全文获取类型
收费全文 | 208篇 |
免费 | 22篇 |
出版年
2021年 | 3篇 |
2018年 | 3篇 |
2015年 | 4篇 |
2014年 | 3篇 |
2013年 | 4篇 |
2012年 | 2篇 |
2011年 | 5篇 |
2010年 | 3篇 |
2009年 | 3篇 |
2008年 | 4篇 |
2007年 | 6篇 |
2006年 | 6篇 |
2005年 | 12篇 |
2004年 | 10篇 |
2003年 | 3篇 |
2002年 | 6篇 |
2001年 | 6篇 |
2000年 | 6篇 |
1999年 | 4篇 |
1998年 | 11篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 6篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 7篇 |
1987年 | 8篇 |
1986年 | 7篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 8篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1970年 | 4篇 |
1969年 | 3篇 |
1968年 | 5篇 |
1967年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有230条查询结果,搜索用时 31 毫秒
111.
The genome of Rhizobium leguminosarum has recognizable core and accessory components 总被引:3,自引:0,他引:3
Young JP Crossman LC Johnston AW Thomson NR Ghazoui ZF Hull KH Wexler M Curson AR Todd JD Poole PS Mauchline TH East AK Quail MA Churcher C Arrowsmith C Cherevach I Chillingworth T Clarke K Cronin A Davis P Fraser A Hance Z Hauser H Jagels K Moule S Mungall K Norbertczak H Rabbinowitsch E Sanders M Simmonds M Whitehead S Parkhill J 《Genome biology》2006,7(4):R34-20
Background
Rhizobium leguminosarum is an α-proteobacterial N2-fixing symbiont of legumes that has been the subject of more than a thousand publications. Genes for the symbiotic interaction with plants are well studied, but the adaptations that allow survival and growth in the soil environment are poorly understood. We have sequenced the genome of R. leguminosarum biovar viciae strain 3841.Results
The 7.75 Mb genome comprises a circular chromosome and six circular plasmids, with 61% G+C overall. All three rRNA operons and 52 tRNA genes are on the chromosome; essential protein-encoding genes are largely chromosomal, but most functional classes occur on plasmids as well. Of the 7,263 protein-encoding genes, 2,056 had orthologs in each of three related genomes (Agrobacterium tumefaciens, Sinorhizobium meliloti, and Mesorhizobium loti), and these genes were over-represented in the chromosome and had above average G+C. Most supported the rRNA-based phylogeny, confirming A. tumefaciens to be the closest among these relatives, but 347 genes were incompatible with this phylogeny; these were scattered throughout the genome but were over-represented on the plasmids. An unexpectedly large number of genes were shared by all three rhizobia but were missing from A. tumefaciens.Conclusion
Overall, the genome can be considered to have two main components: a 'core', which is higher in G+C, is mostly chromosomal, is shared with related organisms, and has a consistent phylogeny; and an 'accessory' component, which is sporadic in distribution, lower in G+C, and located on the plasmids and chromosomal islands. The accessory genome has a different nucleotide composition from the core despite a long history of coexistence. 相似文献112.
Y. Jeffrey Chiang Martha S. Jordan Reiko Horai Pamela L. Schwartzberg Gary A. Koretzky Richard J. Hodes 《The Journal of biological chemistry》2009,284(7):4429-4438
A signaling pathway involving ZAP-70, LAT, and SLP76 has been regarded as
essential for receptor-driven T cell development and activation. Consistent
with this model, mice deficient in SLP76 have a complete block at the double
negative 3 stage of T cell development. Recently, however, it has been
reported that inactivation of Cbl, a ubiquitin-protein isopeptide ligase,
partially rescues T cell development in SLP76-deficient mice. To probe the
influence of Cbl on domain-specific SLP76 functions, we reconstituted
SLP76-/- Cbl-/- mice with Slp76 transgenes
bearing mutations in each of three functional domains of SLP76 as follows:
Y3F, in which the amino-terminal tyrosine residues of SLP76 were mutated,
eliminating sites of SLP76 interaction with Vav, Nck, and Itk; Δ20, in
which 20 amino acids in the proline-rich region of SLP76 were deleted,
removing a binding site for Gads; and RK, in which arginine 448 of SLP76 was
replaced by lysine, abolishing function of the Src homology 2 domain. Although
each of these transgenes has been shown to partially rescue T cell development
in SLP76-/- mice, we report here that Cbl inactivation completely
reverses the severe double negative 3 developmental block that occurs in
SLP76-deficient mice expressing the Y3F transgene (Y3F mice) and
partially rescues the defect in positive selection in T cell receptor
transgenic Y3F mice, but in contrast fails to rescue thymic development of
SLP76-deficient mice expressing the Δ20 or RK transgene. Rescue in
SLP76-/-Cbl-/-Y3F double-positive thymocytes is
associated with enhanced tyrosine phosphorylation of signaling molecules,
including Lck, Vav, PLC-γ1, and ERKs, but not Itk, in response to T cell
receptor stimulation. Thus, our data demonstrate that Cbl suppresses
activation of a bypass signaling pathway and thereby enforces SLP76 dependence
of early T cell development.T cell development proceeds through multiple stages that regulate the
generation and selection of T cells whose T cell receptors
(TCR)2 have an
appropriate range of affinity for peptides presented by major
histocompatibility complex (MHC) molecules
(1). Precursors give rise to
immature CD4-CD8- double negative (DN) cells that can be
further divided into DN1, DN2, DN3, and DN4 stages, distinguished by cell
surface phenotype as well as by critical events, including expansion of DN3
cells that have successfully rearranged TCRβ and have expressed and
signaled through the pre-TCR complex
(2). DN3 cells differentiate to
the DN4 and then CD4+CD8+ double-positive (DP) stage
following pre-TCR signaling. DP thymocytes rearrange TCRα, express a
mature TCRαβ receptor, and develop into mature
CD4+CD8- or CD4-CD8+
single-positive (SP) cells through a process of positive and negative
selection that is based on signaling through this mature TCR and selection of
a T cell repertoire that is tolerant to self but capable of responding to
foreign-peptide-MHC (pMHC) complexes
(1,
3,
4). Finally, SP cells exit from
the thymus as mature T cells capable of recognizing and responding to foreign
antigens.The signals from pre-TCR and TCR, which determine the fate of developing
thymocytes, have been intensely studied. Ligation of the TCR by pMHC complexes
results in activation of a signaling cascade initiated by phosphorylation and
activation of TCR-ζ, Lck, and ZAP-70, which in turn phosphorylate
downstream targets, including LAT and SLP76. ZAP-70, LAT and SLP76 proteins
(3) have been shown to be
essential for thymocyte development by studies, including genetic manipulation
in mice
(5–8).
There are essentially no detectable DP or SP thymocytes or peripheral T cells
in LAT-/- or SLP76-/- mice, in which thymocyte
development is blocked at the DN3 stage
(5,
7). ZAP70-/-
thymocytes are blocked at the DP stage of T cell development, and
ZAP70-/- mice have very few SP thymocytes or peripheral T cells
(6). These studies suggest that
signal transduction required for early T cell development proceeds through a
pathway that involves critical roles of multiple molecules, including ZAP-70,
LAT, and SLP76.SLP76 consists of three functional domains as follows: an amino-terminal
domain containing targets for tyrosine phosphorylation, a proline-rich region,
and a carboxyl-terminal SH2 domain
(9). The amino-terminal
tyrosine residues (Tyr-112, Tyr-128, and Tyr-145) are phosphorylated by
tyrosine kinases following TCR engagement, enabling SLP76 to interact with
Vav, a Rho guanine nucleotide exchange factor, Nck, an adaptor protein, and
Itk, a member of Tec family PTK. The proline-rich region of SLP76 has the
capacity to bind Gads, a Grb2 homolog, which results in the recruitment of
SLP76 to cell surface membrane lipid rafts through binding to LAT following
TCR engagement. The carboxyl-terminal SH2 domain of SLP76 interacts with ADAP
(adhesion and degranulation-promoting protein)
(10) an adaptor protein, and
HPK-1, a serine kinase (9).
Reconstitution of SLP76-deficient mice with transgenes containing mutations in
each of these domains has demonstrated that each region is required for normal
thymocyte development (5,
8). Two groups have
reconstituted SLP76-deficient mice with T cell-specific expression of
wild-type and mutant SLP76 transgenes, including a mutant in which three
tyrosine residues (Tyr-112, Tyr-128, and Tyr-145) in the amino-terminal domain
of SLP76 were substituted by phenylalanines (Y3F); a mutant in which 20 amino
acids (amino acids 224–244) in the proline-rich region of SLP76 were
deleted (Δ20); and a mutant in which arginine 448 of SLP76 was replaced
by lysine (RK) (11,
12). The profound defects in T
cell development and activation that are observed in SLP76 knock-out mice are
completely reversed by reconstitution with a wild-type SLP76 transgene. In
contrast, however, reconstitution with SLP76 that has been mutated in any of
its three functional domains only partially rescues T cell development in
SLP76 knock-out mice.c-Cbl (Cbl) is a ubiquitin ligase and adaptor protein (regulator) with
multiple domains that associate with multiple molecules involved in signal
transduction (13). Thymocytes
from Cbl knock-out mice have enhanced cell surface expression of TCR and CD3
in comparison with control mice
(14,
15). In addition, it has been
observed that phosphorylation of ZAP-70, LAT, and SLP76 is increased in
Cbl-/- mouse thymocytes
(14,
15). Recently, we reported
that inactivation of Cbl partially rescues T cell development in LAT and
SLP76-deficient mice (16), and
Myers et al. (17)
reported that inactivation of Cbl partially rescues T cell development in
ZAP-70-deficient mice. These observations indicate that Cbl mediates
requirements for LAT, SLP76, and ZAP-70 by preventing signaling that is
capable of supporting T cell differentiation independent of LAT, SLP76, or
ZAP-70. However, the rescue of T cell development in these model systems is
strikingly incomplete, failing to substantially reconstitute development
through the pre-TCR-dependent DN3-DN4 transition and thus failing to generate
normal numbers of DP or functionally mature SP thymocytes. These findings
suggest that Cbl inactivation functions to enable pathways that are capable of
bypassing some but not all of the requirements for ZAP-70, LAT, and SLP76
during T cell development. To define these signaling pathways, normally
suppressed by Cbl, that can support T cell development, we assessed the
ability of Cbl inactivation to rescue T cell development in the presence of
Y3F, Δ20, or RK SLP76 mutant transgenes. In this study, we report that
Cbl inactivation completely reverses the DN3-DN4 developmental defect and
partially reverses alterations in positive selection in thymocytes of SLP76
knock-out mice reconstituted with the SLP76 mutant Y3F, which lacks
amino-terminal phosphotyrosine residues. In contrast, Cbl inactivation has no
effect on the thymic developmental defects observed in SLP76 knock-out mice
reconstituted with Slp76 transgenes mutated in the proline-rich
Gads-binding region (Δ20) or the carboxyl-terminal SH2 domain (RK).
Biochemical studies revealed that rescue of development in
SLP76-/-Y3F thymocytes by inactivation of Cbl was marked by
reversal of defects in tyrosine phosphorylation of multiple molecules,
including Lck, Vav, PLC-γ1, and ERKs in response to TCR stimulation of
DP thymocytes. Thus, Cbl normally enforces SLP76 dependence of T cell
development by inhibiting an alternative pathway that may be independent of
SLP76 association with Vav, Nck, and Itk
(18). 相似文献
113.
Carolyn GJ Moonen Kirsten GD Buurma Mouri RJ Faruque Maria G Balta Erol Liefferink Sergio Bizzarro Elena A Nicu Bruno G Loos 《Innate immunity》2020,26(5):331
In periodontitis, polymorphonuclear leucocytes (PMNs) are activated. They entrap and eliminate pathogens by releasing neutrophil extracellular traps (NETs). Abnormal NET degradation is part of a pro-inflammatory status, affecting co-morbidities such as cardiovascular disease. We aimed to investigate the ex vivo NET degradation capacity of plasma from periodontitis patients compared to controls (part 1) and to quantify NET degradation before and after periodontal therapy (part 2). Fresh NETs were obtained by stimulating blood-derived PMNs with phorbol 12-myristate 13-acetate. Plasma samples from untreated periodontitis patients and controls were incubated for 3 h onto freshly generated NETs (part 1). Similarly, for part 2, NET degradation was studied for 91 patients before and 3, 6 and 12 mo after non-surgical periodontal therapy with and without adjunctive systemic antibiotics. Finally, NET degradation was fluorospectrometrically quantified. NET degradation levels did not differ between periodontitis patients and controls, irrespective of subject-related background characteristics. NET degradation significantly increased from 65.6 ± 1.7% before periodontal treatment to 75.7 ± 1.2% at 3 mo post periodontal therapy, and this improvement was maintained at 6 and 12 mo, irrespective of systemic usage of antibiotics. Improved NET degradation after periodontitis treatment is another systemic biomarker reflecting a decreased pro-inflammatory status, which also contributes to an improved cardiovascular condition. 相似文献
114.
Stress-related psychiatric disorders, such as unipolar depression and post-traumatic stress disorder (PTSD), occur more frequently in women than in men. Emerging research suggests that sex differences in receptors for the stress hormones, corticotropin releasing factor (CRF) and glucocorticoids, contribute to this disparity. For example, sex differences in CRF receptor binding in the amygdala of rats may predispose females to greater anxiety following stressful events. Additionally, sex differences in CRF receptor signaling and trafficking in the locus coeruleus arousal center combine to make females more sensitive to low levels of CRF, and less adaptable to high levels. These receptor differences in females could lead to hyperarousal, a dysregulated state associated with symptoms of depression and PTSD. Similar to the sex differences observed in CRF receptors, sex differences in glucocorticoid receptor (GR) function also appear to make females more susceptible to dysregulation after a stressful event. Following hypothalamic pituitary adrenal axis activation, GRs are critical to the negative feedback process that inhibits additional glucocorticoid release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress, effects linked to slower glucocorticoid negative feedback. Thus, under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Together, these studies suggest that sex differences in stress-related receptors shift females more easily into a dysregulated state of stress reactivity, linked to the development of mood and anxiety disorders. The implications of these receptor sex differences for the development of novel pharmacotherapies are also discussed. 相似文献
115.
Wouter D van Dijk Lisette van den Bemt Saskia van den Haak-Rongen Erik Bischoff Chris van Weel Johannes CCM in 't Veen Tjard RJ Schermer 《Respiratory research》2011,12(1):151
Background
A growing number of prognostic indices for chronic obstructive pulmonary disease (COPD) is developed for clinical use. Our aim is to identify, summarize and compare all published prognostic COPD indices, and to discuss their performance, usefulness and implementation in daily practice.Methods
We performed a systematic literature search in both Pubmed and Embase up to September 2010. Selection criteria included primary publications of indices developed for stable COPD patients, that predict future outcome by a multidimensional scoring system, developed for and validated with COPD patients only. Two reviewers independently assessed the index quality using a structured screening form for systematically scoring prognostic studies.Results
Of 7,028 articles screened, 13 studies comprising 15 indices were included. Only 1 index had been explored for its application in daily practice. We observed 21 different predictors and 7 prognostic outcomes, the latter reflecting mortality, hospitalization and exacerbation. Consistent strong predictors were FEV1 percentage predicted, age and dyspnoea. The quality of the studies underlying the indices varied between fairly poor and good. Statistical methods to assess the predictive abilities of the indices were heterogenic. They generally revealed moderate to good discrimination, when measured. Limitations: We focused on prognostic indices for stable disease only and, inevitably, quality judgment was prone to subjectivity.Conclusions
We identified 15 prognostic COPD indices. Although the prognostic performance of some of the indices has been validated, they all lack sufficient evidence for implementation. Whether or not the use of prognostic indices improves COPD disease management or patients'' health is currently unknown; impact studies are required to establish this. 相似文献116.
117.
118.
119.
R J Hodes G B Ahmann K S Hathcock H B Dickler A Singer 《Journal of immunology (Baltimore, Md. : 1950)》1978,121(4):1501-1509
120.