全文获取类型
收费全文 | 117篇 |
免费 | 8篇 |
专业分类
125篇 |
出版年
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 1篇 |
2016年 | 3篇 |
2015年 | 3篇 |
2014年 | 6篇 |
2013年 | 7篇 |
2012年 | 8篇 |
2011年 | 5篇 |
2010年 | 2篇 |
2009年 | 4篇 |
2008年 | 6篇 |
2007年 | 7篇 |
2006年 | 1篇 |
2005年 | 4篇 |
2004年 | 1篇 |
2002年 | 3篇 |
2000年 | 7篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 7篇 |
1982年 | 1篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1971年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有125条查询结果,搜索用时 15 毫秒
51.
52.
Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia 总被引:3,自引:0,他引:3
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nieuwenhuis E Motoyama J Barnfield PC Yoshikawa Y Zhang X Mo R Crackower MA Hui CC 《Molecular and cellular biology》2006,26(17):6609-6622
Hedgehog (Hh) signaling plays pivotal roles in tissue patterning and development in Drosophila melanogaster and vertebrates. The Patched1 (Ptc1) gene, encoding the Hh receptor, is mutated in nevoid basal cell carcinoma syndrome, a human genetic disorder associated with developmental abnormalities and increased incidences of basal cell carcinoma (BCC) and medulloblastoma (MB). Ptc1 mutations also occur in sporadic forms of BCC and MB. Mutational studies with mice have verified that Ptc1 is a tumor suppressor. We previously identified a second mammalian Patched gene, Ptc2, and demonstrated its distinct expression pattern during embryogenesis, suggesting a unique role in development. Most notably, Ptc2 is expressed in an overlapping pattern with Shh in the epidermal compartment of developing hair follicles and is highly expressed in the developing limb bud, cerebellum, and testis. Here, we describe the generation and phenotypic analysis of Ptc2(tm1/tm1) mice. Our molecular analysis suggests that Ptc2(tm1) likely represents a hypomorphic allele. Despite the dynamic expression of Ptc2 during embryogenesis, Ptc2(tm1/tm1) mice are viable, fertile, and apparently normal. Interestingly, adult Ptc2(tm1/tm1) male animals develop skin lesions consisting of alopecia, ulceration, and epidermal hyperplasia. While functional compensation by Ptc1 might account for the lack of a strong mutant phenotype in Ptc2-deficient mice, our results suggest that normal Ptc2 function is required for adult skin homeostasis. 相似文献
53.
54.
Pieter P. E. van Lierop Sigrid M. Swagemakers Charlotte I. de Bie Sabine Middendorp Peter van Baarlen Janneke N. Samsom Wilfred F. J. van IJcken Johanna C. Escher Peter J. van der Spek Edward E. S. Nieuwenhuis 《PloS one》2013,8(11)
Objective
In current clinical practice, optimal treatment of inflammatory bowel disease (IBD) aims at the induction and maintenance of clinical remission. Clinical remission is apparent when laboratory markers of inflammation are normal and clinical symptoms are absent. However, sub-clinical inflammation can still be present. A detailed analysis of the immune status during this inactive state of disease may provide a useful tool to categorize patients with clinical remission into subsets with variable states of immune activation.Design
By using Affymetrix GeneChips, we analysed RNA gene expression profiles of peripheral blood leukocytes from pediatric IBD patients in clinical remission and controls. We performed (un)supervised clustering analysis of IBD-associated genes and applied Ingenuity® pathway software to identify specific molecular profiles between patients.Results
Pediatric IBD patients with disease in clinical remission display heterogeneously distributed gene expression profiles that are significantly distinct from controls. We identified three clusters of IBD patients, each displaying specific expression profiles of IBD-associated genes.Conclusion
The expression of immune- and IBD-associated genes in peripheral blood leukocytes from pediatric IBD patients in clinical remission was different from healthy controls, indicating that sub-clinical immune mechanisms are still active during remission. As such, RNA profiling of peripheral blood may allow for non-invasive patient subclassification and new perspectives in treatment regimes of IBD patients in the future. 相似文献55.
B-lymphocytes were obtained either by thoracic duct cannulation of thymectomized, irradiated rats or by isolation of complement-receptor-bearing lymphocytes from normal rats. They were labeled in vitro with [3H]-leucine and injected iv into syngeneic recipients from which samples of spleen and lymph node were taken at intervals from 15 min to 48 hr after injection. The sites of initial localisation of B- and T-lymphocytes were identical suggesting that the cells migrated into both organs by a common entrance. The two cell types remained closely associated for several hours in the paracortex of lymph nodes and at the periphery of the periarteriolar lymphoid sheath of the spleen. After 1–6 hr, B-cells segregated from T-cells by moving on into the adjacent part of the lymphocyte corona in the follicular area. By 24 hr, B-cells were evenly distributed throughout the corona. A definite minority of B-cells but no T-cells were seen within the germinal centres. In the spleen, T-cells moved into the central area of the periarteriolar sheath before returning to the blood. The immunological significance of the routes of B- and T-cell migration is discussed. 相似文献
56.
Phosphate starvation derepresses a high-affinity phosphate uptake system in Saccharomyces cerevisiae strain A294, while in the same time the low-affinity phosphate uptake system disappears. The protein synthesis inhibitor cycloheximide prevents the derepression, but has no effect as soon as the high-affinity system is fully derepressed. Two other protein synthesis inhibitors, lomofungin and 8-hydroxyquinoline, were found to interfere also with the low-affinity system and with Rb+ uptake. After incubation of the yeast cells in the presence of phosphate the high-affinity system is not derepressed, but the of the low-affinity system has decreased for about 35%. Phosphate supplement after derepression causes the high-affinity system to disappear to a certain extent while in the meantime the low-affinity system reappears. The results are compared with those found in the yeast Candida tropicalis for phosphate uptake. 相似文献
57.
58.
Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
van Zelm MC Geertsema C Nieuwenhuis N de Ridder D Conley ME Schiff C Tezcan I Bernatowska E Hartwig NG Sanders EA Litzman J Kondratenko I van Dongen JJ van der Burg M 《American journal of human genetics》2008,82(2):320-332
Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions ( approximately 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease. 相似文献
59.
60.
Joppe W. R. Hovius Maarten F. Bijlsma Gerritje J. W. van der Windt W. Joost Wiersinga Bastiaan J. D. Boukens Jeroen Coumou Anneke Oei Regina de Beer Alex F. de Vos Cornelis van 't Veer Alje P. van Dam Penghua Wang Erol Fikrig Marcel M. Levi Joris J. T. H. Roelofs Tom van der Poll 《PLoS pathogens》2009,5(5)
The causative agent of Lyme borreliosis, the spirochete Borrelia
burgdorferi, has been shown to induce expression of the urokinase
receptor (uPAR); however, the role of uPAR in the immune response against
Borrelia has never been investigated. uPAR not only acts as
a proteinase receptor, but can also, dependently or independently of ligation to
uPA, directly affect leukocyte function. We here demonstrate that uPAR is
upregulated on murine and human leukocytes upon exposure to B.
burgdorferi both in vitro as well as in vivo. Notably, B.
burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored
significantly higher Borrelia numbers compared to WT controls.
This was associated with impaired phagocytotic capacity of B.
burgdorferi by uPAR knock-out leukocytes in vitro. B.
burgdorferi numbers in vivo, and phagocytotic capacity in vitro,
were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high
fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in
uPAR knock-out mice partially backcrossed to a B. burgdorferi
susceptible C3H/HeN background, higher B. burgdorferi numbers
were associated with more severe carditis and increased local TLR2 and
IL-1β mRNA expression. In conclusion, in B. burgdorferi
infection, uPAR is required for phagocytosis and adequate eradication of the
spirochete from the heart by a mechanism that is independent of binding of uPAR
to uPA or its role in the fibrinolytic system. 相似文献