489 research outputs found
Preventing human immunodeficiency virus infection among sexual assault survivors in Cape Town, South Africa: an observational study.
We describe 131 South African sexual assault survivors offered HIV post-exposure prophylaxis (PEP). While the median days completed was 27 (IQR 27, 28), 34% stopped PEP or missed doses. Controlling for baseline symptoms, PEP was not associated with symptoms (OR = 1.30, 95% CI = 0.66, 2.64). Factors associated with unprotected sex included prior unprotected sex (OR = 6.46, 95% CI = 3.04, 13.74), time since the assault (OR = 1.33, 95% CI = 1.12, 1.57) and age (OR = 1.30, 95% CI = 1.08, 1.57). Trauma counseling was protective (OR = 0.18, 95% CI = 0.05, 0.58). Four instances of seroconversion were observed by 6 months (risk = 3.7%, 95% CI = 1.0, 9.1). Proactive follow-up is necessary to increase the likelihood of PEP completion and address the mental health and HIV risk needs of survivors. Adherence interventions and targeted risk reduction counseling should be provided to minimize HIV acquisition
Kinome Profiling Identifies Druggable Targets for Novel Human Cytomegalovirus (HCMV) Antivirals
Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals. To this end, we applied a kinase capture technique, multiplexed kinase inhibitor bead-mass spectrometry (MIB-MS) kinome, to quantitatively measure perturbations in >240 cellular kinases simultaneously in cells infected with a laboratory-adapted (AD169) or clinical (TB40E) HCMV strain. MIB-MS profiling identified time-dependent increases and decreases in MIB binding of multiple kinases including cell cycle kinases, receptor tyrosine kinases, and mitotic kinases. Based on the kinome data, we tested the antiviral effects of kinase inhibitors and other compounds, several of which are in clinical use or development. Using a novel flow cytometry-based assay and a fluorescent reporter virus we identified three compounds that inhibited HCMV replication with IC 50 values of 3 log decrease in virus replication. These results show the utility of MIB-MS kinome profiling for identifying existing kinase inhibitors that can potentially be repurposed as novel antiviral drugs
Integrated information increases with fitness in the evolution of animats
One of the hallmarks of biological organisms is their ability to integrate
disparate information sources to optimize their behavior in complex
environments. How this capability can be quantified and related to the
functional complexity of an organism remains a challenging problem, in
particular since organismal functional complexity is not well-defined. We
present here several candidate measures that quantify information and
integration, and study their dependence on fitness as an artificial agent
("animat") evolves over thousands of generations to solve a navigation task in
a simple, simulated environment. We compare the ability of these measures to
predict high fitness with more conventional information-theoretic processing
measures. As the animat adapts by increasing its "fit" to the world,
information integration and processing increase commensurately along the
evolutionary line of descent. We suggest that the correlation of fitness with
information integration and with processing measures implies that high fitness
requires both information processing as well as integration, but that
information integration may be a better measure when the task requires memory.
A correlation of measures of information integration (but also information
processing) and fitness strongly suggests that these measures reflect the
functional complexity of the animat, and that such measures can be used to
quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary
video files available on request. Version commensurate with published text in
PLoS Comput. Bio
Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours
Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours.
Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.
Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).
Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs
Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function
The Effects of Electoral Institutions in Rwanda: Why Proportional Representation Supports the Authoritarian Regime
Charge separation relative to the reaction plane in Pb-Pb collisions at TeV
Measurements of charge dependent azimuthal correlations with the ALICE
detector at the LHC are reported for Pb-Pb collisions at TeV. Two- and three-particle charge-dependent azimuthal correlations in
the pseudo-rapidity range are presented as a function of the
collision centrality, particle separation in pseudo-rapidity, and transverse
momentum. A clear signal compatible with a charge-dependent separation relative
to the reaction plane is observed, which shows little or no collision energy
dependence when compared to measurements at RHIC energies. This provides a new
insight for understanding the nature of the charge dependent azimuthal
correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published
version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286
Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at TeV
The inclusive transverse momentum () distributions of primary
charged particles are measured in the pseudo-rapidity range as a
function of event centrality in Pb-Pb collisions at
TeV with ALICE at the LHC. The data are presented in the range
GeV/ for nine centrality intervals from 70-80% to 0-5%.
The Pb-Pb spectra are presented in terms of the nuclear modification factor
using a pp reference spectrum measured at the same collision
energy. We observe that the suppression of high- particles strongly
depends on event centrality. In central collisions (0-5%) the yield is most
suppressed with at -7 GeV/. Above
GeV/, there is a significant rise in the nuclear modification
factor, which reaches for GeV/. In
peripheral collisions (70-80%), the suppression is weaker with almost independently of . The measured nuclear
modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12,
published version, figures at
http://aliceinfo.cern.ch/ArtSubmission/node/284
Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at , 2.76 and 7 TeV
Measurements of the sphericity of primary charged particles in minimum bias
proton--proton collisions at , 2.76 and 7 TeV with the ALICE
detector at the LHC are presented. The observable is linearized to be collinear
safe and is measured in the plane perpendicular to the beam direction using
primary charged tracks with GeV/c in . The
mean sphericity as a function of the charged particle multiplicity at
mid-rapidity () is reported for events with different
scales ("soft" and "hard") defined by the transverse momentum of the leading
particle. In addition, the mean charged particle transverse momentum versus
multiplicity is presented for the different event classes, and the sphericity
distributions in bins of multiplicity are presented. The data are compared with
calculations of standard Monte Carlo event generators. The transverse
sphericity is found to grow with multiplicity at all collision energies, with a
steeper rise at low , whereas the event generators show the
opposite tendency. The combined study of the sphericity and the mean with multiplicity indicates that most of the tested event generators
produce events with higher multiplicity by generating more back-to-back jets
resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with
tune PERUGIA-2011 exhibits a noticeable improvement in describing the data,
compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16,
published version, figures from
http://aliceinfo.cern.ch/ArtSubmission/node/308
Elliptic flow of charged particles in Pb-Pb collisions at 2.76 TeV
We report the first measurement of charged particle elliptic flow in Pb-Pb
collisions at 2.76 TeV with the ALICE detector at the CERN Large Hadron
Collider. The measurement is performed in the central pseudorapidity region
(||<0.8) and transverse momentum range 0.2< < 5.0 GeV/. The
elliptic flow signal v, measured using the 4-particle correlation method,
averaged over transverse momentum and pseudorapidity is 0.087 0.002
(stat) 0.004 (syst) in the 40-50% centrality class. The differential
elliptic flow v reaches a maximum of 0.2 near = 3
GeV/. Compared to RHIC Au-Au collisions at 200 GeV, the elliptic flow
increases by about 30%. Some hydrodynamic model predictions which include
viscous corrections are in agreement with the observed increase.Comment: 10 pages, 4 captioned figures, published version, figures at
http://aliceinfo.cern.ch/ArtSubmission/node/389
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