全文获取类型
收费全文 | 143篇 |
免费 | 10篇 |
专业分类
153篇 |
出版年
2022年 | 3篇 |
2021年 | 1篇 |
2019年 | 2篇 |
2018年 | 1篇 |
2017年 | 1篇 |
2016年 | 6篇 |
2015年 | 10篇 |
2014年 | 10篇 |
2013年 | 9篇 |
2012年 | 12篇 |
2011年 | 14篇 |
2010年 | 4篇 |
2009年 | 5篇 |
2008年 | 6篇 |
2007年 | 8篇 |
2006年 | 6篇 |
2005年 | 5篇 |
2004年 | 3篇 |
2003年 | 8篇 |
2002年 | 1篇 |
2001年 | 1篇 |
2000年 | 3篇 |
1999年 | 2篇 |
1998年 | 4篇 |
1996年 | 1篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1985年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1971年 | 4篇 |
1969年 | 2篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1924年 | 1篇 |
1923年 | 1篇 |
1921年 | 1篇 |
排序方式: 共有153条查询结果,搜索用时 0 毫秒
101.
Bilal E Vassallo K Toppmeyer D Barnard N Rye IH Almendro V Russnes H Børresen-Dale AL Levine AJ Bhanot G Ganesan S 《PloS one》2012,7(6):e38575
Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3-63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% -97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers. 相似文献
102.
The timing of alpha-gustducin expression during cell renewal in rat vallate taste buds 总被引:2,自引:2,他引:0
The G protein subunit alpha-gustducin is expressed in a subset of light
(Type II) but not in dark (Type I) cells in rat vallate taste buds. The
thymidine analogue 5-bromo-2'-deoxyuridine (BrdU) is incorporated into DNA
during the S-phase of the cell cycle and can be used to determine the time
of origin of a cell. In this study, 31 rats were injected with BrdU (50
mg/kg i.p.) and perfused at various times, from 2.5 to 10.5 days, following
BrdU administration. Vallate papillae were embedded in polyester wax, cut
into 4 microm transverse sections, and characterized with antibodies to
BrdU and alpha-gustducin. Sections were processed for indirect
immunofluorescence or with an immunoperoxidase procedure. From
immunoperoxidase material on 21 rats, counts of alpha-gustducin- and
BrdU-labeled cells were obtained from 300-800 taste bud profiles at each
survival time; a total of 4122 taste bud profiles were examined. Cells with
nuclei immunoreactive for BrdU occurred within the taste buds at 2.5 days
and double-labeled cells were clearly evident at 3.5 days; a small number
of double-labeled cells were seen as early as 2.5 days. Double-labeled
cells reached a peak at 6.5 days and did not decline significantly by 10.5
days. Cells labeled for BrdU but not alpha-gustducin peaked at 5.5 days and
showed a significant decline by 8.5 days. These latter cells included light
cells not expressing alpha- gustducin and dark cells, which have previously
been shown to have a shorter life span than light cells. These data suggest
that expression of alpha-gustducin appears very early in a cell's life span
and that these cells are longer lived than many of the cells that do not
express this G protein.
相似文献
103.
Tonic GABAergic inhibition of taste-responsive neurons in the nucleus of the solitary tract 总被引:4,自引:1,他引:3
The effects of gamma-aminobutyric acid (GABA) and the GABAA receptor
antagonist bicuculline methiodide (BICM) on the activity of taste-
responsive neurons in the nucleus of the solitary tract (NST) were examined
electrophysiologically in urethane-anesthetized hamsters. Single neurons in
the NST were recorded extracellularly and drugs (21 nl) were microinjected
into the vicinity of the cell via a multibarrel pipette. The response of
each cell was recorded to lingual stimulation with 0.032 M NaCl, 0.032 M
sucrose, 0.0032 M citric acid and 0.032 M quinine hydrochloride (QHCl).
Forty-six neurons were tested for the effects of GABA; the activity of 29
cells (63%) was inhibited by 5 mM GABA. Whether activity was elicited in
these cells by repetitive anodal current stimulation (25 microA, 0.5 s, 0.1
Hz) of the tongue (n = 13 cells) or the cells were spontaneously active (n
= 13 cells), GABA produced a dose-dependent (1, 2 and 5 mM) decrement in
activity. Forty- seven NST neurons were tested for the effects of BICM on
their responses to chemical stimulation of the tongue; the responses of 28
cells (60%) were enhanced by 10 mM BICM. The gustatory responses of 26 of
these cells were tested with three concentrations (0.2, 2 and 10 mM) of
BICM, which produced a dose-dependent increase in both spontaneous activity
and taste-evoked responses. Nine of these neurons were sucrose- best, seven
were NaCl-best, eight were acid-best and two responded best to QHCl. The
responses to all four tastants were enhanced, with no difference among
neuron types. For 18 cells that were tested with two or more gustatory
stimuli, BICM increased their breadth of responsiveness to their two most
effective stimuli. These data show that approximately 60% of the
taste-responsive neurons in the rostral NST are inhibited by GABA and/or
subject to a tonic inhibitory influence, which is mediated by GABAA
receptors. The modulation of these cells by GABA provides a mechanism by
which the breadth of tuning of the cell can be sharpened. Modulation of
gustatory activity following a number of physiological changes could be
mediated by such a GABAergic circuit.
相似文献
104.
The silver impregnation method of Grimelius has been applied to 100-150 μ thick sections of tissues fixed 2 hr to 1 mo in mixtures containing formaldehyde, glutaraldehyde or picric acid. After silvering, the sections (partly postfixed in 1% OsO4, for 0.5 hr) were processed for electron microscopy. Endocrine granules of pancreatic A cells, enter-ochromaffin and some nonenterochromaffin cells of the gastrointestinal mucosa, thyroid C cells and adrenal medullary cells were found to be selectively stained by silver grains 10-30 nm in diameter, either as a peripheral “halo” or covering the entire granule. At least in some cells, the reactive material should not be identified with the hormonal products known to be stored in the granules. 相似文献
105.
A blocking monoclonal antibody to endothelial-leukocyte adhesion molecule-1 (ELAM1). 总被引:4,自引:0,他引:4
C Benjamin I Dougas G Chi-Rosso S Luhowskyj M Rosa B Newman L Osborn C Vassallo C Hession S Goelz 《Biochemical and biophysical research communications》1990,171(1):348-353
ELAM1 is a leukocyte adhesion molecule induced on human umbilical vein endothelial cells (HUVECs) by inflammatory cytokines. Balb/C mice were immunized with COS cells transiently expressing cell-surface ELAM1 after transfection with ELAM1 cDNA. After fusion, ELAM1-specific monoclonal antibodies (Mabs) were identified by selective adhesion to ELAM1-expressing, but not control, CHO cells, and to cytokine-treated but not untreated HUVECs. One Mab, designated BB11, binds to and immunoprecipitates ELAM1 expressed on HUVECs, COS and CHO cells. BB11 blocks the interaction of ELAM1 with human PMN, the human myelomonocytic cell line HL60, and the human colon carcinoma line HT29. 相似文献
106.
Krebs B Wiebelitz A Balitzki-Korte B Vassallo N Paluch S Mitteregger G Onodera T Kretzschmar HA Herms J 《Journal of neurochemistry》2007,100(2):358-367
The physiological function of the cellular prion protein (PrP(C)) is still under intense investigation. It has been suggested that PrP(C) has a protective role in neuronal cells, particularly against environmental stress caused by reactive oxygen species (ROS). Here we analysed the acute effect of a major ROS, hydrogen peroxide (H(2)O(2)), on intracellular calcium homeostasis in cultured cerebellar granule cells and immortalized hippocampal neuronal cells. Both neuronal cell culture models showed that the rise in intracellular calcium following application of H(2)O(2) was strongly dependent on the presence of PrP(C). Moreover, the N-terminal octapeptide repeats of PrP(C) were required for this effect, because neuronal cells expressing a PrP(C) lacking the N-terminus resembled the PrP(C)-deficient phenotype. Neurones deficient of fyn kinase, or pharmacological inhibition of fyn, also abrogated the calcium response to H(2)O(2) treatment, indicating that fyn activation is a critical step within the PrP(C) signalling cascade. Finally, we identified a possible role of this PrP(C) signalling pathway in the neuroprotective response of PrP(C) to oxidative stress. In conclusion, we put forward the hypothesis that PrP(C) functions as a sensor for H(2)O(2), thereby activating a protective signalling cascade involving fyn kinase that leads to calcium release from intracellular stores. 相似文献
107.
Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content 总被引:3,自引:0,他引:3
Hamid R Kilger E Willem M Vassallo N Kostka M Bornhövd C Reichert AS Kretzschmar HA Haass C Herms J 《Journal of neurochemistry》2007,102(4):1264-1275
Consecutive cleavages of amyloid precursor protein (APP) generate APP intracellular domain (AICD). Its cellular function is still unclear. In this study, we investigated the functional role of AICD in cellular Ca(2+) homeostasis. We could confirm previous observations that endoplasmic reticulum Ca(2+) stores contain less calcium in cells with reduced APP gamma-secretase cleavage products, increased AICD degradation, reduced AICD expression or in cells lacking APP. In addition, we observed an enhanced resting cytosolic calcium concentration under conditions where AICD is decreased or missing. In view of the reciprocal effects of Ca(2+) on mitochondria and of mitochondria on Ca(2+) homeostasis, we analysed further the cellular ATP content and the mitochondrial membrane potential. We observed a reduced ATP content and a mitochondrial hyperpolarisation in cells with reduced amounts of AICD. Blockade of mitochondrial oxidative phosphorylation chain in control cells lead to similar alterations as in cells lacking AICD. On the other hand, substrates of Complex II rescued the alteration in Ca(2+) homeostasis in cells lacking AICD. Based on these observations, our findings indicate that alterations observed in endoplasmic reticulum Ca(2+) storage in cells with reduced amounts of AICD are reciprocally linked to mitochondrial bioenergetic function. 相似文献
108.
109.
110.
Prion protein induced signaling cascades in monocytes 总被引:4,自引:0,他引:4
Krebs B Dorner-Ciossek C Schmalzbauer R Vassallo N Herms J Kretzschmar HA 《Biochemical and biophysical research communications》2006,340(1):13-22
Prion proteins play a central role in transmission and pathogenesis of transmissible spongiform encephalopathies. The cellular prion protein (PrP(C)), whose physiological function remains elusive, is anchored to the surface of a variety of cell types including neurons and cells of the lymphoreticular system. In this study, we investigated the response of a mouse monocyte/macrophage cell line to exposure with PrP(C) fusion proteins synthesized with a human Fc-tag. PrP(C) fusion proteins showed an attachment to the surface of monocyte/macrophages in nanomolar concentrations. This was accompanied by an increase of cellular tyrosine phosphorylation as a result of activated signaling pathways. Detailed investigations exhibited activation of downstream pathways through a stimulation with PrP fusion proteins, which include phosphorylation of ERK(1,2) and Akt kinase. Macrophages opsonize and present antigenic structures, contact lymphocytes, and deliver cytokines. The findings reported here may become the basis of understanding the molecular function of PrP(C) in monocytes and macrophages. 相似文献