全文获取类型
收费全文 | 126篇 |
免费 | 13篇 |
出版年
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 1篇 |
2017年 | 3篇 |
2016年 | 5篇 |
2015年 | 5篇 |
2014年 | 7篇 |
2013年 | 3篇 |
2012年 | 8篇 |
2011年 | 3篇 |
2010年 | 6篇 |
2009年 | 2篇 |
2008年 | 7篇 |
2007年 | 3篇 |
2006年 | 8篇 |
2005年 | 11篇 |
2004年 | 7篇 |
2003年 | 4篇 |
2002年 | 3篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1999年 | 6篇 |
1998年 | 5篇 |
1997年 | 1篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1918年 | 1篇 |
排序方式: 共有139条查询结果,搜索用时 15 毫秒
51.
Cecilia Wieder Clment Frainay Nathalie Poupin Pablo Rodríguez-Mier Florence Vinson Juliette Cooke Rachel PJ Lai Jacob G. Bundy Fabien Jourdan Timothy Ebbels 《PLoS computational biology》2021,17(9)
Over-representation analysis (ORA) is one of the commonest pathway analysis approaches used for the functional interpretation of metabolomics datasets. Despite the widespread use of ORA in metabolomics, the community lacks guidelines detailing its best-practice use. Many factors have a pronounced impact on the results, but to date their effects have received little systematic attention. Using five publicly available datasets, we demonstrated that changes in parameters such as the background set, differential metabolite selection methods, and pathway database used can result in profoundly different ORA results. The use of a non-assay-specific background set, for example, resulted in large numbers of false-positive pathways. Pathway database choice, evaluated using three of the most popular metabolic pathway databases (KEGG, Reactome, and BioCyc), led to vastly different results in both the number and function of significantly enriched pathways. Factors that are specific to metabolomics data, such as the reliability of compound identification and the chemical bias of different analytical platforms also impacted ORA results. Simulated metabolite misidentification rates as low as 4% resulted in both gain of false-positive pathways and loss of truly significant pathways across all datasets. Our results have several practical implications for ORA users, as well as those using alternative pathway analysis methods. We offer a set of recommendations for the use of ORA in metabolomics, alongside a set of minimal reporting guidelines, as a first step towards the standardisation of pathway analysis in metabolomics. 相似文献
52.
BackgroundPeople with severe mental illness (SMI) have higher rates of a range of physical health conditions, yet little is known regarding the clustering of physical health conditions in this population. We aimed to investigate the prevalence and clustering of chronic physical health conditions in people with SMI, compared to people without SMI.Methods and findingsWe performed a cohort-nested accumulated prevalence study, using primary care data from the Clinical Practice Research Datalink (CPRD), which holds details of 39 million patients in the United Kingdom. We identified 68,783 adults with a primary care diagnosis of SMI (schizophrenia, bipolar disorder, or other psychoses) from 2000 to 2018, matched up to 1:4 to 274,684 patients without an SMI diagnosis, on age, sex, primary care practice, and year of registration at the practice. Patients had a median of 28.85 (IQR: 19.10 to 41.37) years of primary care observations. Patients with SMI had higher prevalence of smoking (27.65% versus 46.08%), obesity (24.91% versus 38.09%), alcohol misuse (3.66% versus 13.47%), and drug misuse (2.08% versus 12.84%) than comparators. We defined 24 physical health conditions derived from the Elixhauser and Charlson comorbidity indices and used logistic regression to investigate individual conditions and multimorbidity. We controlled for age, sex, region, and ethnicity and then additionally for health risk factors: smoking status, alcohol misuse, drug misuse, and body mass index (BMI). We defined multimorbidity clusters using multiple correspondence analysis (MCA) and K-means cluster analysis and described them based on the observed/expected ratio. Patients with SMI had higher odds of 19 of 24 conditions and a higher prevalence of multimorbidity (odds ratio (OR): 1.84; 95% confidence interval [CI]: 1.80 to 1.88, p < 0.001) compared to those without SMI, particularly in younger age groups (males aged 30 to 39: OR: 2.49; 95% CI: 2.27 to 2.73; p < 0.001; females aged 18 to 30: OR: 2.69; 95% CI: 2.36 to 3.07; p < 0.001). Adjusting for health risk factors reduced the OR of all conditions. We identified 7 multimorbidity clusters in those with SMI and 7 in those without SMI. A total of 4 clusters were common to those with and without SMI; while 1, heart disease, appeared as one cluster in those with SMI and 3 distinct clusters in comparators; and 2 small clusters were unique to the SMI cohort. Limitations to this study include missing data, which may have led to residual confounding, and an inability to investigate the temporal associations between SMI and physical health conditions.ConclusionsIn this study, we observed that physical health conditions cluster similarly in people with and without SMI, although patients with SMI had higher burden of multimorbidity, particularly in younger age groups. While interventions aimed at the general population may also be appropriate for those with SMI, there is a need for interventions aimed at better management of younger-age multimorbidity, and preventative measures focusing on diseases of younger age, and reduction of health risk factors.In an observational analysis of primary care data from the UK, Naomi Launders and colleagues study the prevalence and clustering of physical health conditions and multimorbidity in individuals with severe mental illnesses. 相似文献
53.
Improved analyses of human mtDNA sequences support a recent African origin for Homo sapiens 总被引:3,自引:1,他引:2
New quantitative methods are applied to the 135 human mitochondrial
sequences from the Vigilant et al. data set. General problems in analyzing
large numbers of short sequences are discussed, and an improved strategy is
suggested. A key feature is to focus not on individual trees but on the
general "landscape" of trees. Over 1,000 searches were made from random
starting trees with only one tree (a local optimum) being retained each
time, thereby ensuring optima were found independently. A new tree
comparison metric was developed that is unaffected by rearrangements of
trees around many very short internal edges. Use of this metric showed that
downweighting hypervariable sites revealed more evolutionary structure than
studies that weighted all sites equally. Our results are consistent with
convergence toward a global optimum. Crucial features are that the best
optima show very strong regional differentiation, a common group of 49
African sequences is found in all the best optima, and the best optima
contain the 16 !Kung sequences in a separate group of San people. The other
86 sequences form a heterogeneous mixture of Africans, Europeans,
Australopapuans, and Asians. Thus all major human lineages occur in Africa,
but only a subset occurs in the rest of the world. The existence of these
African-only groups strongly contradicts multiregional theories for the
origin of Homo sapiens that require widespread migration and interbreeding
over the entire range of H. erectus. Only when the multiregional model is
rejected is it appropriate to consider the root, based on a single locus,
to be the center of origin of a population (otherwise different loci could
give alternative geographic positions for the root). For this data, several
methods locate the root within the group of 49 African sequences and are
thus consistent with the recent African origin of H. sapiens. We
demonstrate that the time of the last common ancestor cannot be the time of
major expansion in human numbers, and our results are thus also consistent
with recent models that differentiate between the last common ancestor,
expansion out of Africa, and the major expansion in human populations. Such
a two-phase model is consistent with a wide range of molecular and
archeological evidence.
相似文献
54.
A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages 总被引:17,自引:13,他引:4
Lockhart PJ; Steel MA; Barbrook AC; Huson DH; Charleston MA; Howe CJ 《Molecular biology and evolution》1998,15(9):1183-1188
The aims of the work were (1) to develop statistical tests to identify
whether substitution takes place under a covariotide model in sequences
used for phylogenetic inference and (2) to determine the influence of
covariotide substitution on phylogenetic trees inferred for photosynthetic
and other organisms. (Covariotide and covarion models are ones in which
sites that are variable in some parts of the underlying tree are invariable
in others and vice versa.) Two tests were developed. The first was a
contingency test, and the second was an inequality test comparing the
expected number of variable sites in two groups with the observed number.
Application of these tests to 16S rDNA and tufA sequences from a range of
nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and
eukaryotes suggests the occurrence of a covariotide mechanism. The degree
of support for partitioning of taxa in reconstructed trees involving these
organisms was determined in the presence or absence of sites showing
particular substitution patterns. This analysis showed that the support for
splits between (1) photosynthetic eukaryotes and prokaryotes and (2)
photosynthetic and nonphotosynthetic organisms could be accounted for by
patterns arising from covariotide substitution. We show that the additional
problem of compositional bias in sequence data needs to be considered in
the context of patterns of covariotide/covarion substitution. We argue that
while covariotide or covarion substitution may give rise to
phylogenetically informative patterns in sequence data, this may not always
be so.
相似文献
55.
56.
Human cytotoxic T cells stimulated by antigen on dendritic cells recognize the N, SH, F, M, 22K, and 1b proteins of respiratory syncytial virus.
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
We examined the human cytotoxic T-cell repertoire of nine adults to 9 of the 10 proteins of respiratory syncytial (RS) virus. Peripheral blood mononuclear cells from normal adults were stimulated with RS virus in vitro. The resulting polyclonal cultures were tested for lysis of B-lymphoblastoid cell lines infected with recombinant vaccinia viruses expressing each of nine individual RS virus proteins. The use of peripheral blood dendritic cells to present antigen gave more easily reproducible results over a shorter culture period than conventional methods. The six RS virus proteins most strongly recognized were the nucleoprotein N (nine of nine donors with greater than 10% above background lysis; P = 0.0004), the surface proteins SH (six of nine donors; P = 0.002) and F (five of nine donors; P = 0.008), the matrix proteins M (five of nine donors; P = 0.004) and 22K (three of nine donors; P = 0.01) and the nonstructural protein 1b (six of nine donors; P = 0.004). There was no significant recognition of the major surface glycoprotein G (two of nine donors), the internal phosphoprotein P (one of nine donors), or the nonstructural protein 1c (one of nine donors). Recognition was major histocompatibility complex class I restricted, but no association between major histocompatibility complex phenotype and protein specificity of T cells was seen. Recognition of F and 22K appeared to be associated with recent infection indicated by increased levels of anti-RS virus immunoglobulin G antibody in serum measured by enzyme-linked immunosorbent assay. Since cytotoxic T-cell recognition of RS virus proteins has been demonstrated to be important in the clearance of virus from infected hosts, the N, M, SH, 1b, F, and 22K proteins should be considered potential vaccine components. 相似文献
57.
Howard WA Bible JM Finlay-Dijsselbloem E Openshaw S Dunn-Walters DK 《Immunogenetics》2005,57(3-4):210-218
The combined processes of immunoglobulin (IG) gene rearrangement and somatic hypermutation allow for the creation of an extremely diverse antibody repertoire. Knowledge of the germline sequence of the IG genes is required so that hypermutation and the affinity matured humoral response can be properly studied. Variable region genes can be arranged into subgroups; in humans, there are 11 IGLV subgroups and six IGKV subgroups. The rhesus macaque (Macaca mulatta) is a relevant non-human primate model for human immunological systems. A number of macaque IGHV, IGHD and IGHJ genes have already been reported, but only one light-chain germline gene has been published so far. Here we report the isolation of new macaque IGKV genes by polymerase chain reaction (PCR) amplification from macaque genomic DNA using primers based on the human sequences. Twenty-eight IGKV1, 22 IGKV2 and 12 IGKV3 germline genes for the macaque were found, the open reading frames of which exhibit high homology to their human counterparts (>96, >99 and >96%, respectively).Supplementary material is available in the online version of this article at .Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under accession numbers AY963709-AY963773.Authors W.A. Howard and J.M. Bible contributed equally to this work. 相似文献
58.
Openshaw AE Race PR Monzó HJ Vázquez-Boland JA Banfield MJ 《The Journal of biological chemistry》2005,280(41):35011-35017
Sphingomyelinases C are enzymes that catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine. Various pathogenic bacteria produce secreted neutral sphingomyelinases C that act as membrane-damaging virulence factors. Mammalian neutral sphingomyelinases C, which display sequence homology to the bacterial enzymes, are involved in sphingolipid metabolism and signaling. This article describes the first structure to be determined for a member of the neutral sphingomyelinase C family, SmcL, from the intracellular bacterial pathogen Listeria ivanovii. The structure has been refined to 1.9-A resolution with phases derived by single isomorphous replacement with anomalous scattering techniques from a single iridium derivative. SmcL adopts a DNase I-like fold, and is the first member of this protein superfamily to have its structure determined that acts as a phospholipase. The structure reveals several unique features that adapt the protein to its phospholipid substrate. These include large hydrophobic beta-hairpin and hydrophobic loops surrounding the active site that may bind and penetrate the lipid bilayer to position sphingomyelin in a catalytically competent position. The structure also provides insight into the proposed general base/acid catalytic mechanism, in which His-325 and His-185 play key roles. 相似文献
59.
TE Willnow C Antignac AW Br?ndli EI Christensen RD Cox D Davidson JA Davies O Devuyst G Eichele ND Hastie PJ Verroust A Schedl IC Meij 《Organogenesis》2005,2(2):42-47
Rapid progress in genome research creates a wealth of information on the functional annotation of mammalian genome sequences. However, as we accumulate large amounts of scientific information we are facing problems of how to integrate and relate the data produced by various genomic approaches. Here, we propose the novel concept of an organ atlas where diverse data from expression maps to histological findings to mutant phenotypes can be queried, compared and visualized in the context of a three-dimensional reconstruction of the organ. We will seek proof of concept for the organ atlas by elucidating genetic pathways involved in development and pathophysiology of the kidney. Such a kidney atlas may provide a paradigm for a new systems-biology approach in functional genome research aimed at understanding the genetic bases of organ development, physiology and disease.Key Words: EuReGene, kidney, genome, development, pathophysiology, genetics 相似文献
60.
Recently, a group of diplomonads has been found to use a genetic code in
which TAA and TAG encode glutamine rather than termination. To survey the
distribution of this characteristic in diplomonads, we sought to identify
TAA and TAG codons at positions where glutamine is expected in genes for
alpha-tubulin, elongation factor-1 alpha, and the gamma subunit of
eukaryotic translation initiation factor-2. These sequences show that the
variant genetic code is utilized by almost all diplomonads, with the genus
Giardia alone using the universal genetic code. Comparative phylogenetic
analysis reveals that the switch to this genetic code took place very early
in the evolution of diplomonads and was likely a single event. Termination
signals and downstream untranslated regions were also cloned from three
Hexamita genes. In all three of these genes, the predicted TGA termination
codon was found at the expected position. Interestingly, the untranslated
regions of these genes are high in AT. This is incongruent with the coding
regions, which are comparatively GC-rich.
相似文献