全文获取类型
收费全文 | 238篇 |
免费 | 2篇 |
专业分类
系统科学 | 2篇 |
丛书文集 | 1篇 |
教育与普及 | 1篇 |
理论与方法论 | 10篇 |
现状及发展 | 91篇 |
研究方法 | 28篇 |
综合类 | 103篇 |
自然研究 | 4篇 |
出版年
2018年 | 1篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 3篇 |
2014年 | 4篇 |
2013年 | 4篇 |
2012年 | 14篇 |
2011年 | 17篇 |
2010年 | 5篇 |
2009年 | 1篇 |
2008年 | 12篇 |
2007年 | 8篇 |
2006年 | 17篇 |
2005年 | 20篇 |
2004年 | 11篇 |
2003年 | 7篇 |
2002年 | 17篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1994年 | 2篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1978年 | 2篇 |
1977年 | 7篇 |
1974年 | 4篇 |
1973年 | 5篇 |
1972年 | 1篇 |
1971年 | 5篇 |
1970年 | 3篇 |
1969年 | 2篇 |
1968年 | 6篇 |
1967年 | 2篇 |
1966年 | 3篇 |
1965年 | 3篇 |
1954年 | 1篇 |
1946年 | 1篇 |
排序方式: 共有240条查询结果,搜索用时 31 毫秒
11.
Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site 总被引:7,自引:0,他引:7
Letessier A Millot GA Koundrioukoff S Lachagès AM Vogt N Hansen RS Malfoy B Brison O Debatisse M 《Nature》2011,470(7332):120-123
Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates. 相似文献
12.
The relationships among the living apes and modern humans have effectively been resolved, but it is much more difficult to locate fossil apes on the tree of life because shared skeletal morphology does not always mean shared recent evolutionary history. Sorting fossil taxa into those that belong on the branch of the tree of life that leads to modern humans from those that belong on other closely related branches is a considerable challenge. 相似文献
13.
Gout AM;ADPKD Gene Variant Consortium Ravine D Harris PC Rossetti S Peters D Breuning M Henske EP Koizumi A Inoue S Shimizu Y Thongnoppakhun W Yenchitsomanus PT Deltas C Sandford R Torra R Turco AE Jeffery S Fontes M Somlo S Furu LM Smulders YM Mercier B Ferec C Burtey S Pei Y Kalaydjieva L Bogdanova N McCluskey M Geon LJ Wouters CH Reiterova J Stekrová J San Millan JL Aguiari G Del Senno L 《Nature genetics》2007,39(4):427-428
14.
Golubchik T Brueggemann AB Street T Gertz RE Spencer CC Ho T Giannoulatou E Link-Gelles R Harding RM Beall B Peto TE Moore MR Donnelly P Crook DW Bowden R 《Nature genetics》2012,44(3):352-355
Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases. 相似文献
15.
Roscioli T Kamsteeg EJ Buysse K Maystadt I van Reeuwijk J van den Elzen C van Beusekom E Riemersma M Pfundt R Vissers LE Schraders M Altunoglu U Buckley MF Brunner HG Grisart B Zhou H Veltman JA Gilissen C Mancini GM Delrée P Willemsen MA Ramadža DP Chitayat D Bennett C Sheridan E Peeters EA Tan-Sindhunata GM de Die-Smulders CE Devriendt K Kayserili H El-Hashash OA Stemple DL Lefeber DJ Lin YY van Bokhoven H 《Nature genetics》2012,44(5):581-585
Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates. 相似文献
16.
Bis JC DeCarli C Smith AV van der Lijn F Crivello F Fornage M Debette S Shulman JM Schmidt H Srikanth V Schuur M Yu L Choi SH Sigurdsson S Verhaaren BF DeStefano AL Lambert JC Jack CR Struchalin M Stankovich J Ibrahim-Verbaas CA Fleischman D Zijdenbos A den Heijer T Mazoyer B Coker LH Enzinger C Danoy P Amin N Arfanakis K van Buchem MA de Bruijn RF Beiser A Dufouil C Huang J Cavalieri M Thomson R Niessen WJ Chibnik LB Gislason GK Hofman A Pikula A Amouyel P Freeman KB Phan TG Oostra BA Stein JL 《Nature genetics》2012,44(5):545-551
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. 相似文献
17.
Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses 总被引:8,自引:0,他引:8
RJ O'Connell MR Thon S Hacquard SG Amyotte J Kleemann MF Torres U Damm EA Buiate L Epstein N Alkan J Altmüller L Alvarado-Balderrama CA Bauser C Becker BW Birren Z Chen J Choi JA Crouch JP Duvick MA Farman P Gan D Heiman B Henrissat RJ Howard M Kabbage C Koch B Kracher Y Kubo AD Law MH Lebrun YH Lee I Miyara N Moore U Neumann K Nordström DG Panaccione R Panstruga M Place RH Proctor D Prusky G Rech R Reinhardt JA Rollins S Rounsley CL Schardl DC Schwartz N Shenoy K Shirasu UR Sikhakolli K Stüber 《Nature genetics》2012,44(9):1060-1065
18.
The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity
in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed
several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and
protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses
to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production,
cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been
associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient’s susceptibility
to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders. 相似文献
19.
Kondo Y Shen L Cheng AS Ahmed S Boumber Y Charo C Yamochi T Urano T Furukawa K Kwabi-Addo B Gold DL Sekido Y Huang TH Issa JP 《Nature genetics》2008,40(6):741-750
Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation. 相似文献
20.
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles 总被引:21,自引:0,他引:21
Seal S Thompson D Renwick A Elliott A Kelly P Barfoot R Chagtai T Jayatilake H Ahmed M Spanova K North B McGuffog L Evans DG Eccles D;Breast Cancer Susceptibility Collaboration 《Nature genetics》2006,38(11):1239-1241
We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers. 相似文献