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33.
H?Bukulmez AL?Matthews CM?Sullivan C?Chen MJ?Kraay RC?Elston RW?Moskowitz VM?Goldberg ML?WarmanEmail author 《Arthritis research & therapy》2005,8(1):R25
In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA),
we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family
histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses
to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis
of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing
total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We
compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings
of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the
siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age
and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to
identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with
hip OA than in those with knee OA. 相似文献
34.
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
35.
Thierry Christophe Mary Jackson Hee Kyoung Jeon Denis Fenistein Monica Contreras-Dominguez Jaeseung Kim Auguste Genovesio Jean-Philippe Carralot Fanny Ewann Eun Hye Kim Sae Yeon Lee Sunhee Kang Min Jung Seo Eun Jung Park Henrieta ?kovierová Ha Pham Giovanna Riccardi Ji Youn Nam Laurent Marsollier Marie Kempf Marie-Laure Joly-Guillou Taegwon Oh Won Kyung Shin Zaesung No Ulf Nehrbass Roland Brosch Stewart T. Cole Priscille Brodin 《PLoS pathogens》2009,5(10)
A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2′ epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials. 相似文献
36.
Rayane Rafei Monzer Hamze Hélène Pailhoriès Matthieu Eveillard Laurent Marsollier Marie-Laure Joly-Guillou Fouad Dabboussi Marie Kempf 《Applied and environmental microbiology》2015,81(7):2359-2367
The presence of Acinetobacter baumannii outside hospitals is still a controversial issue. The objective of our study was to explore the extrahospital epidemiology of A. baumannii in Lebanon. From February 2012 to October 2013, a total of 73 water samples, 51 soil samples, 37 raw cow milk samples, 50 cow meat samples, 7 raw cheese samples, and 379 animal samples were analyzed by cultural methods for the presence of A. baumannii. Species identification was performed by rpoB gene sequencing. Antibiotic susceptibility was investigated, and the A. baumannii population was studied by two genotyping approaches: multilocus sequence typing (MLST) and blaOXA-51 sequence-based typing (SBT). A. baumannii was detected in 6.9% of water samples, 2.7% of milk samples, 8.0% of meat samples, 14.3% of cheese samples, and 7.7% of animal samples. All isolates showed a susceptible phenotype against most of the antibiotics tested and lacked carbapenemase-encoding genes, except one that harbored a blaOXA-143 gene. MLST analysis revealed the presence of 36 sequence types (STs), among which 24 were novel STs reported for the first time in this study. blaOXA-51 SBT showed the presence of 34 variants, among which 21 were novel and all were isolated from animal origins. Finally, 30 isolates had new partial rpoB sequences and were considered putative new Acinetobacter species. In conclusion, animals can be a potential reservoir for A. baumannii and the dissemination of new emerging carbapenemases. The roles of the novel animal clones identified in community-acquired infections should be investigated. 相似文献
37.
Intercalation of proflavine and a platinum derivative of proflavine into double-helical Poly(A)
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The equilibria and kinetics of the interactions of proflavine (PR) and its platinum-containing derivative [PtCl(tmen)(2)HNC(13)H(7)(NHCH(2)CH(2))(2)](+) (PRPt) with double-stranded poly(A) have been investigated by spectrophotometry and Joule temperature-jump relaxation at ionic strength 0.1 M, 25 degrees C, and pH 5.2. Spectrophotometric measurements indicate that base-dye interactions are prevailing. T-jump experiments with polarized light showed that effects due to field-induced alignment could be neglected. Both of the investigated systems display two relaxation effects. The kinetic features of the reaction are discussed in terms of a two-step series mechanism in which a precursor complex DS(I) is formed in the fast step, which is then converted to a final complex in the slow step. The rate constants of the fast step are k(1) = (2.5 +/- 0.4) x 10(6) M(-1) s(-1), k(-1) = (2.4 +/- 0.1) x 10(3) s(-1) for poly(A)-PR and k(1) = (2.3 +/- 0.1) x 10(6) M(-1) s(-1), k(-1) = (1.6 +/- 0.2) x 10(3) s(-1) for poly(A)-PRPt. The rate constants for the slow step are k(2) = (4.5 +/- 0.5) x 10(2) s(-1), k(-2) = (1.7 +/- 0.1) x 10(2) s(-1) for poly(A)-PR and k(2) = 9.7 +/- 1.2 s(-1), k(-2) = 10.6 +/- 0.2 s(-1) for poly(A)-PRPt. Spectrophotometric measurements yield for the equilibrium constants and site size the values K = (4.5 +/- 0.1) x 10(3) M(-1), n = 1.3 +/- 0.5 for poly(A)-PR and K = (2.9 +/- 0.1) x 10(3) M(-1), n = 2.3 +/- 0.6 for poly(A)-PRPt. The values of k(1) are similar and lower than expected for diffusion-limited reactions. The values of k(-1) are similar as well. It is suggested that the formation of DS(I) involves only the proflavine residues in both systems. In contrast, the values of k(2) and k(-2) in poly(A)-PRPt are much lower than in poly(A)-PR. The results suggest that in the complex DS(II) of poly(A)-PRPt both proflavine and platinum residues are intercalated. In addition, a very slow process was detected and ascribed to the covalent binding of Pt(II) to the adenine. 相似文献
38.
Daniel R Getts Meghann T Getts Derrick P McCarthy Emily ML Chastain Stephen D Miller 《MABS-AUSTIN》2010,2(6):682-694
The infusion of animal-derived antibodies has been known for some time to trigger the generation of antibodies directed at the foreign protein as well as adverse events including cytokine release syndrome. These immunological phenomena drove the development of humanized and fully human monoclonal antibodies. The ability to generate human(ized) antibodies has been both a blessing and a curse. While incremental gains in the clinical efficacy and safety for some agents have been realized, a positive effect has not been observed for all human(ized) antibodies. Many human(ized) antibodies trigger the development of anti-drug antibody responses and infusion reactions. The current belief that antibodies need to be human(ized) to have enhanced therapeutic utility may slow the development of novel animal-derived monoclonal antibody therapeutics for use in clinical indications. In the case of murine antibodies, greater than 20% induce tolerable/negligible immunogenicity, suggesting that in these cases humanization may not offer significant gains in therapeutic utility. Furthermore, humanization of some murine antibodies may reduce their clinical effectiveness. The available data suggest that the utility of human(ized) antibodies needs to be evaluated on a case-by-case basis, taking a cost-benefit approach, taking both biochemical characteristics and the targeted therapeutic indication into account.Key words: immunogenicity, human anti-mouse antibody, cytokine release syndrome 相似文献
39.
Josimari M DeSantana Kamilla ML da Cruz Kathleen A Sluka 《Arthritis research & therapy》2013,15(6):222
Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles. 相似文献
40.
Rayane Rafei Fouad Dabboussi Monzer Hamze Matthieu Eveillard Carole Lemarié Marie-Pierre Gaultier Hassan Mallat Rima Moghnieh Rola Husni-Samaha Marie-Laure Joly-Guillou Marie Kempf 《PloS one》2014,9(12)
This study analyzed 42 Acinetobacter baumannii strains collected between 2009–2012 from different hospitals in Beyrouth and North Lebanon to better understand the epidemiology and carbapenem resistance mechanisms in our collection and to compare the robustness of pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), repetitive sequence-based PCR (rep-PCR) and bla
OXA-51 sequence-based typing (SBT). Among 31 carbapenem resistant strains, we have detected three carbapenem resistance genes: 28 carried the bla
OXA-23 gene, 1 the bla
OXA-24 gene and 2 strains the bla
OXA-58 gene. This is the first detection of bla
OXA-23 and bla
OXA-24 in Lebanon. PFGE identified 11 types and was the most discriminating technique followed by rep-PCR (9 types), bla
OXA-51 SBT (8 types) and MLST (7 types). The PFGE type A''/ST2 was the dominant genotype in our collection present in Beyrouth and North Lebanon. The clustering agreement between all techniques was measured by adjust Wallace coefficient. An overall agreement has been demonstrated. High values of adjust Wallace coefficient were found with followed combinations: PFGE to predict MLST types = 100%, PFGE to predict bla
OXA-51 SBT = 100%, bla
OXA-51 SBT to predict MLST = 100%, MLST to predict bla
OXA-51 SBT = 84.7%, rep-PCR to predict MLST = 81.5%, PFGE to predict rep-PCR = 69% and rep-PCR to predict bla
OXA-51 SBT = 67.2%. PFGE and MLST are gold standard methods for outbreaks investigation and population structure studies respectively. Otherwise, these two techniques are technically, time and cost demanding. We recommend the use of bla
OXA-51 SBT as first typing method to screen isolates and assign them to their corresponding clonal lineages. Repetitive sequence-based PCR is a rapid tool to access outbreaks but careful interpretation of results must be always performed. 相似文献