全文获取类型
收费全文 | 722篇 |
免费 | 60篇 |
国内免费 | 11篇 |
出版年
2023年 | 4篇 |
2022年 | 13篇 |
2021年 | 16篇 |
2020年 | 4篇 |
2019年 | 2篇 |
2018年 | 10篇 |
2017年 | 9篇 |
2016年 | 29篇 |
2015年 | 87篇 |
2014年 | 63篇 |
2013年 | 63篇 |
2012年 | 110篇 |
2011年 | 97篇 |
2010年 | 47篇 |
2009年 | 29篇 |
2008年 | 29篇 |
2007年 | 25篇 |
2006年 | 21篇 |
2005年 | 25篇 |
2004年 | 18篇 |
2003年 | 18篇 |
2002年 | 29篇 |
2001年 | 11篇 |
2000年 | 6篇 |
1999年 | 1篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1988年 | 2篇 |
1986年 | 1篇 |
1984年 | 4篇 |
1976年 | 1篇 |
1945年 | 1篇 |
1923年 | 1篇 |
排序方式: 共有793条查询结果,搜索用时 31 毫秒
131.
Field D Garrity GM Sansone SA Sterk P Gray T Kyrpides N Hirschman L Glöckner FO Kottmann R Angiuoli S White O Dawyndt P Thomson N Gil IS Morrison N Tatusova T Mizrachi I Vaughan R Cochrane G Kagan L Murphy S Schriml L;Genomic Standards Consortium 《Omics : a journal of integrative biology》2008,12(2):109-113
132.
133.
Maximum-likelihood estimation of site-specific mutation rates in human mitochondrial DNA from partial phylogenetic classification 下载免费PDF全文
Rosset S Wells RS Soria-Hernanz DF Tyler-Smith C Royyuru AK Behar DM;Genographic Consortium 《Genetics》2008,180(3):1511-1524
The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function. We develop inference and bias correction tools for our estimates and a hypothesis-testing approach for site independence. We demonstrate our methodology using 16,609 HVS-I samples from the Genographic Project. Our results suggest that mutation rates among nucleotide sites in HVS-I are highly variable. The 16,400–16,500 region exhibits significantly lower rates compared to other regions, suggesting potential functional constraints. Several loci identified in the literature as possible termination-associated sequences (TAS) do not yield statistically slower rates than the rest of HVS-I, casting doubt on their functional importance. Our tests do not reject the null hypothesis of independent mutation rates among nucleotide sites, supporting the use of site-independence assumption for analyzing HVS-I. Potential extensions of our methodology include its application to estimation of mutation rates in other genetic regions, like Y chromosome short tandem repeats. 相似文献
134.
Complete DNA sequence and gene analysis of the virulence plasmid pCP301 of Shigella flexneri 2a 总被引:2,自引:0,他引:2
Bacteria Shigella spp. are highly contagious, severely harmful and gram-negative facultative intracellular pathogens. They may cause shigellosis characterized by fever, dehydration and hematochezia in clinic, and shigellosis has been remaining a leading cause of infant mortality in the world. Shigella belongs to the family Enterobacteriaceae and the group Escherichiaeae, which are divided into four species and at least 47 serotypes: Shigella dysenteriae (13 serotypes), Shigella flexneri (15 … 相似文献
135.
F. C. Connell P. Ostergaard C. Carver G. Brice N. Williams S. Mansour P. S. Mortimer Steve Jeffery Lymphoedema Consortium 《Human genetics》2009,124(6):625-631
Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant
inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease.
This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary
lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with
no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated
that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if
positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood
of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (<5%). For the 22 mutation
positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included
in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful
for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no
mutations were identified.
F. C. Connell and P. Ostergaard contributed equally to this work.
An erratum to this article can be found at 相似文献
136.
Atkinson KR Blumenstein M Black MA Wu SH Kasabov N Taylor RS Cooper GJ North RA;SCOPE Consortium 《Journal of lipid research》2009,50(1):71-80
Preeclampsia is a common pregnancy complication that is an important cause of preterm birth and fetal growth restriction. Because there is no diagnostic test yet available for preeclampsia, we used a proteomic approach to identify novel serum/plasma biomarkers for this condition. We conducted case control studies comparing nulliparous women who developed preeclampsia at 36-38 weeks of gestation with healthy nulliparous women matched by gestational age at sampling. Serum/plasma was depleted of six abundant proteins and analyzed by two-dimensional gel electrophoresis (n = 12 per group) and difference gel electrophoresis (n = 12 per group). Differences in abundance of protein spots were detected by univariate and multivariate statistical analyses. Proteins were identified by mass spectrometry and expression of selected proteins was validated by immunoblotting. Proteins whose concentrations were selectively associated with preeclampsia included apolipoprotein E (apoE), apoC-II, complement factor C3c, fibrinogen, transthyretin, and complement factor H-related protein 2. An increase in a deglycosylated isoform of apoE3 and concomitantly decreased amounts of one apoE3 glycoisoform were identified in preeclamptic plasma and confirmed by immunoblotting. Altered production of these preeclampsia-related apoE3 isoforms might impair reverse cholesterol transport, contributing to arterial damage. These findings point to a novel mechanistic link between preeclampsia and subsequent cardiovascular disease. 相似文献
137.
Chris I. Jones Stephen F. Garner William J. Kaiser Bloodomics Consortium Alison H. Goodall 《FEBS letters》2009,583(22):3618-3624
Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits platelet response to collagen and may also inhibit two other major platelet agonists ADP and thrombin although this has been less well explored. We hypothesized that the combined effect of inhibiting these three platelet activating pathways may act to significantly inhibit thrombus formation. We demonstrate a negative relationship between PECAM-1 surface expression and platelet response to cross-linked collagen related peptide (CRP-XL) and ADP, and an inhibitory effect of PECAM-1 clustering on platelet response to CRP-XL, ADP and thrombin. This combined inhibition of multiple signaling pathways results in a marked reduction in thrombus formation. 相似文献
138.
Lee Ratner William Harrington Xuan Feng Christian Grant Steve Jacobson Ariela Noy Joseph Sparano Jeannette Lee Richard Ambinder Nancy Campbell Michael Lairmore for the AIDS Malignancy Consortium 《PloS one》2009,4(2)
Background
Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.Methods and Findings
We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression.Conclusions
EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.Trial Registration
ClinicalTrials.gov NCT00041327相似文献139.
Lauren M. Uhler Nagalingeswaran Kumarasamy Kenneth H. Mayer Anjali Saxena Elena Losina Malaisamy Muniyandi Adam W. Stoler Zhigang Lu Rochelle P. Walensky Timothy P. Flanigan Melissa A. Bender Kenneth A. Freedberg Soumya Swaminathan for the CEPAC International investigators 《PloS one》2010,5(9)
Background
Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India.Methods and Findings
We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy.Conclusions
Referral of all patients with active TB in India for HIV testing will be both effective and cost-effective. While effective implementation of this strategy would require investment, routine, voluntary HIV testing of TB patients in India should be recommended. 相似文献140.
Rose G Romeo G Dato S Crocco P Bruni AC Hervonen A Majamaa K Sevini F Franceschi C Passarino G;GEnetics of Healthy Ageing Project Consortium 《PloS one》2010,5(10):e13395
Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions. 相似文献