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81.
Diahann TSL Jansen Hanane el Bannoudi Ramon Arens Kim LL Habets Marjolijn Hameetman Tom WJ Huizinga Jeroen N. Stoop René EM Toes 《Arthritis research & therapy》2015,17(1)
IntroductionAbatacept is a fusion protein of human cytotoxic T-lymphocyte–associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28–B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 molecules is crucial for activation of naive cells, whereas it is unclear whether the action of already activated CD4+ T cells, which are readily present in established disease, also depends on this interaction. The aim of this study was to determine whether the mode of action of abatacept depends solely on its ability to halt T cell activation in established disease.MethodsArthritis was induced in thymectomized male DBA/1 mice by immunisation with bovine collagen type II. The mice were subsequently depleted for CD4+ T cells. Abatacept or control treatment was started when 80 % of the mice showed signs of arthritis. Arthritis severity was monitored by clinical scoring of the paws, and anti-collagen antibody levels over time were determined by enzyme-linked immunosorbent assay.ResultsTreatment with abatacept in the absence of CD4+ T cells resulted in lower disease activity. This was associated with decreasing levels of collagen-specific IgG1 and IgG2a antibodies, whereas the antibody levels in control or CD4+ T cell–depleted mice increased over time.ConclusionsThese results show that abatacept decreased disease activity in the absence of CD4+ T cells, indicating that the mode of action of abatacept in established arthritis does not depend entirely on its effects on CD4+ T cell activation. 相似文献
82.
Irene EM Bultink D?rte Hamann Marc A Seelen Margreet H Hart Ben AC Dijkmans Mohamed R Daha Alexandre E Voskuyl 《Arthritis research & therapy》2007,8(6):R183
Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE
patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has
also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for
mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with
patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional
MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship
with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with
SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan
as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using
an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected
with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented
infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous
administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented
in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe
MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan
and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels
nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients
frequently suffer from infections, but deficiency of functional MBL does not confer additional risk. 相似文献
83.
Peltola M Kuosmanen T Sinkko H Vesalainen N Pulliainen M Korhonen P Partti-Pellinen K Räsänen JP Rintala J Kolari M Rita H Salkinoja-Salonen M 《Journal of industrial microbiology & biotechnology》2011,38(10):1719-1727
The antifouling potential of electric polarization combined and not combined with biocides was studied in nonsaline warm water with high organic content. Deinococcus geothermalis is a bacterium known for forming colored biofilms in paper machines and for its persistence against cleaning and chemical treatments. When D. geothermalis biofilms grown for 24 h in simulated paper machine water were exposed to cathodic or cathodically weighted pulsed polarization at least 60% (P < 0.05) of the biofilms were removed from stainless steel (AISI 316L). Biofilm removal by 25 ppm (effective substances 5-25 ppm) of oxidizing biocides (bromochloro-5,5-dimethylhydantoin, 2,2-dibromo-2-cyanoacetamide, peracetic acid) increased to 70% when combined with cathodically weighted pulsed polarization. Using a novel instrument that allows real-time detection of reactive oxygen species (ROS) we showed that the polarization program effective in antifouling generated ROS in a pulsed manner on the steel surface. We thus suggest that the observed added value of oxidative biocides combined with polarization depended on ROS. This suggestion was supported by the finding that a reductive biocide, methylene bisthiocyanate, counteracted the antifouling effect of polarization. 相似文献
84.
Phylogenetic analysis of the outer-membrane-protein genes of Chlamydiae, and its implication for vaccine development 总被引:9,自引:0,他引:9
Examination of 18 complete and 6 partial sequences of the major outer-
membrane protein from 24 chlamydiae isolates was used to reconstruct their
evolutionary relationships. From this analysis, assuming that the clades
with 100% bootstrap support are correct, come the following conclusions:
(1) The tree of these sequences is not congruent with the phylogeny of the
hosts, and thus host switching would seem to have occurred, thereby
limiting the extent to which there has been coevolution of parasite and
host. (2) The tree is also noncongruent with clustering by type of cell
infected, thereby limiting the extent to which there has been coevolution
of parasite and the cell type that it infects. (3) The tree is also
noncongruent with clustering by the organ infected (eyes or genitalia),
thereby limiting the extent to which there has been coevolution of parasite
and the organ that it infects. (4) The tree is also noncongruent with
genital strains arising from lymphogranuloma venereum strains. (5) The tree
is also noncongruent with the geographic site at which the isolates were
obtained, thereby limiting the extent of divergence explained by geographic
separation. (6) There are estimated to be 185 amino acid positions that are
invariable (as opposed to unvaried) in the major outer-membrane protein.
There are 10 unvaried positions in the variable domains, of which 9 appear
to be invariable, giving some reason to hope that development of a vaccine
might be possible. (7) The rate of change of this protein is too small to
see increased divergence over the time span of isolation of these genes,
giving hope to any vaccine having longevity. Bootstrapping supports those
portions of the tree on which the first five conclusions above depend. The
picture that these results provide is more one of pathogen versatility than
one of coevolutionary constraints. In addition, we examined 10 60-KDa,
outer-membrane protein- 2 genes, all but one of which were from these same
strains. The tree was not, among the trachomatis strains, congruent with
the major-outer- membrane protein tree, suggesting that gene exchange could
be occurring among strains. Moreover, there is an apparent slowdown in
divergence in this gene, among the trachomatis strains.
相似文献
85.
Xiang Zhao Juha Kuja-Panula Maria Sundvik Yu-Chia Chen Vilma Aho Marjaana A. Peltola Tarja Porkka-Heiskanen Pertti Panula Heikki Rauvala 《The Journal of biological chemistry》2014,289(29):19958-19975
The Amigo protein family consists of three transmembrane proteins characterized by six leucine-rich repeat domains and one immunoglobulin-like domain in their extracellular moieties. Previous in vitro studies have suggested a role as homophilic adhesion molecules in brain neurons, but the in vivo functions remain unknown. Here we have cloned all three zebrafish amigos and show that amigo1 is the predominant family member expressed during nervous system development in zebrafish. Knockdown of amigo1 expression using morpholino oligonucleotides impairs the formation of fasciculated tracts in early fiber scaffolds of brain. A similar defect in fiber tract development is caused by mRNA-mediated expression of the Amigo1 ectodomain that inhibits adhesion mediated by the full-length protein. Analysis of differentiated neural circuits reveals defects in the catecholaminergic system. At the behavioral level, the disturbed formation of neural circuitry is reflected in enhanced locomotor activity and in the inability of the larvae to perform normal escape responses. We suggest that Amigo1 is essential for the development of neural circuits of zebrafish, where its mechanism involves homophilic interactions within the developing fiber tracts and regulation of the Kv2.1 potassium channel to form functional neural circuitry that controls locomotion. 相似文献
86.
Angelika Wientzek María‐José Tormo Díaz Jose Maria Huerta Castaño Pilar Amiano Larraitz Arriola Kim Overvad Jane Nautrup Østergaard Marie‐Aline Charles Guy Fagherazzi Domenico Palli Benedetta Bendinelli Guri Skeie Kristin Benjaminsen Borch Wanda Wendel‐Vos Ellen de Hollander Anne M. May Marjolein EM den Ouden Antonia Trichopoulou Elissavet Valanou Stefan Söderberg Paul W. Franks Soren Brage Matthäus Vigl Heiner Boeing Ulf Ekelund 《Obesity (Silver Spring, Md.)》2014,22(5):E127-E134
87.
88.
Tuula Jyske Markku Manner Harri Mäkinen Pekka Nöjd Heli Peltola Tapani Repo 《Trees - Structure and Function》2012,26(2):405-419
We studied the effects of artificial soil frost on cambial activity and xylem formation on 47-year-old Norway spruce [Picea abies (L.) Karst.] trees grown on medium fertile site type (with moraine soil) in eastern Finland (62°42′N; 29°45′E). Different
soil frost treatments applied were: (1) natural snow accumulation and melting (control, CTRL); (2) artificial removal of snow
from soil surface during two consecutive winters (OPEN); and (3) snow clearing and insulation (FROST), which was in other
ways similar to OPEN, but the ground was insulated in early spring to delay soil thawing. Each treatment was replicated in
three blocks, and two sample trees in each plot were repeatedly microcored during growing seasons of 2006–2007 for the analysis
of the onset, cessation and the duration of xylem formation. The phases of tracheid differentiation (tracheids in radial enlargement,
secondary cell wall formation, and mature tracheids) were measured from the microcores of 2007. The intra-ring growth and
wood density variables were analysed based on X-ray densitometry. In FROST in 2006, xylem formation started a week later than
in the other treatments. In 2007, no difference was found between the treatments. The discrepancy in results between the two
study years may be explained by between-years variation in weather, i.e., the winter was colder in 2005/2006 than in 2006/2007.
No effects of soil frost treatments on tracheid differentiation and on most of the intra-ring growth and density variables
were discovered. Our results suggest that the delayed thawing of moraine soil may slightly affect the onset, timing and duration
of xylem formation in Norway spruce. However, the effects of delayed soil frost may depend also on the soil type and become
more evident with increasing water holding capacity of the soil. 相似文献
89.
High-dimensional datasets with large amounts of redundant information are nowadays available for hypothesis-free exploration of scientific questions. A particular case is genome-wide association analysis, where variations in the genome are searched for effects on disease or other traits. Bayesian variable selection has been demonstrated as a possible analysis approach, which can account for the multifactorial nature of the genetic effects in a linear regression model.Yet, the computation presents a challenge and application to large-scale data is not routine. Here, we study aspects of the computation using the Metropolis-Hastings algorithm for the variable selection: finite adaptation of the proposal distributions, multistep moves for changing the inclusion state of multiple variables in a single proposal and multistep move size adaptation. We also experiment with a delayed rejection step for the multistep moves. Results on simulated and real data show increase in the sampling efficiency. We also demonstrate that with application specific proposals, the approach can overcome a specific mixing problem in real data with 3822 individuals and 1,051,811 single nucleotide polymorphisms and uncover a variant pair with synergistic effect on the studied trait. Moreover, we illustrate multimodality in the real dataset related to a restrictive prior distribution on the genetic effect sizes and advocate a more flexible alternative. 相似文献
90.
The aim of this study was to analyze the effects of intensive management and forest landscape structure (in terms of age class distribution) on timber and energy wood production (m3?ha?1), net present value (NPV, ? ha?1) with implications on net CO2 emissions (kg CO2 MWh?1 per energy unit) from energy wood use of Norway spruce grown on medium to fertile sites. This study employed simulations using a forest ecosystem model and the Emission Calculation Tool, considering in its analyses: timber (saw logs, pulp) and energy wood (small-sized stem wood and/or logging residuals for top part of stem, branches, and needles) from the first thinning and harvesting residuals and stumps from the final felling. At the stand level, both fertilization and high pre-commercial stand density clearly increased timber production and the amount of energy wood. Short rotation length (40 and 60?years) outputted, on average, the highest annual stem wood production (most fertile and medium fertile sites), the 60?year rotation also outputted the highest average annual net present value (NPV with interest rates of 1?C4%). On the other hand, even longer rotation lengths, up to 80 and 100?years, were needed to output the lowest net CO2 emissions per year in energy wood use. At the landscape level, the largest productivity (both for timber and energy wood) was obtained using rotation lengths of 60 and 80?years with an initial forest landscape structure dominated by older mature stands (a right-skewed age-class distribution). If the rotation length was 120?years, the initial forest landscape dominated by young stands (a left-skewed age-class distribution) provided the highest productivity. However, the NPV with interest rate of 2% was, on average, the highest with a right-skewed distribution regardless of the rotation length. If the rotation length was 120?years, normal age class distribution provided, on average, the highest NPV. On the other hand, the lowest emissions (kg CO2 MWh?1a?1) were obtained with the left-skewed age-class distribution using the rotation lengths of 60 and 80?years, and with the normal age-class distribution using the rotation length of 120?years. Altogether, the management regimes integrating both timber and energy wood production and using fertilization provided, on average, the lowest emissions over all management alternatives considered. 相似文献