214 research outputs found
Synthesis and structural characterization of a mimetic membrane-anchored prion protein
During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP
Promoting STI testing among senior vocational students in Rotterdam, the Netherlands: effects of a cluster randomized study
Background: Adolescents are a risk group for acquiring sexually transmitted infections (STIs). In the Netherlands, senior vocational school students are particular at risk. However, STI test rates among adolescents are low and interventions that promote testing are scarce. To enhance voluntary STI testing, an intervention was designed and evaluated in senior vocational schools. The intervention combined classroom health education with sexual health services at the school site. The purpose of this study was to assess the combined and single effects on STI testing of health education and school-based sexual health services. Methods. In a cluster-randomized study the intervention was evaluated in 24 schools, using three experimental conditions: 1) health education, 2) sexual health services; 3) both components; and a control group. STI testing was assessed by self reported behavior and registrations at regional sexual health services. Follow-up measurements were performed at 1, 3, and 6-9 months. Of 1302 students present at baseline, 739 (57%) completed at least 1 follow-up measurement, of these students 472 (64%) were sexually experienced, and considered to be susceptible for the intervention. Multi-level analyses were conducted. To perform analyses according to the principle of intention-to-treat, missing observations at follow-up on the outcome measure were imputed with multiple imputation techniques. Results were compared with the complete cases analysis. Results: Sexually experienced students that received the combined intervention of health education and sexual health services reported more STI testing (29%) than students in the control group (4%) (OR = 4.3, p < 0.05). Test rates in the group that received education or sexual health services only were 5.7% and 19.9%, not reaching statistical significance in multilevel analyses. Female students were more often tested then male students: 21.5% versus 5.4%. The STI-prevalence in the study group was low with 1.4%. Conclusions: Despite a low dose of intervention that was received by the students and a high attrition, we were able to show an intervention effect among sexually experienced students on STI testing. This study confirmed our hypothesis that offering health education to vocational students in combination with sexual health services at school sites is more effective in enhancing STI testing than offering services or education only
Mutation of pescadillo Disrupts Oligodendrocyte Formation in Zebrafish
Background: In vertebrates, the myelin sheath is essential for efficient propagation of action potentials along the axon shaft. Oligodendrocytes are the cells of the central nervous system that create myelin sheaths. During embryogenesis, ventral neural tube precursors give rise to oligodendrocyte progenitor cells, which divide and migrate throughout the central nervous system. This study aimed to investigate mechanisms that regulate oligodendrocyte progenitor cell formation. Methodology/Principal Findings: By conducting a mutagenesis screen in transgenic zebrafish, we identified a mutation, designated vu166, by an apparent reduction in the number of oligodendrocyte progenitor cells in the dorsal spinal cord. We subsequently determined that vu166 is an allele of pescadillo, a gene known to play a role in ribosome biogenesis and cell proliferation. We found that pescadillo function is required for both the proper number of oligodendrocyte progenitors to form, by regulating cell cycle progression, and for normal levels of myelin gene expression. Conclusions/Significance: Our data provide evidence that neural precursors require pes function to progress through th
Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters
Recent progress in studies of globular clusters has shown that they are not
simple stellar populations, being rather made of multiple generations. Evidence
stems both from photometry and spectroscopy. A new paradigm is then arising for
the formation of massive star clusters, which includes several episodes of star
formation. While this provides an explanation for several features of globular
clusters, including the second parameter problem, it also opens new
perspectives about the relation between globular clusters and the halo of our
Galaxy, and by extension of all populations with a high specific frequency of
globular clusters, such as, e.g., giant elliptical galaxies. We review progress
in this area, focusing on the most recent studies. Several points remain to be
properly understood, in particular those concerning the nature of the polluters
producing the abundance pattern in the clusters and the typical timescale, the
range of cluster masses where this phenomenon is active, and the relation
between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review
Measurements of the properties of Lambda_c(2595), Lambda_c(2625), Sigma_c(2455), and Sigma_c(2520) baryons
We report measurements of the resonance properties of Lambda_c(2595)+ and
Lambda_c(2625)+ baryons in their decays to Lambda_c+ pi+ pi- as well as
Sigma_c(2455)++,0 and Sigma_c(2520)++,0 baryons in their decays to Lambda_c+
pi+/- final states. These measurements are performed using data corresponding
to 5.2/fb of integrated luminosity from ppbar collisions at sqrt(s) = 1.96 TeV,
collected with the CDF II detector at the Fermilab Tevatron. Exploiting the
largest available charmed baryon sample, we measure masses and decay widths
with uncertainties comparable to the world averages for Sigma_c states, and
significantly smaller uncertainties than the world averages for excited
Lambda_c+ states.Comment: added one reference and one table, changed order of figures, 17
pages, 15 figure
Search for a New Heavy Gauge Boson Wprime with Electron + missing ET Event Signature in ppbar collisions at sqrt(s)=1.96 TeV
We present a search for a new heavy charged vector boson decaying
to an electron-neutrino pair in collisions at a center-of-mass
energy of 1.96\unit{TeV}. The data were collected with the CDF II detector
and correspond to an integrated luminosity of 5.3\unit{fb}^{-1}. No
significant excess above the standard model expectation is observed and we set
upper limits on . Assuming standard
model couplings to fermions and the neutrino from the boson decay to
be light, we exclude a boson with mass less than
1.12\unit{TeV/}c^2 at the 95\unit{%} confidence level.Comment: 7 pages, 2 figures Submitted to PR
Unification of New Zealand's local vertical datums: iterative gravimetric quasigeoid computations
New Zealand uses 13 separate local vertical datums (LVDs) based on normal-orthometric-corrected precise geodetic levelling from 12 different tide-gauges. We describe their unification using a regional gravimetric quasigeoid model and GPS-levelling data on each LVD. A novel application of iterative quasigeoid computation is used, where the LVD offsets computed from earlier models are used to apply additional gravity reductions from each LVD to that model. The solution converges after only three iterations yielding LVD offsets ranging from 0.24 m to 0.58 m with an average standard deviation of 0.08 m. The so-computed LVD offsets agree, within expected data errors, with geodetically levelled height differences at common benchmarks between adjacent LVDs. This shows that iterated quasigeoid models do have a role in vertical datum unification
Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis
Aims/hypothesis The innate immune cells, invariant natural
killer T cells (iNKT cells), are implicated in the pathogenesis
of psoriasis, an inflammatory condition associated with
obesity and other metabolic diseases, such as diabetes and
dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an
incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor
agonist. This was independent of change in glycaemic control.
We proposed that this unexpected clinical outcome resulted
from a direct effect of GLP-1 on iNKTcells.
Methods We measured circulating and psoriatic plaque
iNKT cell numbers in two patients with type 2 diabetes
and psoriasis before and after commencing GLP-1 analogue
therapy. In addition, we investigated the in vitro effects of
GLP-1 on iNKT cells and looked for a functional GLP-1
receptor on these cells.
Results The Psoriasis Area and Severity Index improved in
both patients following 6 weeks of GLP-1 analogue
therapy. This was associated with an alteration in iNKT
cell number, with an increased number in the circulation
and a decreased number in psoriatic plaques. The GLP-1
receptor was expressed on iNKT cells, and GLP-1 induced
a dose-dependent inhibition of iNKT cell cytokine secretion,
but not cytolytic degranulation in vitro.
Conclusions/interpretation The clinical effect observed and
the direct interaction between GLP-1 and the immune
system raise the possibility of therapeutic applications for
GLP-1 in inflammatory conditions such as psoriasis
Invited Commentary: Broadening the Evidence for Adolescent Sexual and Reproductive Health and Education in the United States
Globular cluster systems and galaxy formation
Globular clusters are compact, gravitationally bound systems of up to a
million stars. The GCs in the Milky Way contain some of the oldest stars known,
and provide important clues to the early formation and continuing evolution of
our Galaxy. More generally, GCs are associated with galaxies of all types and
masses, from low-mass dwarf galaxies to the most massive early-type galaxies
which lie in the centres of massive galaxy clusters. GC systems show several
properties which connect tightly with properties of their host galaxies. For
example, the total mass of GCs in a system scales linearly with the dark matter
halo mass of its host galaxy. Numerical simulations are at the point of being
able to resolve globular cluster formation within a cosmological framework.
Therefore, GCs link a range of scales, from the physics of star formation in
turbulent gas clouds, to the large-scale properties of galaxies and their dark
matter. In this Chapter we review some of the basic observational approaches
for GC systems, some of their key observational properties, and describe how
GCs provide important clues to the formation of their parent galaxies.Comment: 32 pages, 6 figures. Accepted for publication in the book "Reviews in
Frontiers of Modern Astrophysics: From Space Debris to Cosmology" (eds
Kabath, Jones and Skarka; publisher Springer Nature) funded by the European
Union Erasmus+ Strategic Partnership grant "Per Aspera Ad Astra Simul"
2017-1-CZ01-KA203-03556
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