全文获取类型
收费全文 | 137篇 |
免费 | 1篇 |
国内免费 | 2篇 |
专业分类
系统科学 | 4篇 |
理论与方法论 | 7篇 |
现状及发展 | 33篇 |
研究方法 | 25篇 |
综合类 | 66篇 |
自然研究 | 5篇 |
出版年
2021年 | 2篇 |
2018年 | 4篇 |
2017年 | 5篇 |
2016年 | 2篇 |
2015年 | 2篇 |
2014年 | 1篇 |
2013年 | 3篇 |
2012年 | 11篇 |
2011年 | 9篇 |
2010年 | 8篇 |
2009年 | 3篇 |
2008年 | 10篇 |
2007年 | 13篇 |
2006年 | 16篇 |
2005年 | 9篇 |
2004年 | 8篇 |
2003年 | 9篇 |
2002年 | 9篇 |
2001年 | 1篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1988年 | 1篇 |
1985年 | 2篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有140条查询结果,搜索用时 176 毫秒
91.
Mario Vallon Junlei Chang Haijing Zhang Calvin J. Kuo 《Cellular and molecular life sciences : CMLS》2014,71(18):3489-3506
Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases. 相似文献
92.
M Krauthammer Y Kong BH Ha P Evans A Bacchiocchi JP McCusker E Cheng MJ Davis G Goh M Choi S Ariyan D Narayan K Dutton-Regester A Capatana EC Holman M Bosenberg M Sznol HM Kluger DE Brash DF Stern MA Materin RS Lo S Mane S Ma KK Kidd NK Hayward RP Lifton J Schlessinger TJ Boggon R Halaban 《Nature genetics》2012,44(9):1006-1014
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit. 相似文献
93.
Takeda Y Costa S Delamarre E Roncal C Leite de Oliveira R Squadrito ML Finisguerra V Deschoemaeker S Bruyère F Wenes M Hamm A Serneels J Magat J Bhattacharyya T Anisimov A Jordan BF Alitalo K Maxwell P Gallez B Zhuang ZW Saito Y Simons M De Palma M Mazzone M 《Nature》2011,479(7371):122-126
PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders. 相似文献
94.
STAR Consortium Saar K Beck A Bihoreau MT Birney E Brocklebank D Chen Y Cuppen E Demonchy S Dopazo J Flicek P Foglio M Fujiyama A Gut IG Gauguier D Guigo R Guryev V Heinig M Hummel O Jahn N Klages S Kren V Kube M Kuhl H Kuramoto T Kuroki Y Lechner D Lee YA Lopez-Bigas N Lathrop GM Mashimo T Medina I Mott R Patone G Perrier-Cornet JA Platzer M Pravenec M Reinhardt R Sakaki Y Schilhabel M Schulz H Serikawa T Shikhagaie M Tatsumoto S Taudien S Toyoda A Voigt B Zelenika D Zimdahl H Hubner N 《Nature genetics》2008,40(5):560-566
The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies. 相似文献
95.
96.
Bmi1 is expressed in vivo in intestinal stem cells 总被引:1,自引:0,他引:1
Bmi1 plays an essential part in the self-renewal of hematopoietic and neural stem cells. To investigate its role in other adult stem cell populations, we generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. We found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly four cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of beta-catenin in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1(+) cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. These experiments identify Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis. 相似文献
97.
Covadonga Huidobro Agustin F. Fernandez Mario F. Fraga 《Cellular and molecular life sciences : CMLS》2013,70(9):1543-1573
Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein–Taybi syndrome, Coffin–Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease. 相似文献
98.
Bencherif M Lippiello PM Lucas R Marrero MB 《Cellular and molecular life sciences : CMLS》2011,68(6):931-949
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis,
psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated
inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial
changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines
such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting
alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines.
This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7
receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach
could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory
components. 相似文献
99.
Rosy El Ramy Najat Magroun Nadia Messadecq Laurent R. Gauthier François D. Boussin Ullas Kolthur-Seetharam Valérie Schreiber Michael W. McBurney Paolo Sassone-Corsi Françoise Dantzer 《Cellular and molecular life sciences : CMLS》2009,66(19):3219-3234
Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD+-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the
in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late
post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development.
We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either
SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric
heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these
findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone
modifications associated with constitutive heterochromatin integrity. 相似文献
100.
1. Introduction The Analytic Hierarchy Process (AHP) for decision-making uses objective mathematics to process the inescapably subjective and personal preferences of an individual or a group in making a decision. With the AHP, we construct hierarchies that have a first level of strategic or politic criteria, then expand each one of these criteria into more specific subcriteria until reach the terminal criteria, the behavior indicators. Later, makes judgments or performs measurements on pai… 相似文献