇 |
1962年 | 2篇 |
1954年 | 1篇 |
1953年 | 1篇 |
排序方式: 共有474条查询结果,搜索用时 46 毫秒
81.
Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. 总被引:8,自引:0,他引:8
M P Sch?n A Arya E A Murphy C M Adams U G Strauch W W Agace J Marsal J P Donohue H Her D R Beier S Olson L Lefrancois M B Brenner M J Grusby C M Parker 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(11):6641-6649
The mucosal lymphocyte integrin alpha E(CD103)beta 7 is thought to be important for intraepithelial lymphocyte (IEL) localization or function. We cloned the murine integrin gene encoding alpha E, localized it to chromosome 11, and generated integrin alpha E-deficient mice. In alpha E-/- mice, intestinal and vaginal IEL numbers were reduced, consistent with the known binding of alpha E beta 7 to E-cadherin expressed on epithelial cells. However, it was surprising that lamina propria T lymphocyte numbers were diminished, as E-cadherin is not expressed in the lamina propria. In contrast, peribronchial, intrapulmonary, Peyer's patch, and splenic T lymphocyte numbers were not reduced in alpha E-deficient mice. Thus, alpha E beta 7 was important for generating or maintaining the gut and vaginal T lymphocytes located diffusely within the epithelium or lamina propria but not for generating the gut-associated organized lymphoid tissues. Finally, the impact of alpha E deficiency upon intestinal IEL numbers was greater at 3-4 wk of life than in younger animals, and affected the TCR alpha beta+ CD8+ T cells more than the gamma delta T cells or the TCR alpha beta+ CD4+CD8- population. These findings suggest that alpha E beta 7 is involved in the expansion/recruitment of TCR alpha beta+ CD8+ IEL following microbial colonization. Integrin alpha E-deficient mice will provide an important tool for studying the role of alpha E beta 7 and of alpha E beta 7-expressing mucosal T lymphocytes in vivo. 相似文献
82.
In sexually dimorphic zebra finches (Taeniopygia guttata), only males learn to sing their father's song, whereas females learn to recognize the songs of their father or mate but cannot sing themselves. Memory of learned songs is behaviorally expressed in females by preferring familiar songs over unfamiliar ones. Auditory association regions such as the caudomedial mesopallium (CMM; or caudal mesopallium) have been shown to be key nodes in a network that supports preferences for learned songs in adult females. However, much less is known about how song preferences develop during the sensitive period of learning in juvenile female zebra finches. In this study, we used blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to trace the development of a memory-based preference for the father's song in female zebra finches. Using BOLD fMRI, we found that only in adult female zebra finches with a preference for learned song over novel conspecific song, neural selectivity for the father's song was localized in the thalamus (dorsolateral nucleus of the medial thalamus; part of the anterior forebrain pathway, AFP) and in CMM. These brain regions also showed a selective response in juvenile female zebra finches, although activation was less prominent. These data reveal that neural responses in CMM, and perhaps also in the AFP, are shaped during development to support behavioral preferences for learned songs. 相似文献
83.
Singh AR Joshi S Arya R Kayastha AM Srivastava KK Tripathi LM Saxena JK 《Parasitology international》2008,57(3):354-361
5' EST from filarial gene database has been subjected to 3' rapid amplification of cDNA ends (RACE), semi-nested PCR and PCR to obtain full-length cDNA of Brugia malayi. Full-length hexokinase gene was obtained from cDNA using gene specific primers. The elicited PCR product was cloned, sequenced and expressed as an active enzyme in Escherichia coli. Sequence analysis of B. malayi hexokinase (BmHk) revealed 59% identity with nematode Caenorhabditis elegans but low similarity with all other available hexokinases including human. BmHk, an apparent tetramer with subunit molecular mass of 72 kDa, was able to phosphorylate glucose, fructose, mannose, maltose and galactose. The Km values for glucose, fructose and ATP were found to be 0.035+/-0.005, 75+/-0.3 and 1.09+/-0.5 mM respectively. BmHk was strongly inhibited by ADP, glucosamine, N-acetyl glucosamine and mannoheptulose. The recombinant enzyme was found to be activated by glucose-6-phosphate. ADP exhibited noncompetitive inhibition with the substrate glucose (Ki=0.55 mM) while, mixed type of inhibition was observed with inorganic pyrophosphate (PPi) when ATP was used as substrate (Ki=9.92 microM). The enzyme activity is highly dependent on maintenance of free sulfhydryl groups. CD analysis indicated that BmHk is composed of 37% alpha-helices and 26% beta-sheets. The observed differences in kinetic properties of BmHk as compared to host enzyme may facilitate designing of specific inhibitors against BmHk. 相似文献
84.
Jorge Mansilla-Soto Miran Yoon-Robarts William J. Rice Shailee Arya Carlos R. Escalante R. Michael Linden 《PLoS pathogens》2009,5(7)
Rep68 is a multifunctional protein of the adeno-associated virus (AAV), a parvovirus that is mostly known for its promise as a gene therapy vector. In addition to its role as initiator in viral DNA replication, Rep68 is essential for site-specific integration of the AAV genome into human chromosome 19. Rep68 is a member of the superfamily 3 (SF3) helicases, along with the well-studied initiator proteins simian virus 40 large T antigen (SV40-LTag) and bovine papillomavirus (BPV) E1. Structurally, SF3 helicases share two domains, a DNA origin interaction domain (OID) and an AAA+ motor domain. The AAA+ motor domain is also a structural feature of cellular initiators and it functions as a platform for initiator oligomerization. Here, we studied Rep68 oligomerization in vitro in the presence of different DNA substrates using a variety of biophysical techniques and cryo-EM. We found that a dsDNA region of the AAV origin promotes the formation of a complex containing five Rep68 subunits. Interestingly, non-specific ssDNA promotes the formation of a double-ring Rep68, a known structure formed by the LTag and E1 initiator proteins. The Rep68 ring symmetry is 8-fold, thus differing from the hexameric rings formed by the other SF3 helicases. However, similiar to LTag and E1, Rep68 rings are oriented head-to-head, suggesting that DNA unwinding by the complex proceeds bidirectionally. This novel Rep68 quaternary structure requires both the DNA binding and AAA+ domains, indicating cooperativity between these regions during oligomerization in vitro. Our study clearly demonstrates that Rep68 can oligomerize through two distinct oligomerization pathways, which depend on both the DNA structure and cooperativity of Rep68 domains. These findings provide insight into the dynamics and oligomeric adaptability of Rep68 and serve as a step towards understanding the role of this multifunctional protein during AAV DNA replication and site-specific integration. 相似文献
85.
86.
Ian Caterson Walmir Coutinho Nick Finer Luc Van Gaal Aldo Maggioni Christian Torp‐Pedersen Arya M. Sharma Hong Ge Donatella Santoro Gillian Shepherd Philip James SCOUT Investigators 《Obesity (Silver Spring, Md.)》2010,18(5):987-994
The Sibutramine Cardiovascular Outcomes (SCOUT) trial protocol defines a patient population predominantly outside current European Union label criteria. This article explores responses to sibutramine during the 6‐week, single‐blind, lead‐in period between patients who conformed to the label requirements (“conformers”) and those who did not (“nonconformers”). SCOUT is an ongoing, randomized, double‐blind, placebo‐controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. In total, 10,742 patients received sibutramine and weight management during the lead‐in period. Initial responses were assessed post hoc in label conformers and nonconformers. Of that 8.1% patients met label criteria; 91.9%, the majority with cardiovascular disease and/or blood pressure >145/90 mm Hg, were nonconformers. Conformers and nonconformers had similar reductions in body weight (median change ?2.2 kg) and waist circumference (women: ?2.0 cm for both groups; men: ?1.5 cm vs. ?2.0 cm for conformers and nonconformers, respectively) over the 6‐week period. Greater blood pressure falls were evident in nonconformers (median change ?3.5/?1.0 vs. ?1.0/0.0 mm Hg). Both groups had small pulse rate increases; median 1.5 bpm (nonconformers) vs. 3.0 bpm (conformers). There was a low incidence of serious adverse events (conformers: 1.0%; nonconformers: 2.8%) and ~93% of patients in both groups completed the 6‐week period. The SCOUT lead‐in period evaluating weight management with sibutramine confirms its good tolerability and efficacy in patients who meet current label criteria. Preliminary data from high‐risk patients for whom sibutramine is currently contraindicated suggest a low discontinuation rate and few serious adverse events but confirmation from the SCOUT outcome data is needed. 相似文献
87.
Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity
下载免费PDF全文
![点击此处可从《Cellular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nataliya Zlotnikov Ashkan Javid Mijhgan Ahmed Azad Eshghi Tian Tian Tang Anoop Arya Anil Bansal Fatima Matar Maitry Parikh Rhodaba Ebady Adeline Koh Nupur Gupta Peng Song Yang Zhang Susan Newbigging Gary P. Wormser Ira Schwartz Robert Inman Michael Glogauer Tara J. Moriarty 《Cellular microbiology》2017,19(5)
Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high‐fat diet‐induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil‐ and macrophage‐based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi‐infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high‐fat diet, toll‐like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow‐derived macrophages from obese, B. burgdorferi‐infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice. 相似文献
88.
Kulkarni SD Muralidharan B Panda AC Bakthavachalu B Vindu A Seshadri V 《The Journal of biological chemistry》2011,286(16):14146-14156
Insulin is the key regulator of glucose homeostasis in mammals, and glucose-stimulated insulin biosynthesis is essential for maintaining glucose levels in a narrow range in mammals. Glucose specifically promotes the translation of insulin in pancreatic β-islet, and the untranslated regions of insulin mRNA play a role in such regulation. Specific factors in the β-islets bind to the insulin 5' UTR and regulate its translation. In the present study we identify protein-disulfide isomerase (PDI) as a key regulator of glucose-stimulated insulin biosynthesis. We show that both in vitro and in vivo PDI can specifically associate with the 5' UTR of insulin mRNA. Immunodepletion of PDI from the islet extract results in loss of glucose-stimulated translation indicating a critical role for PDI in insulin biosynthesis. Similarly, transient overexpression of PDI resulted in specific translation activation by glucose. We show that the RNA binding activity of PDI is mediated through PABP. PDI catalyzes the reduction of the PABP disulfide bond resulting in specific binding of PABP to the insulin 5' UTR. We also show that glucose stimulation of the islets results in activation of a specific kinase that can phosphorylate PDI. These findings identify PDI and PABP as important players in glucose homeostasis. 相似文献
89.
The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? 总被引:8,自引:0,他引:8
Engeli S Schling P Gorzelniak K Boschmann M Janke J Ailhaud G Teboul M Massiéra F Sharma AM 《The international journal of biochemistry & cell biology》2003,35(6):807-825
Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome. 相似文献
90.
In this genomics and proteomics age, highly functionalized natural products or natural-product-like compounds are likely to play important roles in understanding the functions of emerging biological targets because they serve as small-molecule chemical probes in modulating a target's specific actions (i.e. activation or deactivation). Development of stereoselective reaction-derived methods on solid phase provides a means of obtaining functionalized chiral core structures that may be used for high-throughout syntheses. 相似文献