全文获取类型
收费全文 | 261篇 |
免费 | 25篇 |
出版年
2023年 | 2篇 |
2021年 | 2篇 |
2019年 | 2篇 |
2018年 | 3篇 |
2017年 | 3篇 |
2016年 | 7篇 |
2015年 | 4篇 |
2014年 | 5篇 |
2013年 | 19篇 |
2012年 | 34篇 |
2011年 | 14篇 |
2010年 | 10篇 |
2009年 | 4篇 |
2008年 | 14篇 |
2007年 | 15篇 |
2006年 | 15篇 |
2005年 | 12篇 |
2004年 | 10篇 |
2003年 | 8篇 |
2002年 | 11篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1970年 | 1篇 |
1966年 | 1篇 |
1963年 | 1篇 |
1962年 | 2篇 |
1961年 | 1篇 |
1958年 | 1篇 |
1953年 | 1篇 |
排序方式: 共有286条查询结果,搜索用时 31 毫秒
81.
AbstractAn assemblage of microfossils consisting of non-marine ostracods (Cypridopsis, Gomphocythere, Zonocypris, Eucypris, and Frambocythere), charophyte gyrogonites (Platychara), molluscs (Viviparus, Valvata, and Lymnaea), and fish remains (mainly Phareodus), is here reported from a new intertrappean locality near the town of Manawar, District Dhar, Madhya Pradesh, Central India. The biotic component recovered suggests a Late Cretaceous (Maastrichtian) age for the intertrappean deposit near Manawar. Paleoenvironmentally, the overall biotic assemblage recovered indicates the presence of a freshwater palustrine/lacustrine depositional system connected to a low energy stream/river. Paleobiogeographically, the known high diversity of ostracod genera, especially Eucypris, Cypridopsis, and Gomphocythere, hints at endemism within the Indian Subcontinent during the Late Cretaceous (Maastrichtian). However, the cosmopolitan distribution of the charophyte genus Platychara in the K-Pg interval across the globe (Africa, Europe, and America) and its absence in the Upper Cretaceous of China and Mongolia is quite intriguing. 相似文献
82.
83.
Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins 总被引:1,自引:0,他引:1
Li Y Yan J De P Chang HC Yamauchi A Christopherson KW Paranavitana NC Peng X Kim C Munugalavadla V Munugulavadla V Kapur R Chen H Shou W Stone JC Kaplan MH Dinauer MC Durden DL Quilliam LA 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(12):8322-8331
The Ras-related GTPases Rap1a and 1b have been implicated in multiple biological events including cell adhesion, free radical production, and cancer. To gain a better understanding of Rap1 function in mammalian physiology, we deleted the Rap1a gene. Although loss of Rap1a expression did not initially affect mouse size or viability, upon backcross into C57BL/6J mice some Rap1a-/- embryos died in utero. T cell, B cell, or myeloid cell development was not disrupted in Rap1a-/- mice. However, macrophages from Rap1a null mice exhibited increased haptotaxis on fibronectin and vitronectin matrices that correlated with decreased adhesion. Chemotaxis of lymphoid and myeloid cells in response to CXCL12 or CCL21 was significantly reduced. In contrast, an increase in FcR-mediated phagocytosis was observed. Because Rap1a was previously copurified with the human neutrophil NADPH oxidase, we addressed whether GTPase loss affected superoxide production. Neutrophils from Rap1a-/- mice had reduced fMLP-stimulated superoxide production as well as a weaker initial response to phorbol ester. These results suggest that, despite 95% amino acid sequence identity, similar intracellular distribution, and broad tissue distribution, Rap1a and 1b are not functionally redundant but rather differentially regulate certain cellular events. 相似文献
84.
Kristi L. Norris Rui Hao Liang-Fu Chen Chun-Hsiang Lai Meghan Kapur Peter J. Shaughnessy Dennis Chou Jin Yan J. Paul Taylor Simone Engelender Anna E. West Kah-Leong Lim Tso-Pang Yao 《The Journal of biological chemistry》2015,290(22):13862-13874
Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining mitochondrial integrity and suppressing Parkinsonism. Here, we report that under moderate mitochondrial stress, parkin does not translocate to mitochondria to induce mitophagy; rather, it stimulates mitochondrial connectivity. Mitochondrial stress-induced fusion requires PINK1 (PARK6), mitofusins, and parkin ubiquitin ligase activity. Upon exposure to mitochondrial toxins, parkin binds α-synuclein (PARK1), and in conjunction with the ubiquitin-conjugating enzyme Ubc13, stimulates K63-linked ubiquitination. Importantly, α-synuclein inactivation phenocopies parkin overexpression and suppresses stress-induced mitochondria fission, whereas Ubc13 inactivation abrogates parkin-dependent mitochondrial fusion. The convergence of parkin, PINK1, and α-synuclein on mitochondrial dynamics uncovers a common function of these PARK genes in the mitochondrial stress response and provides a potential physiological basis for the prevalence of α-synuclein pathology in Parkinson disease. 相似文献
85.
86.
87.
Katherine E. Tansey Michel Guipponi Nader Perroud Guido Bondolfi Enrico Domenici David Evans Stephanie K. Hall Joanna Hauser Neven Henigsberg Xiaolan Hu Borut Jerman Wolfgang Maier Ole Mors Michael O'Donovan Tim J. Peters Anna Placentino Marcella Rietschel Daniel Souery Katherine J. Aitchison Ian Craig Anne Farmer Jens R. Wendland Alain Malafosse Peter Holmans Glyn Lewis Cathryn M. Lewis Tine Bryan Stensb?l Shitij Kapur Peter McGuffin Rudolf Uher 《PLoS medicine》2012,9(10)
Background
It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.Methods and Findings
The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10−8). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10−8) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.Conclusions
No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors'' Summary 相似文献88.
Ryan M. McAdams Jeroen Vanderhoeven Richard P. Beyer Theo K. Bammler Federico M. Farin H. Denny Liggitt Raj P. Kapur Michael G. Gravett Craig E. Rubens Kristina M. Adams Waldorf 《PloS one》2012,7(10)
Background
Intrauterine exposure to amniotic fluid (AF) cytokines is thought to predispose to bronchopulmonary dysplasia (BPD). We evaluated the effects of GBS exposure on RNA expression in fetal lung tissue to determine early molecular pathways associated with fetal lung injury that may progress to BPD.Methods
Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n = 5) or 2) saline (n = 5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.Results
Despite uterine quiescence in most cases, fetal lung injury occurred in four GBS cases (intra-alveolar neutrophils, interstitial thickening) and one control (peri-mortem hemorrhage). Significant elevations of AF cytokines (TNF-α, IL-8, IL-1β, IL-6) were detected in GBS versus controls (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable by culture and PCR in the AF and fetal lungs. A total of 335 genes were differentially expressed greater than 1.5 fold (p<0.05) with GBS exposure associated with a striking upregulation of genes in innate and adaptive immunity and downregulation of pathways for angiogenesis, morphogenesis, and cellular growth and development.Conclusions
A transient choriodecidual infection may induce fetal lung injury with profound alterations in the genetic program of the fetal lung before signs of preterm labor. Our results provide a window for the first time into early molecular pathways disrupting fetal lung angiogenesis and morphogenesis before preterm labor occurs, which may set the stage for BPD. A strategy to prevent BPD should target the fetus in utero to attenuate alterations in the fetal lung genetic program. 相似文献89.
In this study, we present pituitary adenoma volumetry using the free and open source medical image computing platform for biomedical research: (3D) Slicer. Volumetric changes in cerebral pathologies like pituitary adenomas are a critical factor in treatment decisions by physicians and in general the volume is acquired manually. Therefore, manual slice-by-slice segmentations in magnetic resonance imaging (MRI) data, which have been obtained at regular intervals, are performed. In contrast to this manual time consuming slice-by-slice segmentation process Slicer is an alternative which can be significantly faster and less user intensive. In this contribution, we compare pure manual segmentations of ten pituitary adenomas with semi-automatic segmentations under Slicer. Thus, physicians drew the boundaries completely manually on a slice-by-slice basis and performed a Slicer-enhanced segmentation using the competitive region-growing based module of Slicer named GrowCut. Results showed that the time and user effort required for GrowCut-based segmentations were on average about thirty percent less than the pure manual segmentations. Furthermore, we calculated the Dice Similarity Coefficient (DSC) between the manual and the Slicer-based segmentations to proof that the two are comparable yielding an average DSC of 81.97±3.39%. 相似文献
90.
F Traina V Visconte AM Jankowska H Makishima CL O'Keefe P Elson Y Han FH Hsieh MA Sekeres RS Mali M Kalaycio AE Lichtin AS Advani HK Duong E Copelan R Kapur ST Olalla Saad JP Maciejewski RV Tiu 《PloS one》2012,7(8):e43090
We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients. 相似文献