全文获取类型
收费全文 | 329篇 |
免费 | 18篇 |
国内免费 | 1篇 |
专业分类
348篇 |
出版年
2023年 | 4篇 |
2022年 | 5篇 |
2021年 | 9篇 |
2020年 | 8篇 |
2019年 | 7篇 |
2018年 | 18篇 |
2017年 | 7篇 |
2016年 | 12篇 |
2015年 | 13篇 |
2014年 | 24篇 |
2013年 | 19篇 |
2012年 | 32篇 |
2011年 | 22篇 |
2010年 | 20篇 |
2009年 | 6篇 |
2008年 | 17篇 |
2007年 | 18篇 |
2006年 | 12篇 |
2005年 | 7篇 |
2004年 | 12篇 |
2003年 | 11篇 |
2002年 | 6篇 |
2001年 | 4篇 |
2000年 | 7篇 |
1999年 | 6篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 7篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1979年 | 1篇 |
1978年 | 4篇 |
1969年 | 1篇 |
排序方式: 共有348条查询结果,搜索用时 0 毫秒
101.
Background
We previously showed that mice exposed to cigarette smoke for three weeks exhibit loss of bone marrow B cells at the Pro-B-to-pre-B cell transition, but the reason for this is unclear. The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been used as a chemopreventive agent to reduce adverse effects of cigarette smoke exposure on lung function. Here we determined whether smoke exposure impairs B cell development by inducing cell cycle arrest or apoptosis, and whether NAC treatment prevents smoking-induced loss of developing B cells.Methodology/Principal Findings
Groups of normal mice were either exposed to filtered room air or cigarette smoke with or without concomitant NAC treatment for 5 days/week for three weeks. Bone marrow B cell developmental subsets were enumerated, and sorted pro-B (B220+CD43+) and pre-B (B220+CD43−) cell fractions were analyzed for cell cycle status and the percentage of apoptotic cells. We find that, compared to sham controls, smoke-exposed mice have ∼60% fewer pro-B/pre-B cells, regardless of NAC treatment. Interestingly, NAC-treated mice show a 21–38% increase in total bone marrow cellularity and lymphocyte frequency and about a 2-fold increase in the pro-B/pre-B cell subset, compared to sham-treated controls. No significant smoking- or NAC-dependent differences were detected in frequency of apoptotic cells or the percentage cells in the G1, S, or G2 phases of the cycle.Conclusions/Significance
The failure of NAC treatment to prevent smoking-induced loss of bone marrow pre-B cells suggests that oxidative stress is not directly responsible for this loss. The unexpected expansion of the pro-B/pre-B cell subset in response to NAC treatment suggests oxidative stress normally contributes to cell loss at this developmental stage, and also reveals a potential side effect of therapeutic administration of NAC to prevent smoking-induced loss of lung function. 相似文献102.
103.
Hossain MA Rosengren KJ Samuel CS Shabanpoor F Chan LJ Bathgate RA Wade JD 《The Journal of biological chemistry》2011,286(43):37555-37565
H2 relaxin is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways. It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises 53 amino acids and is characterized by two separate polypeptide chains (A-B) that are cross-linked by three disulfide bonds. This size and complex structure represents a considerable challenge for the chemical synthesis of H2 relaxin, a major limiting factor for the exploration of modifications and derivatizations of this peptide, to optimize effect and drug-like characteristics. To address this issue, we describe the solid phase peptide synthesis and structural and functional evaluation of 24 analogues of H2 relaxin with truncations at the termini of its peptide chains. We show that it is possible to significantly truncate both the N and C termini of the B-chain while still retaining potent biological activity. This suggests that these regions are not critical for interactions with the H2 relaxin receptor, RXFP1. In contrast, truncations do reduce the activity of H2 relaxin for the related receptor RXFP2 by improving RXFP1 selectivity. In addition to new mechanistic insights into the function of H2 relaxin, this study identifies a critical active core with 38 amino acids. This minimized core shows similar antifibrotic activity as native H2 relaxin when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics. 相似文献
104.
105.
About 10% of the coding capacity of the Mycobacterium tuberculosis (M. tb) genome is devoted to the PE/PPE family of genes scattered throughout the genome. We have identified 28 PE/PPE operons which are organized within the M. tb genome in such a way that most PE members are upstream to PPE members. One example of such a gene arrangement is the PPE gene Rv2430c, earlier shown by us to code for a highly antigenic protein eliciting strong B-cell responses in TB patients [Choudhary, R.K., Mukhopadhyay, S., Chakhaiyar, P., Sharma, N., Murthy, K.J.R., Katoch V.M. and Hasnain, S.E. (2003) PPE antigen Rv2430c of Mycobacterium tuberculosis induces a strong B cell response. Infect. Immun. 71, 6338-6343], situated downstream to PE gene Rv2431c. Rv2431c and Rv2430c are transcribed as an operon. Expression of either rRv2431c or rRv2430c alone in E. coli limited their localization to the inclusion bodies. However, when they were co-expressed, both the proteins appeared in the soluble fraction. These two proteins interact with each other and form oligomers when alone, however, when present together they exist as heteromer. 相似文献
106.
Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice 总被引:2,自引:0,他引:2
Lee Y Naseem RH Park BH Garry DJ Richardson JA Schaffer JE Unger RH 《Biochemical and biophysical research communications》2006,344(1):446-452
Alpha-lipoic acid (alpha-LA) mimics the hypothalamic actions of leptin on food intake, energy expenditure, and activation of AMP-activated protein kinase (AMPK). To determine if, like leptin, alpha-LA protects against cardiac lipotoxicity, alpha-LA was fed to transgenic mice with cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS) gene. Untreated ACS-transgenic mice died prematurely with increased triacylglycerol content and dilated cardiomyopathy, impaired systolic function and myofiber disorganization, apoptosis, and interstitial fibrosis on microscopy. In alpha-LA-treated ACS-transgenic mice heart size, echocardiogram and TG content were normal. Plasma TG fell 50%, hepatic-activated phospho-AMPK rose 6-fold, sterol regulatory element-binding protein-1c declined 50%, and peroxisome proliferator-activated receptor-gamma cofactor-1alpha mRNA rose 4-fold. Since food restriction did not prevent lipotoxicity, we conclude that alpha-LA treatment, like hyperleptinemia, protects the heart of ACS-transgenic mice from lipotoxicity. 相似文献
107.
Vassilios Tzotzes Vassilios Tzilalis Sotirios Giannakakis Theodosios Saranteas Asimakis Papas Iordanis Mourouzis Constantinos Mourouzis Apostolos Zarros Constantinos Pantos Dennis Cokkinos Haris Carageorgiou 《Biometals》2007,20(1):83-91
The effect of acute and chronic cadmium (Cd) administration on the vascular function of the rat aorta was studied. The rats
were randomly divided into four main groups (A: saline controls under chronic administration, B: Cd-treated rats under chronic
administration, C: saline controls under acute administration, D: Cd-treated rats under acute administration). After their
sacrifice, the aortic rings were divided into rings with endothelium (E+) and without (E−), and suspended in an isolated organ
bath with Krebs–Henseleit buffer. Maximal tension (T
max, in g) was measured in response to potassium chloride (KCl) and phenylephrine (PE) in all aortic rings. Relaxation response
to acetylcholine (ACh) administration was expressed as percent of maximal tension induced by PE. Chronic administration: A statistically significant increase of the contraction was observed between groups B (i.m. Cd 0.5 mg/kg for 120 days) and
A (i.m. 0.9% NaCl for 120 days) in response to KCl (20–60 mM) and the T
max as well (in both the E+ and the E− subgroups). No statistically significant difference was observed in response to PE and
ACh exposure. Acute administration: A statistically significant increase was observed between group D(E+) (i.m. Cd 2 mg/kg, 8 h before sacrifice) and group
C(E+) (i.m. 0.9% NaCl, 8 h before sacrifice) in response to 10–30 mM of KCl, and a significant decrease between D(E−) and
C(E−) in response to 10−7–10−6 M of PE, though T
max was increased between D(E−) and C(E−) with PE exposure. The contractile response levels of the E+ aortic rings to PE and
ACh showed no statistically significant difference. 相似文献
108.
Fazel Shabanpoor Ross A D Bathgate Mohammed Akhter Hossain Eleni Giannakis John D Wade Richard A Hughes 《Journal of peptide science》2007,13(2):113-120
Insulin-like peptide 3 (INSL3) is a peptide hormone belonging to the relaxin-insulin superfamily of peptides that plays important roles in testes descent, oocyte maturation and the control of male germ cell apoptosis. These actions are mediated via a specific G-protein coupled receptor, LGR8. Previous structure-activity studies have shown that the key binding site of INSL3 is situated within its B-chain. Recent studies in our laboratory have led to the identification of a cyclic peptide mimetic 2 of the INSL3 B-chain, which we have shown to compete with the binding of [33P]-relaxin to LGR8 expressed in HEK293T cells, and to inhibit cAMP-mediated signaling in these cells, i.e. it is an antagonist of INSL3. In order to further define the structure-activity relationships of cyclic analogues of the INSL3 B-chain, we used a structure-based approach to design a series of cyclic, disulfide-constrained INSL3 B-chain mimetics. To do this, we first created a model of the 3D structure of INSL3 using the crystal structure of human relaxin as a template. This model of INSL3 was then used as a template to design a series of disulfide-constrained mimetics of the INSL3 B-chain. The peptides were synthesized by solid-phase peptide synthesis using pseudoproline dipeptides to improve the synthesis outcome. Of the seven prepared INSL3 B-chain mimetics, three compounds were found to have partial displacement activity, while four were able to completely displace [33P]-relaxin from LGR8, including compounds that were markedly shorter than compound 2. The best of these, mimetic 6, showed significantly greater affinity for LGR8 than compound 2, but still displayed around 1000-fold less affinity for LGR8 than native INSL3. Analysis of selected mimetics for their alpha-helical content using circular dichroism (CD) spectroscopy revealed that, generally, the mimetics showed less than expected helicity. The inability of the compounds to display true native INSL3 structure is likely contributing to their reduced receptor binding affinity. We are currently examining alternative INSL3 B-chain mimetics that might better present key receptor binding residues in the native INSL3-like conformation. 相似文献
109.
We have shown previously that SNM1A colocalizes with 53BP1 at sites of double-strand breaks (DSBs) induced by IR, and that these proteins interact with or without DNA damage. However, the role of SNM1A in the DNA damage response has not been elucidated. Here, we show that SNM1A is required for an efficient G1 checkpoint arrest after IR exposure. Interestingly, the localization of SNM1A to sites of DSBs does not require either 53BP1 or H2AX, nor does the localization of 53BP1 require SNM1A. However, the localization of SNM1A does require ATM. Furthermore, SNM1A is shown to be a phosphorylation substrate of ATM in vitro, and to interact with ATM in vivo particularly after exposure of cells to IR. In addition, in the absence of SNM1A the activation of the downstream ATM target p53 is reduced. These findings suggest that SNM1A acts with ATM to promote the G1 cell cycle checkpoint. 相似文献
110.
Wang NC Chicos A Banthia S Bergner DW Lahiri MK Ng J Subacius H Kadish AH Goldberger JJ 《American journal of physiology. Heart and circulatory physiology》2011,301(3):H912-H920
There is an increased risk of cardiac events after exercise, which may, in part, be mediated by the sympathoexcitation that accompanies exercise. The duration and extent of this sympathoexcitation following moderate exercise is unknown, particularly in those with coronary artery disease (CAD). Twenty control subjects (mean age, 51 years) and 89 subjects with CAD (mean age, 58 years) underwent two 16-min bicycle exercise sessions followed by 30-45 min of recovery. Session 1 was performed under physiological conditions to peak workloads of 50-100 W. In session 2, parasympathetic blockade with atropine (0.04 mg/kg) was achieved at end exercise at the same workload as session 1. RR interval was continually recorded, and plasma catecholamines were measured at rest and selected times during exercise and recovery. Parasympathetic effect, measured as the difference in RR interval with and without atropine, did not differ between controls and CAD subjects in recovery. At 30 and 45 min of recovery, RR intervals were 12% and 9%, respectively, shorter than at rest. At 30 and 45 min of recovery, plasma norepinephrine levels were 15% and 12%, respectively, higher than at rest. A brief period of moderate exercise is associated with a prolonged period of sympathoexcitation extending >45 min into recovery and is quantitatively similar among control subjects and subjects with CAD, with or without left ventricular dysfunction. Parasympathetic reactivation occurs early after exercise and is also surprisingly quantitatively similar in controls and subjects with CAD. The role of these autonomic changes in precipitating cardiac events requires further evaluation. 相似文献