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81.
Kish DD Volokh N Baldwin WM Fairchild RL 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(4):2117-2126
Contact hypersensitivity is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to elicit the response to hapten challenge requires prior CXCL1/KC-directed neutrophil infiltration within 3-6 h after challenge and is dependent on IFN-γ and IL-17 produced by the hapten-primed CD8 T cells. Mechanisms directing hapten-primed CD8 T cell localization and activation in the Ag challenge site to induce this early CXCL1 production in response to 2,4-dinitrofluorobenzene were investigated. Both TNF-α and IL-17, but not IFN-γ, mRNA was detectable within 1 h of hapten challenge of sensitized mice and increased thereafter. Expression of ICAM-1 was observed by 1 h after challenge of sensitized and nonsensitized mice and was dependent on TNF-α. The induction of IL-17, IFN-γ, and CXCL1 in the challenge site was not observed when ICAM-1 was absent or neutralized by specific Ab. During the elicitation of the contact hypersensitivity response, endothelial cells expressed ICAM-1 and produced CXCL1 suggesting this as the site of CD8 T cell localization and activation. Endothelial cells isolated from challenged skin of naive and sensitized mice had acquired the hapten and the ability to activate hapten-primed CD8 T cell cytokine production. These results indicate that hapten application to the skin of sensitized animals initiates an inflammatory response promoting hapten-primed CD8 T cell localization to the challenge site through TNF-α-induced ICAM-1 expression and CD8 T cell activation to produce IFN-γ and IL-17 through endothelial cell presentation of hapten. 相似文献
82.
Schenk S Kish DD He C El-Sawy T Chiffoleau E Chen C Chen C Wu Z Sandner S Gorbachev AV Fukamachi K Heeger PS Sayegh MH Turka LA Fairchild RL 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(6):3741-3748
Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.H-2bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25+ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2bm12 heart grafts. Similarly, reconstitution of B6.Rag(-/-) recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2bm12 heart grafts only if CD25+ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25+ regulatory cells that restrict the clonal expansion of alloreactive T cells. 相似文献
83.
Kaminaga Y Schnepp J Peel G Kish CM Ben-Nissan G Weiss D Orlova I Lavie O Rhodes D Wood K Porterfield DM Cooper AJ Schloss JV Pichersky E Vainstein A Dudareva N 《The Journal of biological chemistry》2006,281(33):23357-23366
We have isolated and characterized Petunia hybrida cv. Mitchell phenylacetaldehyde synthase (PAAS), which catalyzes the formation of phenylacetaldehyde, a constituent of floral scent. PAAS is a cytosolic homotetrameric enzyme that belongs to group II pyridoxal 5'-phosphate-dependent amino-acid decarboxylases and shares extensive amino acid identity (approximately 65%) with plant L-tyrosine/3,4-dihydroxy-L-phenylalanine and L-tryptophan decarboxylases. It displays a strict specificity for phenylalanine with an apparent Km of 1.2 mM. PAAS is a bifunctional enzyme that catalyzes the unprecedented efficient coupling of phenylalanine decarboxylation to oxidation, generating phenylacetaldehyde, CO2, ammonia, and hydrogen peroxide in stoichiometric amounts. 相似文献
84.
Mimi L. Quan Donald J.P. Pinto Karen A. Rossi Steven Sheriff Richard S. Alexander Eugene Amparo Kevin Kish Robert M. Knabb Joseph M. Luettgen Paul Morin Angela Smallwood Francis J. Woerner Ruth R. Wexler 《Bioorganic & medicinal chemistry letters》2010,20(4):1373-1377
We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate. 相似文献
85.
The restriction enzyme TaqI digests 0.2% of the genomic DNA from the
grasshopper Caledia captiva to a family of sequences 168 bp in length
(length of consensus sequence). The sequence variation of this "Taq family"
of repeat units was examined among four races from C. captiva to assay the
pattern of evolution within this highly repeated DNA. The Taq-family
repeats are located in C-banded heterochromatin on at least one member of
each homologous pair of chromosomes; the locations range from centromeric
to telomeric. Thirty-nine cloned repeats isolated from two population 1A
individuals along with 11 clones from seven populations taken from three of
the races demonstrated sequence variation at 72 positions. Pairwise
comparisons of the cloned repeats, both within an individual and between
different races, indicate that levels of intraspecific divergence, as
measured by reproductive incompatibility, do not correlate with sequence
divergence among the 168-bp repeats. A number of subsequences within the
repeat remain unchanged among all 50 clones; the longest of these is 18 bp.
That the same 18-bp subsequence is present in all clones examined is a
finding that departs significantly (P less than 0.01) from what would be
expected to occur at random. Two other cloned repeats, from a
reproductively isolated race of C. captiva, have sequences that show 56%
identity with this 18-bp conserved region. An analysis showed that the
frequency of occurrence of an RsaI recognition site within the 168- bp
repeat in the entire Taq family agreed with that found in the cloned
sequences. These data, along with a partial sequence for the entire Taq
family obtained by sequencing uncloned repeats, suggest that the consensus
sequence from the cloned copies is representative of this highly repeated
family and is not a biased sample resulting from the cloning procedure. The
18-bp conserved sequence is part of a 42-bp sequence that possesses dyad
symmetry typical of protein-binding sites. We speculate that this may be
significant in the evolution of the Taq family of sequences.
相似文献
86.
Stephen T. Wrobleski Shuqun Lin T.G. Murali Dhar Alaric J. Dyckman Tianle Li Sidney Pitt Rosemary Zhang Yi Fan Arthur M. Doweyko John S. Tokarski Kevin F. Kish Susan E. Kiefer John S. Sack John A. Newitt Mark R. Witmer Murray McKinnon Joel C. Barrish John H. Dodd Katerina Leftheris 《Bioorganic & medicinal chemistry letters》2013,23(14):4120-4126
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. 相似文献
87.
Stephen J. Kish 《CMAJ》2008,178(13):1679-1682
Crystal meth is a form of the stimulant drug methamphetamine that, when smoked, can rapidly achieve high concentrations in the brain. Methamphetamine causes the release of the neurotransmitters dopamine, norepinephrine and serotonin and activates the cardiovascular and central nervous systems. The levels of dopamine are low in the brain of some drug users, but whether this represents neuronal loss is uncertain. The areas of the brain involved in methamphetamine addiction are unknown but probably include the dopamine-rich striatum and regions that interact with the striatum. There is no medication approved for the treatment of relapses of methamphetamine addiction; however, potential therapeutic agents targeted to dopamine and nondopamine (e.g., opioid) systems are in clinical testing.Crystal meth (methamphetamine hydrochloride, “ice,” “Tina”) is a smokable, crystalline solid form of methamphetamine, a stimulant that is used for recreational purposes.1 To a recreational drug user, the advantage of the smokable form of methamphetamine over the oral form is the very rapid and intense “high.” The advantage over the intravenous form, which also has comparably high bioavailability, is the decreased risk and inconvenience associated with the use of needles. The elimination half-life of smoked crystal meth and methamphetamine administered by intranasal or intravenous routes is about 11 hours.1Apart from the generic risks associated with all forms of methamphetamine, the special public health concern with crystal meth is that this form can cause more overall harm to the public than other forms,1,2 because it rapidly achieves a high drug concentration with a correspondingly high potential for drug addiction and other toxicities. 相似文献
88.
Shafiqur Rahman †‡Peter P. Li §L. Trevor Young Ora Kofman †‡¶#Stephen J. Kish †‡# Jerry J. Warsh 《Journal of neurochemistry》1997,68(1):297-304
Abstract: Findings of increased Gs α levels and forskolin-stimulated adenylyl cyclase activity in selective cerebral cortical postmortem brain regions in bipolar affective disorder (BD) implicate increased cyclic AMP (cAMP)-mediated signaling in this illness. Accumulating evidence suggests that intracellular levels of cAMP modulate the abundance and disposition of the regulatory subunits of cAMP-dependent protein kinase (cAMP-dPK). Thus, in the present study, we tested further whether hyperfunctional Gs α-linked cAMP signaling occurs in BD by determining [3 H]cAMP binding, a measure of the levels of regulatory subunits of cAMP-dPK, in cytosolic and membrane fractions from discrete brain regions of postmortem BD brain. Specific [3 H]cAMP (5 n M ) binding was determined in autopsied brain obtained from 10 patients with DSM-III-R diagnoses of BD compared with age- and postmortem delay-matched controls. [3 H]cAMP binding was significantly reduced across all brain regions in cytosolic fractions of BD frontal (−22%), temporal (−23%), occipital (−22%) and parietal (−15%) cortex, cerebellum (−36%), and thalamus (−13%) compared with controls, but there were no differences in [3 H]cAMP binding in the membrane fractions from these same regions. These results suggest that changes occur in the cAMP-dPK regulatory subunits in BD brain, possibly resulting from increased cAMP signaling. The possibility that antemortem lithium and/or other mood stabilizer treatment may contribute to the above changes, however, cannot be ruled out. 相似文献
89.
BACKGROUND: Insect symbionts employ multiple strategies to enhance their spread through populations, and some play a dual role as both a mutualist and a reproductive manipulator. It has recently been found that this is the case for some strains of Wolbachia, which both cause cytoplasmic incompatibility and protect their hosts against viruses. Here, we carry out the first test as to whether a male-killing strain of Wolbachia also provides a direct benefit to its host by providing antiviral protection to its host Drosophila bifasciata. We infected flies with two positive sense RNA viruses known to replicate in a range of Drosophila species (Drosophila C virus and Flock House virus) and measure the rate of death in Wolbachia positive and negative host lines with the same genetic background. RESULTS: Both viruses caused considerable mortality to D. bifasciata flies, with Drosophila C virus killing 43% more flies than the uninfected controls and Flock House virus killing 78% more flies than the uninfected controls. However, viral induced mortality was unaffected by the presence of Wolbachia. CONCLUSION: In the first male-killing Wolbachia strain tested for antiviral effects, we found no evidence that it conferred protection against two RNA viruses. We show that although antiviral resistance is widespread across the Wolbachia phylogeny, the trait seems to have been lost or gained along some lineages. We discuss the potential mechanisms of this, and can seemingly discount protection against these viruses as a reason why this symbiont has spread through Drosophila populations. 相似文献
90.