首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   194篇
  免费   10篇
  2022年   1篇
  2021年   5篇
  2020年   6篇
  2019年   4篇
  2018年   6篇
  2017年   4篇
  2016年   10篇
  2015年   10篇
  2014年   14篇
  2013年   9篇
  2012年   20篇
  2011年   31篇
  2010年   11篇
  2009年   7篇
  2008年   7篇
  2007年   7篇
  2006年   6篇
  2005年   14篇
  2004年   10篇
  2003年   6篇
  2002年   2篇
  2001年   4篇
  1998年   2篇
  1994年   2篇
  1991年   1篇
  1988年   1篇
  1985年   2篇
  1977年   1篇
  1970年   1篇
排序方式: 共有204条查询结果,搜索用时 31 毫秒
61.
BACKGROUND: Oncolytic adenoviruses show promise in targeting gliomas because they do not replicate in normal brain cells. However, clinical responses occur only in a subset of patients. One explanation could be the heterogenic expression level of virus receptors. Another contributing factor could be variable activity of tumor antiviral defenses in different glioma subtypes. METHODS: We established a collection of primary low-passage cell lines from different glioma subtypes (3 glioblastomas, 3 oligoastrocytomas, and 2 oligodendrogliomas) and assessed them for receptor expression and sensitivity to human adenovirus (HAd) serotypes 3, 5, and 11p. To gauge the impact of antiviral defenses, we also compared the infectivity of the oncolytic adenoviruses in interferon (IFN)-pretreated cells with IFN-sensitive Semliki Forest virus (SFV). RESULTS: Immunostaining revealed generally low expression of HAd5 receptor CAR in both primary tumors and derived cell lines. HAd11p receptor CD46 levels were maintained at moderate levels in both primary tumor samples and derived cell lines. HAd3 receptor DSG-2 was reduced in the cell lines compared to the tumors. Yet, at equal multiplicities of infection, the oncolytic potency of HAd5 in vitro in tumor-derived cells was comparable to HAd11p, whereas HAd3 lysed fewer cells than either of the other two HAd serotypes in 72 hours. IFN blocked replication of SFV, while HAds were rather unaffected. CONCLUSIONS: Adenovirus receptor levels on glioma-derived cell lines did not correlate with infection efficacy and may not be a relevant indicator of clinical oncolytic potency. Adenovirus receptor analysis should be preferentially performed on biopsies obtained perioperatively.  相似文献   
62.
We calculated annual mean stem volume increment (AMSVI) and total litter fall to produce forest net primary production (NPP) maps at 1‐km2 and half‐degree resolutions in Finland and Sweden. We used a multi‐scale methodology to link field inventory data reported at plot and forestry district levels through a remotely sensed total plant biomass map derived from 1‐km2 AVHRR image. Total litter fall was estimated as function of elevation and latitude. Leaf litter fall, a surrogate for fine root production, was estimated from total litter fall by forest type. The gridded NPP estimates agreed well with previously reported NPP values, based on point measurements. Regional NPP increases from northeast to southwest. It is positively related to annual mean temperature and annual mean total precipitation (strongly correlated with temperature) and is negatively related to elevation at broad scale. Total NPP (TNPP) values for representative cells selected based on three criteria were highly correlated with simulated values from a process‐based model (CEVSA) at 0.5°× 0.5° resolution. At 1‐km2 resolution, mean above‐ground NPP in the region was 408 g/m2/yr ranging from 172 to 1091 (standard deviation (SD) = 134). Mean TNPP was 563 (252 to 1426, SD = 176). Ranges and SD were reduced while the mean values of the estimated NPP stayed almost constant as cell size increased from 1‐km2 to 0.5°× 0.5°, as expected. Nordic boreal forests seem to have lower productivity among the world boreal forests.  相似文献   
63.
The timing of the commencement of photosynthesis (P*) in spring is an important determinant of growing‐season length and thus of the productivity of boreal forests. Although controlled experiments have shed light on environmental mechanisms triggering release from photoinhibition after winter, quantitative research for trees growing naturally in the field is scarce. In this study, we investigated the environmental cues initiating the spring recovery of boreal coniferous forest ecosystems under field conditions. We used meteorological data and above‐canopy eddy covariance measurements of the net ecosystem CO2 exchange (NEE) from five field stations located in northern and southern Finland, northern and southern Sweden, and central Siberia. The within‐ and intersite variability for P* was large, 30–60 days. Of the different climate variables examined, air temperature emerged as the best predictor for P* in spring. We also found that ‘soil thaw’, defined as the time when near‐surface soil temperature rapidly increases above 0°C, is not a useful criterion for P*. In one case, photosynthesis commenced 1.5 months before soil temperatures increased significantly above 0°C. At most sites, we were able to determine a threshold for air‐temperature‐related variables, the exceeding of which was required for P*. A 5‐day running‐average temperature (T5) produced the best predictions, but a developmental‐stage model (S) utilizing a modified temperature sum concept also worked well. But for both T5 and S, the threshold values varied from site to site, perhaps reflecting genetic differences among the stands or climate‐induced differences in the physiological state of trees in late winter/early spring. Only at the warmest site, in southern Sweden, could we obtain no threshold values for T5 or S that could predict P* reliably. This suggests that although air temperature appears to be a good predictor for P* at high latitudes, there may be no unifying ecophysiological relationship applicable across the entire boreal zone.  相似文献   
64.
Three different lines of analysis have been applied to approach the problem of the allergenicity of certain proteins: biological functions, molecular structures and immunological properties. It is immediately obvious that these three are interdependent. The lipocalin family of proteins includes a significant number of allergens. A considerable amount of data is already available of lipocalins and some insights about allergenic determinants can now be presented. However, more information on the molecular structures and immunological parameters of lipocalin allergens is required.  相似文献   
65.
The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available.  相似文献   
66.
We studied the effects of restoration on water‐table depth (WTD), element concentrations of peat and vegetation composition of peatlands drained for forestry in southern Finland. The restoration aimed to return the trajectory of vegetation succession toward that of undisturbed systems through the blockage of ditches and the removal of trees. Permanent plots established on a bog and a fen were sampled 1 year before, and 1, 2, 3, and 10 years after the restoration. The restoration resulted in a long‐term rise of the water‐table in both peatlands. Ten years after restoration, the mineral element concentrations (Ca, K, Mg, Mn, and P) of peat corresponded to those reported from comparable pristine peatlands. In particular, the increase of K and Mn concentrations at both sites suggests the recovery of ecosystem functionality in terms of nutrient cycling between peat and plants. The restoration resulted in the succession of plant communities toward the targeted peatland vegetation of wetter condition at both sites. This was evident from the decreased abundance of species benefiting from drainage and the corresponding increase of peatland species. However, many species typical of pristine peatlands were missing 10 years after restoration. We conclude that the restoration led to a reversal of the effects of drainage in vegetation and studied habitat conditions. However, due to the slow recovery of peatland ecosystems and the possibility that certain failures in the restoration measures may become apparent only after extended time periods, long‐term monitoring is needed to determine whether the goals of restoration will be met.  相似文献   
67.
We report the investigation of label-free protein detection directly from lysed cells using microcantilever sensors. The integration of an internally referenced microcantilever sensor combined with peptide aptamer technology enables scalable and label-free detection of proteins from a complex biological environment (e.g. cell lysate). The internally referenced microcantilever sensor was found to be effective in minimizing both the effects of thermal drift and non-specific binding interactions with the backside of the cantilever, thereby allowing protein detection in a complex biological background. Highly specific peptide aptamers are used to modify the cantilever surface to specifically detect less than 80nM CDK2 protein from yeast cell lysate. This binding of CDK2 on the microcantilever generates a tensile surface stress of average magnitude equal to 70+/-22mN/m. Similar experiments conducted with quartz crystal microbalance (QCM) technology are consistent with the response observed using microcantilever sensors.  相似文献   
68.
The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, Aβ42, implicated in Alzheimer disease) in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aβ42 is retarded by DNAJB6 in a concentration-dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry studies suggest that the high inhibitory efficiency is due to the interactions of the chaperone with aggregated forms of Aβ42 rather than the monomeric form of the peptide. This interaction prevents the growth of such species to longer fibrils and inhibits the formation of new amyloid fibrils through both primary and secondary nucleation. A low dissociation rate of DNAJB6 from Aβ42 aggregates leads to its incorporation into growing fibrils and hence to its gradual depletion from solution with time. When DNAJB6 is eventually depleted, fibril proliferation takes place, but the inhibitory activity can be prolonged by introducing DNAJB6 at regular intervals during the aggregation reaction. These results reveal the highly efficacious mode of action of this molecular chaperone against protein aggregation, and demonstrate that the role of molecular chaperones can involve interactions with multiple aggregated species leading to the inhibition of both principal nucleation pathways through which aggregates are able to form.  相似文献   
69.
Genetic diversity is shaped by mutation, genetic drift, gene flow, recombination, and selection. The dynamics and interactions of these forces shape genetic diversity across different parts of the genome, between populations and species. Here, we have studied the effects of linked selection on nucleotide diversity in outcrossing populations of two Brassicaceae species, Arabidopsis lyrata and Capsella grandiflora, with contrasting demographic history. In agreement with previous estimates, we found evidence for a modest population size expansion thousands of generations ago, as well as efficient purifying selection in C. grandiflora. In contrast, the A. lyrata population exhibited evidence for very recent strong population size decline and weaker efficacy of purifying selection. Using multiple regression analyses with recombination rate and other genomic covariates as explanatory variables, we can explain 47% of the variance in neutral diversity in the C. grandiflora population, while in the A. lyrata population, only 11% of the variance was explained by the model. Recombination rate had a significant positive effect on neutral diversity in both species, suggesting that selection at linked sites has an effect on patterns of neutral variation. In line with this finding, we also found reduced neutral diversity in the vicinity of genes in the C. grandiflora population. However, in A. lyrata no such reduction in diversity was evident, a finding that is consistent with expectations of the impact of a recent bottleneck on patterns of neutral diversity near genes. This study thus empirically demonstrates how differences in demographic history modulate the impact of selection at linked sites in natural populations.  相似文献   
70.
All human cells are covered by glycans, the carbohydrate units of glycoproteins, glycolipids, and proteoglycans. Most glycans are localized to cell surfaces and participate in events essential for cell viability and function. Glycosylation evolves during carcinogenesis, and therefore carcinoma-related glycan structures are potential cancer biomarkers. Colorectal cancer is one of the world''s three most common cancers, and its incidence is rising. Novel biomarkers are essential to identify patients for targeted and individualized therapy. We compared the N-glycan profiles of five rectal adenomas and 18 rectal carcinomas of different stages by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Paraffin-embedded tumor samples were deparaffinized, and glycans were enzymatically released and purified. We found differences in glycosylation between adenomas and carcinomas: monoantennary, sialylated, pauci-mannose, and small high-mannose N-glycan structures were more common in carcinomas than in adenomas. We also found differences between stage I–II and stage III carcinomas. Based on these findings, we selected two glycan structures: pauci-mannose and sialyl Lewis a, for immunohistochemical analysis of their tissue expression in 220 colorectal cancer patients. In colorectal cancer, poor prognosis correlated with elevated expression of sialyl Lewis a, and in advanced colorectal cancer, poor prognosis correlated with elevated expression of pauci-mannose. In conclusion, by mass spectrometry we found several carcinoma related glycans, and we demonstrate a method of transforming these results into immunohistochemistry, a readily applicable method to study biomarker expression in patient samples.Glycans, the carbohydrate units of glycoproteins, glycolipids, and proteoglycans, that cover all human cells. Around 1% of the human genome participates in the biosynthesis of glycans(1). This biosynthesis is the most complex post-translational modification of proteins, and the great variability in glycan structures contains a tremendous ability to fine-tune the chemical and biological properties of glycoproteins. The glycosylation process occurs most abundantly in the Golgi apparatus and the endoplasmic reticulum, but also occurs in the cytoplasm and nucleus (2). Most glycoconjugates are localized to cell surfaces, where glycans participate in events essential for cell viability and function, such as cell adhesion, motility, and intracellular signaling (2). Changes in these functions are key steps seen when normal cells transform to malignant ones, and these are also reflected in changes of a cell''s glycan profile, observed in many cancers (3, 4). Specific structural changes in glycans may serve as cancer biomarkers (5, 6), and changes in glycosylation profiles are related to aggressive behavior in tumor cells (79).Cancer-associated asparagine-linked glycan (N-glycan) structures may play specific roles in supporting tumor progression; growth (10, 11), invasion (12, 13), and angiogenesis (14). Changes in the N-glycan profile emerge in numerous cancers, including lung (15, 16), breast (17), and colorectal cancer (CRC)1 (16, 18). Balog et al. (18) comparing the N-glycomic profile of CRC tissue to adjacent normal mucosa, reported differences in specific glycan structures. Moreover, serum N-glycosylation profile from patients with CRC differ from those of healthy controls (19).Colorectal cancer is the third most common cause of cancer-related death worldwide and its incidence is rising; 40% of CRCs are of rectal origin. Roughly 40% of patients have localized disease (stage I–II; Dukes A–B), another 40% loco regional disease (stage III; Dukes C), and 20% metastasized disease (stage IV; Dukes D) (20). Although stage at diagnosis is the most important factor determining prognosis, clinical outcome, and response to adjuvant treatment can markedly vary within each stage. Adjuvant therapy routinely goes to stage III patients, but the benefit of adjuvant treatment for stage II patients is unclear. Of stage II patients, 80% are cured by radical surgery alone. To identify patients who will benefit from postoperative treatment, we need novel biomarkers. The glycan profile of the tumor tissue could provide new biomarkers for diagnosis and prognosis of cancer.In this study, we characterized the N-glycomic profiles of rectal adenomas and carcinomas by MALDI-TOF mass spectrometric (MS) profiling of asparagine-linked glycans. Our aim was to identify differences between adenomas and carcinomas, and also between cancers of different stages. Based on glycan profiling, we also chose, for immunohistochemical expression studies of a series of 220 CRC patients, two glycan markers: sialyl Lewis a and pauci-mannose.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号