全文获取类型
收费全文 | 283篇 |
免费 | 31篇 |
国内免费 | 1篇 |
出版年
2021年 | 5篇 |
2017年 | 5篇 |
2016年 | 7篇 |
2015年 | 7篇 |
2014年 | 9篇 |
2013年 | 9篇 |
2012年 | 15篇 |
2011年 | 13篇 |
2010年 | 17篇 |
2009年 | 14篇 |
2008年 | 10篇 |
2007年 | 11篇 |
2006年 | 11篇 |
2005年 | 8篇 |
2004年 | 12篇 |
2003年 | 5篇 |
2002年 | 9篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 4篇 |
1998年 | 14篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1994年 | 3篇 |
1993年 | 9篇 |
1992年 | 2篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1979年 | 4篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1967年 | 2篇 |
1965年 | 2篇 |
1938年 | 2篇 |
1935年 | 1篇 |
排序方式: 共有315条查询结果,搜索用时 15 毫秒
1.
2.
Inhibition of cathepsin B by peptidyl aldehydes and ketones: slow-binding behavior of a trifluoromethyl ketone 总被引:1,自引:0,他引:1
Inhibition of the cysteine proteinase cathepsin B by a series of N-benzyloxycarbonyl-L-phenylalanyl-L-alanine ketones and the analogous aldehyde has been investigated. Surprisingly, whereas the aldehyde was found to be almost as potent a competitive reversible inhibitor as the natural peptidyl aldehyde, leupeptin, the corresponding trifluoromethyl ketone showed comparatively weak (and slow-binding) reversible inhibition. Evaluation of competitive hydration and hemithioketal formation in a model system led to a structure-activity correlation spanning several orders of magnitude in both cathepsin B inhibition constants (Ki) and model system equilibrium data (KRSH,apparent). 相似文献
3.
We have broadly defined the DNA regions regulating esterase6 activity in
several life stages and tissue types of D. melanogaster using P-
element-mediated transformation of constructs that contain the esterase6
coding region and deletions or substitutions in 5' or 3' flanking DNA.
Hemolymph is a conserved ancestral site of EST6 activity in Drosophila and
the primary sequences regulating its activity lie between -171 and -25 bp
relative to the translation initiation site: deletion of these sequences
decrease activity approximately 20-fold. Hemolymph activity is also
modulated by four other DNA regions, three of which lie 5' and one of which
lies 3' of the coding region. Of these, two have positive and two have
negative effects, each of approximately twofold. Esterase6 activity is
present also in two male reproductive tract tissues; the ejaculatory bulb,
which is another ancestral activity site, and the ejaculatory duct, which
is a recently acquired site within the melanogaster species subgroup.
Activities in these tissues are at least in part independently regulated:
activity in the ejaculatory bulb is conferred by sequences between -273 and
-172 bp (threefold decrease when deleted), while activity in the
ejaculatory duct is conferred by more distal sequences between -844 and
-614 bp (fourfold decrease when deleted). The reproductive tract activity
is further modulated by two additional DNA regions, one in 5' DNA (-613 to
-284 bp; threefold decrease when deleted) and the other in 3' DNA (+1860 to
+2731 bp; threefold decrease when deleted) that probably overlaps the
adjacent esteraseP gene. Collating these data with previous studies
suggests that expression of EST6 in the ancestral sites is mainly regulated
by conserved proximal sequences while more variable distal sequences
regulate expression in the acquired ejaculatory duct site.
相似文献
4.
Litman GW; Rast JP; Shamblott MJ; Haire RN; Hulst M; Roess W; Litman RT; Hinds- Frey KR; Zilch A; Amemiya CT 《Molecular biology and evolution》1993,10(1):60-72
Immunoglobulins are encoded by a large multigene system that undergoes
somatic rearrangement and additional genetic change during the development
of immunoglobulin-producing cells. Inducible antibody and antibody-like
responses are found in all vertebrates. However, immunoglobulin possessing
disulfide-bonded heavy and light chains and domain-type organization has
been described only in representatives of the jawed vertebrates. High
degrees of nucleotide and predicted amino acid sequence identity are
evident when the segmental elements that constitute the immunoglobulin gene
loci in phylogenetically divergent vertebrates are compared. However, the
organization of gene loci and the manner in which the independent elements
recombine (and diversify) vary markedly among different taxa. One striking
pattern of gene organization is the "cluster type" that appears to be
restricted to the chondrichthyes (cartilaginous fishes) and limits
segmental rearrangement to closely linked elements. This type of gene
organization is associated with both heavy- and light-chain gene loci. In
some cases, the clusters are "joined" or "partially joined" in the germ
line, in effect predetermining or partially predetermining, respectively,
the encoded specificities (the assumption being that these are expressed)
of the individual loci. By relating the sequences of transcribed gene
products to their respective germ-line genes, it is evident that, in some
cases, joined-type genes are expressed. This raises a question about the
existence and/or nature of allelic exclusion in these species. The
extensive variation in gene organization found throughout the vertebrate
species may relate directly to the role of intersegmental
(V<==>D<==>J) distances in the commitment of the individual
antibody-producing cell to a particular genetic specificity. Thus, the
evolution of this locus, perhaps more so than that of others, may reflect
the interrelationships between genetic organization and function.
相似文献
5.
G. S. Krantz 《Human Evolution》1995,10(2):107-117
Homo erectus fossils can be divided into four zoogeographic zones that show different rates of endocranial expansion during the Pleistocene.
When these are also grouped into three time levels, we find small increases from early to middle forms, and regularly greater
increases from middle to late forms. These increases fit a regular pattern that also accomodates all archaic types, including
Neandertals, as late subspecies ofH. erectus. 相似文献
6.
Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon. 总被引:6,自引:0,他引:6
IL-1 inhibits erythropoiesis in vivo and in vitro. This inhibition was studied by comparing the effect of recombinant human IL-1 (rhIL-1) on highly purified CFU-erythroid (E) generated from peripheral blood burst-forming units-erythroid (BFU-E) (mean purity 44.4%) with its effect on unpurified marrow CFU-E (mean purity 0.36%). Colony formation by marrow CFU-E was significantly inhibited by rhIL-1, while colony formation by highly purified CFU-E was not inhibited. However, purified CFU-E colonies were inhibited by rhIL-1 in the presence of autologous T-lymphocytes, and also by cell-free conditioned medium prepared from T-lymphocytes stimulated by rhIL-1. This inhibitory effect was ablated by neutralizing antibodies to gamma interferon (IFN), but not by antibodies to human IL-1, tumor necrosis factor, or beta IFN. Colony formation by highly purified CFU-E was also inhibited by recombinant human gamma IFN (rh gamma IFN). IL-1 and gamma IFN play significant roles in the pathogenesis of the anemia of chronic disease. These studies indicate that rhIL-1 inhibits CFU-E colony formation by an indirect mechanism involving T-lymphocytes and requiring gamma IFN and that gamma IFN itself is most probably the direct mediator of this effect. 相似文献
7.
8.
Schistosomiasis vector snails are subjected to extreme seasonal changes, particularly in ephemeral rivers and lentic waterbodies. In the tropics, aestivation is one of the adaptive strategies for survival and is used by snails in times of extremely high temperatures and desiccation. Aestivation therefore plays an important role in maintaining the transmission of schistosomiasis. This review assesses the possible impacts of climate change on the temporal and spatial distribution of schistosomiasis-transmitting snails with special emphasis on aestivation, and discusses the effect of schistosome infection on aestivation ability. The impacts of parasite development on snails, as well as physiological changes, are discussed with reference to schistosomiasis transmission. This review shows that schistosome-infected snails have lower survival rates during aestivation, and that those that survive manage to get rid of the infection. In general, snail aestivation ability is poor and survival chances diminish with time. Longer dry periods result in fewer, as well as uninfected, snails. However, the ability of the surviving snails to repopulate the habitats is high. 相似文献
9.
Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase
下载免费PDF全文
![点击此处可从《EMBO reports》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Sharon C Mithoe Christina Ludwig Michiel JC Pel Mara Cucinotta Alberto Casartelli Malick Mbengue Jan Sklenar Paul Derbyshire Silke Robatzek Corné MJ Pieterse Ruedi Aebersold Frank LH Menke 《EMBO reports》2016,17(3):441-454
Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN‐SENSITIVE 2 (FLS2) induces the activation of mitogen‐activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin‐triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7‐mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex. 相似文献
10.
Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer
Moase EH Qi W Ishida T Gabos Z Longenecker BM Zimmermann GL Ding L Krantz M Allen TM 《Biochimica et biophysica acta》2001,1510(1-2):43-55
The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions. 相似文献