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51.
Than M Myat KA Khadijah S Jamaludin N Isa MN 《Anthropologischer Anzeiger; Bericht über die biologisch-anthropologische Literatur》1998,56(4):351-365
There has been no recent report on the dermatoglyphics of the Malays (normal population as well as patients with Down's syndrome). A study on the frequencies of the dermal patterns (dermatoglyphics) of the digits, palms and hallucal areas was done therefore in 40 Malay patients with Down's syndrome and 200 unrelated normal controls. Only the patients with the standard 21 trisomy karyotype were included in the study. Comparison was made with the published data on studies done in various racial groups. Significant differences of the dermal patterns were found not only between the controls but also among patients of different races. 相似文献
52.
Paul Corwin Les Toop Graham McGeoch Martin Than Simon Wynn-Thomas J Elisabeth Wells Robin Dawson Paul Abernethy Alan Pithie Stephen Chambers Lynn Fletcher Dee Richards 《BMJ (Clinical research ed.)》2005,330(7483):129
Objectives To compare the efficacy, safety, and acceptability of treatment with intravenous antibiotics for cellulitis at home and in hospital.Design Prospective randomised controlled trial.Setting Christchurch, New Zealand.Participants 200 patients presenting or referred to the only emergency department in Christchurch who were thought to require intravenous antibiotic treatment for cellulitis and who did not have any contraindications to home care were randomly assigned to receive treatment either at home or in hospital.Main outcome measures Days to no advancement of cellulitis was the primary outcome measure. Days on intravenous and oral antibiotics, days in hospital or in the home care programme, complications, degree of functioning and pain, and satisfaction with site of care were also recorded.Results The two treatment groups did not differ significantly for the primary outcome of days to no advancement of cellulitis, with a mean of 1.50 days (SD 0.11) for the group receiving treatment at home and 1.49 days (SD 0.10) for the group receiving treatment in hospital (mean difference 0.01 days, 95% confidence interval -0.3 to 0.28). None of the other outcome measures differed significantly except for patients'' satisfaction, which was greater in patients treated at home.Conclusions Treatment of cellulitis requiring intravenous antibiotics can be safely delivered at home. Patients prefer home treatment, but in this study only about one third of patients presenting at hospital for intravenous treatment of cellulitis were considered suitable for home treatment. 相似文献
53.
Magnus C. Mayer Daniela Kaden Linda Schauenburg Mark A. Hancock Philipp Voigt Dirk Roeser Christian Barucker Manuel E. Than Michael Schaefer Gerhard Multhaup 《The Journal of biological chemistry》2014,289(27):19019-19030
The amyloid precursor protein (APP) and the APP-like proteins 1 and 2 (APLP1 and APLP2) are a family of multidomain transmembrane proteins possessing homo- and heterotypic contact sites in their ectodomains. We previously reported that divalent metal ions dictate the conformation of the extracellular APP E2 domain (Dahms, S. O., Könnig, I., Roeser, D., Gührs, K.-H., Mayer, M. C., Kaden, D., Multhaup, G., and Than, M. E. (2012) J. Mol. Biol. 416, 438–452), but unresolved is the nature and functional importance of metal ion binding to APLP1 and APLP2. We found here that zinc ions bound to APP and APLP1 E2 domains and mediated their oligomerization, whereas the APLP2 E2 domain interacted more weakly with zinc possessing a less surface-exposed zinc-binding site, and stayed monomeric. Copper ions bound to E2 domains of all three proteins. Fluorescence resonance energy transfer (FRET) analyses examined the effect of metal ion binding to APP and APLPs in the cellular context in real time. Zinc ions specifically induced APP and APLP1 oligomerization and forced APLP1 into multimeric clusters at the plasma membrane consistent with zinc concentrations in the blood and brain. The observed effects were mediated by a novel zinc-binding site within the APLP1 E2 domain as APLP1 deletion mutants revealed. Based upon its cellular localization and its dominant response to zinc ions, APLP1 is mainly affected by extracellular zinc among the APP family proteins. We conclude that zinc binding and APP/APLP oligomerization are intimately linked, and we propose that this represents a novel mechanism for regulating APP/APLP protein function at the molecular level. 相似文献
54.
Singh OP Chandra D Nanda N Sharma SK Htun PT Adak T Subbarao SK Dash AP 《Journal of biosciences》2006,31(5):671-677
Anopheles fluviatilis andAn. minimus complexes, each comprising of at least three sibling species, are closely related and important malaria vectors in Oriental
Region. RecentlyAn. fluviatilis species S, which is a highly efficient malaria vector in India, has been made conspecific withAn. minimus species C (senior synonym) on the basis of homology in 335 base pair nucleotide sequence of D3 domain of 28S ribosomal DNA(rDNA).
We examined the conspecificity of these two nominal species by obtaining and analysing the DNA sequences of nuclear ribosomal
loci internal transcribed spacer 2 (ITS2) and D2-D3 domain of 28S rDNA (28S-D2/D3) from those ofAn. fluviatilis S andAn. minimus C. We found that the sequences ofAn. fluviatilis S are appreciably different from those ofAn. minimus C with pair-wise distance (Kimura-2-parametre model) of 3.6 and 0.7% for loci ITS2 and 28S-D2/D3, respectively. Pair-wise
distance and phylogenetic analyses using ITS2 sequences of members of Minimus and Fluviatilis Complexes revealedthat An. fluviatilis S is distantly related toAn. minimus C as compared to any other members of the Fluviatilis Complex. These findings suggest that the two nominal species,An. fluviatilis S andAn. minimus C, do not merit synonymy. The study also confirms that the reported speciesAn. fluviatilis X is synonym with species S. 相似文献
55.
Masakiyo Sakaguchi Ken Kataoka Fernando Abarzua Ryuta Tanimoto Masami Watanabe Hitoshi Murata Swe Swe Than Kaoru Kurose Yuji Kashiwakura Kazuhiko Ochiai Yasutomo Nasu Hiromi Kumon Nam-ho Huh 《The Journal of biological chemistry》2009,284(21):14236-14244
We previously showed that the tumor suppressor gene
REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC),
exhibited a dramatic therapeutic effect on human cancers through a mechanism
triggered by endoplasmic reticulum stress. Adenovirus vectors show no target
cell specificity and thus may elicit unfavorable side effects through
infection of normal cells even upon intra-tumoral injection. In this study, we
examined possible effects of Ad-REIC on normal cells. We found that infection
of normal human fibroblasts (NHF) did not cause apoptosis but induced
production of interleukin (IL)-7. The induction was triggered by endoplasmic
reticulum stress and mediated through IRE1α, ASK1, p38, and IRF-1. When
Ad-REIC-infected NHF were transplanted in a mixture with untreated human
prostate cancer cells, the growth of the cancer cells was significantly
suppressed. Injection of an IL-7 antibody partially abrogated the suppressive
effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has
another arm against human cancer, an indirect host-mediated effect because of
overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect
on cancer cells.Cancer cells, like normal cells, cannot be free from regulation by other
cells in the body (1). The
microenvironment can exert both promotive and suppressive effects on malignant
cells (2). The embryonic
environment has been shown to suppress malignant phenotypes
(3,
4), and this was recently
indicated to be due to suppression of Nodal function by Lefty
(5). Cells comprising cancer
stroma in adult tissues are also involved in tumor suppression
(6,
7). Mobilization of such
potential tumor-suppressive effects of the microenvironment would provide an
additional arm for cancer therapy
(8).Adenovirus vectors combined with appropriate cargo genes have great
potential in cancer gene therapy because of their high infection efficiency
and marginal genotoxicity (9).
However, they show no target cell specificity and thus may also infect normal
cells present in the surroundings of cancer cells. Provided that the
interaction between cancer cells and normal cells is relevant to
progression/suppression of cancer, it is critically important to understand
not only cell autonomous phenomena in individual cell types infected by a
therapeutic virus vector but also potential effects of the therapeutic virus
vector on the composite system of interacting cell populations.We have been studying the possible utility of an adenovirus vector carrying
the tumor suppressor gene REIC/Dkk-3 (Ad-REIC) for gene
therapy against human cancer. REIC/Dkk-3 was first
identified as a gene that was down-regulated in association with
immortalization of normal human fibroblasts
(NHF)2
(10). Expression of
REIC/Dkk-3 gene was shown to be reduced in many human cancer
cells and tissues, including prostate cancer, renal clear cell carcinoma,
testicular cancer, and non-small cell lung cancer
(11–14),
probably due to hypermethylation of the promoter
(15). A single injection of
Ad-REIC into tumors formed by transplantation of human prostate cancer cells
(PC3 cells) into mice resulted in 4 of 5 mice becoming tumor-free
(13). Subsequently, we found
that Ad-REIC was effective also for human cancers derived from the testis,
pleura, and breast (14,
16,
17). The potent multitargeting
anti-cancer function of Ad-REIC shows great promise for clinical application,
which will be shortly initiated.REIC/Dkk-3 is a highly glycosylated secretory protein and
is considered to physiologically act on cells via a yet-unidentified receptor.
However, we found that the induction of apoptosis in cancer cells by Ad-REIC
was because of endoplasmic reticulum (ER) stress loaded by overproduction of
the REIC/Dkk-3 protein and that exogenously applied REIC/Dkk-3 protein showed
no apoptosis inducing activity for cancer cells
(13,
14). Activation of c-Jun
N-terminal kinase (JNK) was shown to be an essential step for the induction of
apoptosis by Ad-REIC. ER stress is evoked by overload of unfolded/misfolded
proteins in the ER, and eukaryotic cells respond to the threat by activating
an unfolded protein response, i.e. attenuating de novo
protein synthesis, promoting protein degradation by proteasomes, and inducing
chaperone proteins to help proper folding of proteins
(18). When ER stress remains
at a level manageable by the unfolded protein response, cells can survive. On
the other hand, overload of unfolded/misfolded protein beyond the cellular
adoptive response leads to apoptotic cell death. Although Ad-REIC strongly
induces apoptosis in many types of cancer cells, normal cells thus far
examined are resistant to Ad-REIC-induced apoptosis despite expression of
REIC/Dkk-3 at a level similar to that in cancer cells
(13). The aim of this study
was to determine the mechanisms of differential response of normal cells and
cancer cells to Ad-REIC and to reveal the possible effect of Ad-REIC on a
composite interacting system of normal cells and cancer cells. We found that
Ad-REIC induced NHF to produce IL-7 via ER stress-triggered activation of p38.
Furthermore, Ad-REIC-infected NHF significantly suppressed tumor growth of
untreated PC3 cells transplanted in a mixture in vivo. These results
mean that, in addition to its direct cancer cell-killing activity, Ad-REIC has
another mechanism of action against human cancer, an indirect host-mediated
effect because of overproduction of IL-7 by mis-targeted NHF. 相似文献
56.
Sandhya Vasan Sarah J. Schlesinger Zhiwei Chen Arlene Hurley Angela Lombardo Soe Than Phumla Adesanya Catherine Bunce Mark Boaz Rosanne Boyle Eddy Sayeed Lorna Clark Daniel Dugin Mar Boente-Carrera Claudia Schmidt Qing Fang Lei Yaoxing Huang Gerasimos J. Zaharatos David F. Gardiner Marina Caskey Laura Seamons Martin Ho Len Dally Carol Smith Josephine Cox Dilbinder Gill Jill Gilmour Michael C. Keefer Patricia Fast David D. Ho 《PloS one》2010,5(1)
Background
We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B''/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.Methodology/Principal Findings
ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×107 (low), 5×107 (mid), or 2.5×108 pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA.ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.Conclusions/Significance
ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.Trial Registration
Clinicaltrials.gov NCT00252148相似文献57.
Mie Shinohara Maria D. Ybanez Sanda Win Tin Aung Than Shilpa Jain William A. Gaarde Derick Han Neil Kaplowitz 《The Journal of biological chemistry》2010,285(11):8244-8255
Previously we demonstrated that c-Jun N-terminal kinase (JNK) plays a central role in acetaminophen (APAP)-induced liver injury. In the current work, we examined other possible signaling pathways that may also contribute to APAP hepatotoxicity. APAP treatment to mice caused glycogen synthase kinase-3β (GSK-3β) activation and translocation to mitochondria during the initial phase of APAP-induced liver injury (∼1 h). The silencing of GSK-3β, but not Akt-2 (protein kinase B) or glycogen synthase kinase-3α (GSK-3α), using antisense significantly protected mice from APAP-induced liver injury. The silencing of GSK-3β affected several key pathways important in conferring protection against APAP-induced liver injury. APAP treatment was observed to promote the loss of glutamate cysteine ligase (GCL, rate-limiting enzyme in GSH synthesis) in liver. The silencing of GSK-3β decreased the loss of hepatic GCL, and promoted greater GSH recovery in liver following APAP treatment. Silencing JNK1 and -2 also prevented the loss of GCL. APAP treatment also resulted in GSK-3β translocation to mitochondria and the degradation of myeloid cell leukemia sequence 1 (Mcl-1) in mitochondrial membranes in liver. The silencing of GSK-3β reduced Mcl-1 degradation caused by APAP treatment. The silencing of GSK-3β also resulted in an inhibition of the early phase (0–2 h), and blunted the late phase (after 4 h) of JNK activation and translocation to mitochondria in liver following APAP treatment. Taken together our results suggest that activation of GSK-3β is a key mediator of the initial phase of APAP-induced liver injury through modulating GCL and Mcl-1 degradation, as well as JNK activation in liver. 相似文献
58.
Than J. Boves David A. Buehler James Sheehan Petra Bohall Wood Amanda D. Rodewald Jeffrey L. Larkin Patrick D. Keyser Felicity L. Newell Gregory A. George Marja H. Bakermans Andrea Evans Tiffany A. Beachy Molly E. McDermott Kelly A. Perkins Matthew White T. Bently Wigley 《PloS one》2013,8(1)
Forest cover in the eastern United States has increased over the past century and while some late-successional species have benefited from this process as expected, others have experienced population declines. These declines may be in part related to contemporary reductions in small-scale forest interior disturbances such as fire, windthrow, and treefalls. To mitigate the negative impacts of disturbance alteration and suppression on some late-successional species, strategies that emulate natural disturbance regimes are often advocated, but large-scale evaluations of these practices are rare. Here, we assessed the consequences of experimental disturbance (using partial timber harvest) on a severely declining late-successional species, the cerulean warbler (Setophaga cerulea), across the core of its breeding range in the Appalachian Mountains. We measured numerical (density), physiological (body condition), and demographic (age structure and reproduction) responses to three levels of disturbance and explored the potential impacts of disturbance on source-sink dynamics. Breeding densities of warblers increased one to four years after all canopy disturbances (vs. controls) and males occupying territories on treatment plots were in better condition than those on control plots. However, these beneficial effects of disturbance did not correspond to improvements in reproduction; nest success was lower on all treatment plots than on control plots in the southern region and marginally lower on light disturbance plots in the northern region. Our data suggest that only habitats in the southern region acted as sources, and interior disturbances in this region have the potential to create ecological traps at a local scale, but sources when viewed at broader scales. Thus, cerulean warblers would likely benefit from management that strikes a landscape-level balance between emulating natural disturbances in order to attract individuals into areas where current structure is inappropriate, and limiting anthropogenic disturbance in forests that already possess appropriate structural attributes in order to maintain maximum productivity. 相似文献
59.
Ina Coburger Sven O. Dahms Dirk Roeser Karl-Heinz Gührs Peter Hortschansky Manuel E. Than 《PloS one》2013,8(12)
The amyloid precursor protein (APP) and its processing by the α-, β- and γ-secretases is widely believed to play a central role during the development of Alzheimer´s disease. The three-dimensional structure of the entire protein, its physiologic function and the regulation of its proteolytic processing remain, however, largely unclear to date. To gain a deeper understanding of the structure of APP that underlies all of its functions, we first cloned and recombinantly expressed different constructs in E. coli. Using limited proteolysis followed by mass spectrometry and Edman degradation as well as analytical gel permeation chromatography coupled static light scattering, we experimentally analyzed the structural domain boundaries and determined that the large ectodomain of APP consists of exactly two rigidly folded domains – the E1-domain (Leu18-Ala190) and the E2-domain (Ser295-Asp500). Both, the acidic domain (AcD) connecting E1 and E2 as well as the juxtamembrane region (JMR) connecting E2 to the single transmembrane helix are highly flexible and extended. We identified in-between the E1-domain and the AcD an additional domain of conservation and partial flexibility that we termed extension domain (ED, Glu191-Glu227). Using Bio-layer interferometry, pull-down assays and analytical gel filtration experiments we demonstrated that the E1-domain does not tightly interact with the E2-domain, both in the presence and in the absence of heparin. APP hence forms an extended molecule that is flexibly tethered to the membrane. Its multi-domain architecture enables together with the many known functionalities the concomitant performance of several, independent functions, which might be regulated by cellular, compartment specific pH-changes. 相似文献