全文获取类型
收费全文 | 279篇 |
免费 | 28篇 |
出版年
2023年 | 2篇 |
2022年 | 1篇 |
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 5篇 |
2018年 | 3篇 |
2017年 | 5篇 |
2016年 | 4篇 |
2015年 | 5篇 |
2014年 | 14篇 |
2013年 | 19篇 |
2012年 | 15篇 |
2011年 | 17篇 |
2010年 | 11篇 |
2009年 | 12篇 |
2008年 | 15篇 |
2007年 | 7篇 |
2006年 | 12篇 |
2005年 | 20篇 |
2004年 | 13篇 |
2003年 | 12篇 |
2002年 | 11篇 |
2001年 | 16篇 |
2000年 | 18篇 |
1999年 | 8篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有307条查询结果,搜索用时 15 毫秒
71.
Gianpiero Spedale R Andrew Atkinson Christophe Romier Ali Hamiche W W M Pim Pijnappel H Th Marc Timmers László Tora Didier Devys Bruno Kieffer 《EMBO reports》2010,11(8):612-618
SAGA (Spt–Ada–Gcn5 acetyltransferase), a coactivator complex involved in chromatin remodelling, harbours both histone acetylation and deubiquitination activities. ATXN7/Sgf73 and ATXN7L3, two subunits of the SAGA deubiquitination module, contain an SCA7 domain characterized by an atypical zinc‐finger. We show that the yeast Sgf73–SCA7 domain is not required to recruit Sgf73 into SAGA. Instead, it binds to nucleosomes, a property that is conserved in the human ATXN7–SCA7 domain but is lost in the ATXN7L3 domain. The solution structures of the SCA7 domain of both ATXN7 and ATXN7L3 reveal a new, common zinc‐finger motif at the heart of two distinct folds, providing a molecular basis for the observed functional differences. 相似文献
72.
Scott B. Widenmaier Su-Jin Kim Gary K. Yang Thomas De Los Reyes Cuilan Nian Ali Asadi Yutaka Seino Timothy J. Kieffer Yin Nam Kwok Christopher H. S. McIntosh 《PloS one》2010,5(3)
Aims
The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured β-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala2-GIP1–30 (D-GIP1–30), on glucose homeostasis and β-cell mass in rat models of diabetes.Materials and Methods
The insulinotropic and pro-survival potency of D-GIP1–30 was evaluated in perfused pancreas preparations and cultured INS-1 β-cells, respectively, and receptor selectivity evaluated using wild type and GIP receptor knockout mice. Effects of D-GIP1–30 on β-cell function and glucose homeostasis, in vivo, were determined using Lean Zucker rats, obese Vancouver diabetic fatty rats, streptozotocin treated rats, and obese Zucker diabetic fatty rats, with effects on β-cell mass determined in histological studies of pancreatic tissue. Lipogenic effects of D-GIP1–30 were evaluated on cultured 3T3-L1 adipocytes.Results
Acutely, D-GIP1–30 improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP1–30 reduced levels of islet pro-apoptotic proteins in Vancouver diabetic fatty rats and preserved β-cell mass in streptozotocin treated rats and Zucker diabetic fatty rats, resulting in improved insulin responses and glycemic control in each animal model, with no change in body weight. In in vitro studies, D-GIP1–30 exhibited equivalent potency to GIP1–42 on β-cell function and survival, but greatly reduced action on lipoprotein lipase activity in 3T3-L1 adipocytes.Conclusions
These findings demonstrate that truncated forms of GIP exhibit potent anti-diabetic actions, without pro-obesity effects, and that the C-terminus contributes to the lipogenic actions of GIP. 相似文献73.
Covey SD Wideman RD McDonald C Unniappan S Huynh F Asadi A Speck M Webber T Chua SC Kieffer TJ 《Cell metabolism》2006,4(4):291-302
The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity. 相似文献
74.
Reini W Bretveld Chris MG Thomas Paul TJ Scheepers Gerhard A Zielhuis Nel Roeleveld 《Reproductive biology and endocrinology : RB&E》2006,4(1):30
Some pesticides may interfere with the female hormonal function, which may lead to negative effects on the reproductive system
through disruption of the hormonal balance necessary for proper functioning. Previous studies primarily focused on interference
with the estrogen and/or androgen receptor, but the hormonal function may be disrupted in many more ways through pesticide
exposure. The aim of this review is to give an overview of the various ways in which pesticides may disrupt the hormonal function
of the female reproductive system and in particular the ovarian cycle. Disruption can occur in all stages of hormonal regulation:
1. hormone synthesis; 2. hormone release and storage; 3. hormone transport and clearance; 4. hormone receptor recognition
and binding; 5. hormone postreceptor activation; 6. the thyroid function; and 7. the central nervous system. These mechanisms
are described for effects of pesticide exposure in vitro and on experimental animals in vivo. For the latter, potential effects of endocrine disrupting pesticides on the female reproductive system, i.e. modulation
of hormone concentrations, ovarian cycle irregularities, and impaired fertility, are also reviewed. In epidemiological studies,
exposure to pesticides has been associated with menstrual cycle disturbances, reduced fertility, prolonged time-to-pregnancy,
spontaneous abortion, stillbirths, and developmental defects, which may or may not be due to disruption of the female hormonal
function. Because pesticides comprise a large number of distinct substances with dissimilar structures and diverse toxicity,
it is most likely that several of the above-mentioned mechanisms are involved in the pathophysiological pathways explaining
the role of pesticide exposure in ovarian cycle disturbances, ultimately leading to fertility problems and other reproductive
effects. In future research, information on the ways in which pesticides may disrupt the hormonal function as described in
this review, can be used to generate specific hypotheses for studies on the effects of pesticides on the ovarian cycle, both
in toxicological and epidemiological settings. 相似文献
75.
Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression 总被引:1,自引:0,他引:1
Lam NT Lewis JT Cheung AT Luk CT Tse J Wang J Bryer-Ash M Kolls JK Kieffer TJ 《Molecular endocrinology (Baltimore, Md.)》2004,18(6):1333-1345
Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance. 相似文献
76.
Cellular lamellipodia bind to the matrix and probe its rigidity through forces generated by rearward F-actin transport. Cells respond to matrix rigidity by moving toward more rigid matrices using an unknown mechanism. In spreading and migrating cells we find local periodic contractions of lamellipodia that depend on matrix rigidity, fibronectin binding and myosin light chain kinase (MLCK). These contractions leave periodic rows of matrix bound beta3-integrin and paxillin while generating waves of rearward moving actin bound alpha-actinin and MLCK. The period between contractions corresponds to the time for F-actin to move across the lamellipodia. Shortening lamellipodial width by activating cofilin decreased this period proportionally. Increasing lamellipodial width by Rac signaling activation increased this period. We propose that an actin bound, contraction-activated signaling complex is transported locally from the tip to the base of the lamellipodium, activating the next contraction/extension cycle. 相似文献
77.
This research examined the influence of acute changes of water temperature on the recovery processes following exhaustive exercise in juvenile Atlantic salmon (Salmo salar). White muscle phosphocreatine (PCr), ATP, lactate, glycogen, glucose, pyruvate, plasma lactate, and plasma osmolality were measured during rest and at 0, 1, 2, and 4 h following exhaustive exercise in fish acclimated and exercised at 12 degrees C and acutely exposed to either 6 degrees C or 18 degrees C water during recovery. An acute exposure to 6 degrees C water during the recovery period resulted in a severe reduction of metabolic recovery in salmon. However, metabolites such as muscle PCr and ATP and plasma lactate recovered very quickly (2-4 h) in fish acutely exposed to 18 degrees C during recovery. Overall, differences exist when postexercise metabolite levels are compared between acclimated fish and those fish acutely exposed to different water temperatures (either higher or lower). Taken together, the findings of the acute experiments suggest that at some point following exercise fish may seek warmer environments to speed the recovery process. However, the relationship between behavioural thermoregulation and recovery following exhaustive exercise in fish is not well understood. 相似文献
78.
To further understand the role of LPS in the pathogenesis of Francisella infection, we characterized murine infection with F. novicida, and compared immunobiological activities of F. novicida LPS and the LPS from F. tularensis live vaccine strain (LVS). F. novicida had a lower intradermal LD(50) in BALB/cByJ mice than F. tularensis LVS, and mice given a lethal F. novicida dose intraperitoneally died faster than those given the same lethal F. tularensis LVS dose. However, the pattern of in vivo dissemination was similar, and in vitro growth of both bacteria in bone marrow-derived macrophages was comparable. F. novicida LPS stimulated very modest in vitro proliferation of mouse splenocytes at high doses, but F. tularensis LVS LPS did not. Murine bone marrow macrophages treated in vitro with F. novicida LPS produced IL12 and TNF-alpha, but did not produce detectable interferon-gamma, IL10, or nitric oxide; in contrast, murine macrophages treated with F. tularensis LVS LPS produced none of these mediators. In contrast to clear differences in stimulation of proliferation and especially cytokines, both types of purified LPS stimulated early protection against lethal challenge of mice with F. tularensis LVS, but not against lethal challenge with F. novicida. Thus, although LPS recognition may not be a major factor in engendering protection, the ability of F. novicida LPS to stimulate the production of proinflammatory cytokines including TNF-alpha likely contributes to the increased virulence for mice of F. novicida compared to F. tularensis LVS. 相似文献
79.
Mollinari C Reynaud C Martineau-Thuillier S Monier S Kieffer S Garin J Andreassen PR Boulet A Goud B Kleman JP Margolis RL 《Developmental cell》2003,5(2):295-307
Passenger proteins migrate from inner centromeres to the spindle midzone during late mitosis, and those described to date are essential both for proper chromosome segregation and for completion of cell cleavage. We have purified and cloned the human passenger protein TD-60, and we here report that it is a member of the RCC1 family and that it binds preferentially the nucleotide-free form of the small G protein Rac1. Using siRNA, we further demonstrate that the absence of TD-60 substantially suppresses overall spindle assembly, blocks cells in prometaphase, and activates the spindle assembly checkpoint. These defects suggest TD-60 may have a role in global spindle assembly or may be specifically required to integrate kinetochores into the mitotic spindle. The latter is consistent with a TD-60 requirement for recruitment of the passenger proteins survivin and Aurora B, and suggests that like other passenger proteins, TD-60 is involved in regulation of cell cleavage. 相似文献
80.
Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. 总被引:4,自引:0,他引:4
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
F Simonin O Valverde C Smadja S Slowe I Kitchen A Dierich M Le Meur B P Roques R Maldonado B L Kieffer 《The EMBO journal》1998,17(4):886-897
***micro***-, delta- and kappa-opioid receptors are widely expressed in the central nervous system where they mediate the strong analgesic and mood-altering actions of opioids, and modulate numerous endogenous functions. To investigate the contribution of the kappa-opioid receptor (KOR) to opioid function in vivo, we have generated KOR-deficient mice by gene targeting. We show that absence of KOR does not modify expression of the other components of the opioid system, and behavioural tests indicate that spontaneous activity is not altered in mutant mice. The analysis of responses to various nociceptive stimuli suggests that the KOR gene product is implicated in the perception of visceral chemical pain. We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic kappa-agonist U-50, 488H. Finally, our results indicate that this receptor does not contribute to morphine analgesia and reward, but participates in the expression of morphine abstinence. Together, our data demonstrate that the KOR-encoded receptor plays a modulatory role in specific aspects of opioid function. 相似文献