全文获取类型
收费全文 | 265篇 |
免费 | 29篇 |
专业分类
294篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 8篇 |
2019年 | 3篇 |
2018年 | 6篇 |
2017年 | 5篇 |
2016年 | 9篇 |
2015年 | 15篇 |
2014年 | 19篇 |
2013年 | 27篇 |
2012年 | 29篇 |
2011年 | 21篇 |
2010年 | 18篇 |
2009年 | 17篇 |
2008年 | 20篇 |
2007年 | 17篇 |
2006年 | 15篇 |
2005年 | 16篇 |
2004年 | 7篇 |
2003年 | 5篇 |
2002年 | 7篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1994年 | 1篇 |
1991年 | 1篇 |
1989年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1976年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有294条查询结果,搜索用时 15 毫秒
41.
Bindi Dangi Marcus Obeng Julie M. Nauroth Mah Teymourlouei Micah Needham Krishna Raman Linda M. Arterburn 《The Journal of biological chemistry》2009,284(22):14744-14759
Enzymatically oxygenated derivatives of the ω-3 fatty acids
cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) and
cis-5,8,11,14,17-eicosapentaenoic acid, known as resolvins, have
potent inflammation resolution activity (Serhan, C. N., Clish, C. B., Brannon,
J., Colgan, S. P., Chiang, N., and Gronert, K. (2000) J. Exp. Med.
192, 1197–1204; Hong, S., Gronert, K., Devchand, P. R., Moussignac, R.,
and Serhan, C. N. (2003) J. Biol. Chem. 278,
14677–14687). Our objective was to determine whether similar derivatives
are enzymatically synthesized from other C-22 fatty acids and whether these
molecules possess inflammation resolution properties. The reaction of DHA,
DPAn-3, and DPAn-6 with 5-, 12-, and 15-lipoxygenases produced oxylipins,
which were identified and characterized by liquid chromatography coupled with
tandem mass-spectrometry. DPAn-6 and DPAn-3 proved to be good substrates for
15-lipoxygenase. 15-Lipoxygenase proved to be the most efficient enzyme of the
three tested for conversion of long chain polyunsaturated fatty acids to
corresponding oxylipins. Since DPAn-6 is a major component of Martek
DHA-S™ oil, we focused our attention on reaction products obtained from
the DPAn-6 and 15-lipoxygenase reaction. (17S)-hydroxy-DPAn-6 and
(10,17S)-dihydroxy-DPAn-6 were the main products of this reaction.
These compounds were purified by preparatory high performance liquid
chromatography techniques and further characterized by NMR, UV
spectrophotometry, and tandem mass spectrometry. We tested both compounds in
two animal models of acute inflammation and demonstrated that both compounds
are potent anti-inflammatory agents that are active on local intravenous as
well as oral administration. These oxygenated DPAn-6 compounds can thus be
categorized as a new class of DPAn-6-derived resolvins.Enzymatically formed oxygenation products of C-20 and C-22 long chain
polyunsaturated fatty acids
(LC-PUFAs),4 have
important biological roles in inflammation, allergies, and blood clotting and
are thus believed to have therapeutic potential in several chronic immune
diseases
(1–10)
Several biologically important products of
cis-5,8,11,14-eicosatetraenoic acid/arachidonic acid (ARA),
cis-5,8,11,14,17-eicosapentaenoic acid (EPA), and
cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) have been described
(4,
11,
12). Proinflammatory
oxylipins, such as leukotrienes and some prostaglandins, are derived from ARA,
an ω-6 fatty acid. Interestingly, the same fatty acid also serves as a
precursor to anti-inflammatory or proresolution molecules like lipoxins
(13,
14). Stable analogues of
lipoxins are being developed as drugs for asthma and other inflammatory airway
diseases (15,
16). Oxylipins derived from
ω-3 fatty acids, such as DHA and EPA, known as resolvins, are primarily
anti-inflammatory in nature
(17). EPA acts as a precursor
to the E-series resolvins that have shown potential in the treatment of
colitis, arthritis, and periodontitis
(18–20).
The resolvins of the D-series derived from DHA are useful as neuroprotective
agents. 10,17-Dihydroxy-4,7,11,13,15,19-docosahexaenoic acid (10,17-HDHA) or
neuroprotectin D1 is a resolvin that is formed endogenously in the human brain
and eye and is believed to exert its protective effect against cell
injury-induced oxidative stress
(21–23).The main enzymes responsible for the production of these oxygenated LC-PUFA
products are primarily lipoxygenases and, in addition, cyclo-oxygenases and
cytochromes P450. These enzymes produce oxylipins via transcellular activity,
often involving multiple cell types
(24). This activity mainly
results in mono-, di-, and tri-hydroxylation products of fatty acids that have
varying potencies, depending on the exact structure of the compound.
Lipoxygenases are non-heme, iron-containing dioxygenases that catalyze the
regioselective and enantioselective oxidation of polyunsaturated fatty acids
containing one or more cis,cis-1,4-pentadienoic moieties to give the
corresponding hydroperoxy derivatives
(25,
26). We thus considered that,
in addition to DHA and EPA, other C-22 PUFAs containing such methylene
interrupted double bonds may also be substrates for lipoxygenases and that
resulting products may have anti-inflammatory activity similar to DHA-derived
resolvins. DPAn-6 (cis-4,7,10,13,16-docosapentaenoic acid) is present
in algal oils, and recent studies have demonstrated that this fatty acid has
anti-inflammatory activities in vitro and, in conjunction with DHA,
also has anti-inflammatory activity in
vivo.5 Also, it
has been suggested that a combination of DHA and DPAn-6 could be a beneficial
natural therapy in neuroinflammatory conditions like Alzheimer disease.
Specifically, in a 3×Tg-AD mouse model of Alzheimer disease, DPAn-6 was
shown to reduce levels of early stage phospho-Tau epitopes, which in turn
correlated with a reduction in phosphorylated c-Jun N-terminal kinase, a
putative Tau kinase (27).
Although the precise mechanism of action of DPAn-6 in these inflammatory
milieus is not known, it suggests a possible role for oxylipin products of
DPAn-6 in resolution of inflammation. Also, another LC-PUFA, DPAn-3
(cis-7,10,13,16,19-docosapentaenoic acid) usually present along with
DHA and EPA in marine oils is known to be a potent inhibitor of platelet
aggregation
(28–30).
In addition, this LC-PUFA has a potent inhibitory effect on angiogenesis
through the suppression of VEGFR-2 (vascular endothelial-cell growth factor
receptor 2) expression. Angiogenesis is known to contribute to tumor growth,
inflammation, and microangiopathy, again pointing to the possibility that
anti-inflammatory activity of DPAn-3 might be mediated through resolvin-like
products as in the case of DHA and EPA
(31).The purpose of this research was to determine whether oxylipins are formed
from the C-22 LC-PUFAs, DPAn-6 and DPAn-3, by lipoxygenase activity; to
compare them to products formed from DHA; to chemically characterize products;
to purify key oxylipin products from the DPAn-6/15-lipoxygenase reaction; and
to test whether these compounds have resolvin-like anti-inflammatory activity.
This research also sets the stage for preparation and isolation of a wide
range of other C-22 oxylipins that could be evaluated as potential
anti-inflammatory compounds. 相似文献
42.
Grace X. Ma Steve Shive Yin Tan Wanzhen Gao Joanne Rhee Micah Park Jaesool Kim Jamil I. Toubbeh 《Cancer epidemiology》2009,33(5):381-386
Background: Despite evidence of a decline in both incidence and prevalence of colorectal cancer nationwide, it remains the second most commonly diagnosed cancer and the third highest cause of mortality among Asian Americans, including Korean Americans. This community-based and theoretically guided study evaluated a culturally appropriate intervention program that included a bilingual cancer educational program among Korean Americans including information on CRC risks, counseling to address psychosocial and access barriers, and patient navigation assistance. Methods: A two-group quasi-experimental design with baseline and post-intervention assessment and a 12-month follow-up on screening was used in the study. Korean Americans (N = 167) were enrolled from six Korean churches. The intervention group received culturally appropriate intervention program addressing accessibility and psychosocial barriers, and navigation assistance for screening. The control group received general health education that included cancer-related health issues and screening. Results: There was a significant difference (p < 0.05) between the post-intervention and control groups in awareness of CRC risk factors. There was also a significant improvement in the pre–post across HBM measures in the intervention group for perceived susceptibility (p < 0.05) and benefits and barriers to screening (p < 0.001). At baseline, 13% of participants in the intervention group and 10% in control group reported having had a CRC cancer screening test in the previous year. At the 12-month post-intervention follow-up, 77.4% of participants in the intervention group had obtained screening compared to 10.8% in the control group. Conclusion: While health disparities result from numerous factors, a culturally appropriate and church-based intervention can be highly effective in increasing knowledge of and access to, and in reducing barriers to CRC screening among underserved Koreans. 相似文献
43.
Latisha D. Heinlen Micah T. McClain Lauren L. Ritterhouse Benjamin F. Bruner Colin C. Edgerton Michael P. Keith Judith A. James John B. Harley 《PloS one》2010,5(3)
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns. 相似文献
44.
Nikitin PA Yan CM Forte E Bocedi A Tourigny JP White RE Allday MJ Patel A Dave SS Kim W Hu K Guo J Tainter D Rusyn E Luftig MA 《Cell host & microbe》2010,8(6):510-522
Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in?vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as?a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization. 相似文献
45.
Cédric Berney Andreea Ciuprina Sara Bender Juliet Brodie Virginia Edgcomb Eunsoo Kim Jeena Rajan Laura Wegener Parfrey Sina Adl Stéphane Audic David Bass David A. Caron Guy Cochrane Lucas Czech Micah Dunthorn Stefan Geisen Frank Oliver Glöckner Frédéric Mahé Christian Quast Jonathan Z. Kaye Alastair G. B. Simpson Alexandros Stamatakis Javier del Campo Pelin Yilmaz Colomban de Vargas 《The Journal of eukaryotic microbiology》2017,64(3):407-411
Universal taxonomic frameworks have been critical tools to structure the fields of botany, zoology, mycology, and bacteriology as well as their large research communities. Animals, plants, and fungi have relatively solid, stable morpho‐taxonomies built over the last three centuries, while bacteria have been classified for the last three decades under a coherent molecular taxonomic framework. By contrast, no such common language exists for microbial eukaryotes, even though environmental ‘‐omics’ surveys suggest that protists make up most of the organismal and genetic complexity of our planet's ecosystems! With the current deluge of eukaryotic meta‐omics data, we urgently need to build up a universal eukaryotic taxonomy bridging the protist ‐omics age to the fragile, centuries‐old body of classical knowledge that has effectively linked protist taxa to morphological, physiological, and ecological information. UniEuk is an open, inclusive, community‐based and expert‐driven international initiative to build a flexible, adaptive universal taxonomic framework for eukaryotes. It unites three complementary modules, EukRef, EukBank, and EukMap, which use phylogenetic markers, environmental metabarcoding surveys, and expert knowledge to inform the taxonomic framework. The UniEuk taxonomy is directly implemented in the European Nucleotide Archive at EMBL‐EBI, ensuring its broad use and long‐term preservation as a reference taxonomy for eukaryotes. 相似文献
46.
Proper functioning of the innate immune response depends on migration of circulating neutrophils into tissues at sites of infection and inflammation. Migration of highly motile, amoeboid cells such as neutrophils has significant physiological relevance, yet the traction forces that drive neutrophil motion in response to chemical cues are not well characterized. To better understand the relationship between chemotactic signals and the organization of forces in motile neutrophils, force measurements were made on hydrogel surfaces under well-defined chemotactic gradients created with a microfluidic device. Two parameters, the mean chemoattractant concentration (CM) and the gradient magnitude (Δc/Δx) were varied. Cells experiencing a large gradient with CM near the chemotactic receptor KD displayed strong punctate centers of uropodial contractile force and strong directional motion on stiff (12 kPa) surfaces. Under conditions of ideal chemotaxis—cells in strong gradients with mean chemoattractant near the receptor KD and on stiffer substrates—there is a correlation between the magnitude of force generation and directional motion as measured by the chemotactic index. However, on soft materials or under weaker chemotactic conditions, directional motion is uncorrelated with the magnitude of traction force. Inhibition of either β2 integrins or Rho-associated kinase, a kinase downstream from RhoA, greatly reduced rearward traction forces and directional motion, although some vestigial lamellipodium-driven motility remained. In summary, neutrophils display a diverse repertoire of methods for organizing their internal machinery to generate directional motion. 相似文献
47.
48.
Synaptic function is critical for proper cognition, and synaptopathologies have
been implicated in diverse neuropsychiatric disorders. STriatal-Enriched protein
tyrosine Phosphatase (STEP) is a brain-enriched tyrosine phosphatase that
normally opposes synaptic strengthening by dephosphorylating key neuronal
signaling molecules. STEP targets include N-methyl D-aspartate receptors
(NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
(AMPARs), as well as extracellular signal-regulated kinase (ERK) and the
tyrosine kinase Fyn. STEP-mediated dephosphorylation promotes the
internalization of NMDARs and AMPARs and the inactivation of ERK and Fyn.Regulation of STEP is complex, and recent work has implicated STEP dysregulation
in the pathophysiology of several neuropsychiatric disorders. Both high levels
and low levels of STEP are found in a diverse group of illnesses. This review
focuses on the role of STEP in three disorders in which STEP levels are
elevated: Alzheimer’s disease, fragile X syndrome, and schizophrenia. The
presence of elevated STEP in all three of these disorders raises the intriguing
possibility that cognitive deficits resulting from diverse etiologies may share
a common molecular pathway. 相似文献
49.
Consistent patterns of high alpha and low beta diversity in tropical parasitic and free‐living protists 下载免费PDF全文
Guillaume Lentendu Frédéric Mahé David Bass Sonja Rueckert Thorsten Stoeck Micah Dunthorn 《Molecular ecology》2018,27(13):2846-2857
Tropical animals and plants are known to have high alpha diversity within forests, but low beta diversity between forests. By contrast, it is unknown whether microbes inhabiting the same ecosystems exhibit similar biogeographic patterns. To evaluate the biogeographies of tropical protists, we used metabarcoding data of species sampled in the soils of three lowland Neotropical rainforests. Taxa–area and distance–decay relationships for three of the dominant protist taxa and their subtaxa were estimated at both the OTU and phylogenetic levels, with presence–absence and abundance‐based measures. These estimates were compared to null models. High local alpha and low regional beta diversity patterns were consistently found for both the parasitic Apicomplexa and the largely free‐living Cercozoa and Ciliophora. Similar to animals and plants, the protists showed spatial structures between forests at the OTU and phylogenetic levels, and only at the phylogenetic level within forests. These results suggest that the biogeographies of macro‐ and micro‐organismal eukaryotes in lowland Neotropical rainforests are partially structured by the same general processes. However, and unlike the animals and plants, the protist OTUs did not exhibit spatial structures within forests, which hinders our ability to estimate the local and regional diversity of protists in tropical forests. 相似文献
50.