241 research outputs found
Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study
OBJECTIVES: We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry.
METHODS: Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 Δ32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored.
RESULTS: Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 × 10(-8)) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 Δ32 genotype in the nongenome-wide analysis.
CONCLUSIONS: No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage
Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice
Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy
Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels
Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading
Observational Diagnostics of Gas Flows: Insights from Cosmological Simulations
Galactic accretion interacts in complex ways with gaseous halos, including
galactic winds. As a result, observational diagnostics typically probe a range
of intertwined physical phenomena. Because of this complexity, cosmological
hydrodynamic simulations have played a key role in developing observational
diagnostics of galactic accretion. In this chapter, we review the status of
different observational diagnostics of circumgalactic gas flows, in both
absorption (galaxy pair and down-the-barrel observations in neutral hydrogen
and metals; kinematic and azimuthal angle diagnostics; the cosmological column
density distribution; and metallicity) and emission (Lya; UV metal lines; and
diffuse X-rays). We conclude that there is no simple and robust way to identify
galactic accretion in individual measurements. Rather, progress in testing
galactic accretion models is likely to come from systematic, statistical
comparisons of simulation predictions with observations. We discuss specific
areas where progress is likely to be particularly fruitful over the next few
years.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics
and Space Science Library, eds. A. J. Fox & R. Dave, to be published by
Springer. Typos correcte
Cancer Appetite and Symptom Questionnaire (CASQ) for Brazilian Patients: Cross-Cultural Adaptation and Validation Study
Background
Appetite and symptoms, conditions generally reported by the patients with cancer, are
somewhat challenging for professionals to measure directly in clinical routine (latent conditions).
Therefore, specific instruments are required for this purpose. This study aimed to perform
a cultural adaptation of the Cancer Appetite and Symptom Questionnaire (CASQ), into
Portuguese and evaluate its psychometric properties on a sample of Brazilian cancer
patients.
Methods
This is a validation study with Brazilian cancer patients. The face, content, and construct
(factorial and convergent) validities of the Cancer Appetite and Symptom Questionnaire,
the study tool, were estimated. Further, a confirmatory factor analysis (CFA) was conducted.
The ratio of chi-square and degrees of freedom (χ2
/df), comparative fit index (CFI),
goodness of fit index (GFI) and root mean square error of approximation (RMSEA) were
used for fit model assessment. In addition, the reliability of the instrument was estimated
using the composite reliability (CR) and Cronbach’s alpha coefficient (α), and the invariance
of the model in independent samples was estimated by a multigroup analysis (Δχ2).
Results
Participants included 1,140 cancer patients with a mean age of 53.95 (SD = 13.25) years;
61.3% were women. After the CFA of the original CASQ structure, 2 items with inadequate
factor weights were removed. Four correlations between errors were included to provide
adequate fit to the sample (χ2
/df = 8.532, CFI = .94, GFI = .95, and RMSEA = .08). Themodel exhibited a low convergent validity (AVE = .32). The reliability was adequate
(CR = .82 α = .82). The refined model showed strong invariance in two independent samples
(Δχ2
: λ: p = .855; i: p = .824; Res: p = .390). A weak stability was obtained between
patients undergoing chemotherapy and radiotherapy (Δχ2
: λ: p = .155; i: p < .001; Res:
p < .001), and between patients undergoing chemotherapy combined with radiotherapy
and palliative care (Δχ2
: λ: p = .058; i: p < .001; Res: p < .001).
Conclusion
The Portuguese version of the CASQ had good face and construct validity and reliability.
However, the CASQ still presented invariance in independent samples of Brazilian patients
with cancer. However, the tool has low convergent validity and weak invariance in samples
with different treatment
Gas Accretion in Star-Forming Galaxies
Cold-mode gas accretion onto galaxies is a direct prediction of LCDM
simulations and provides galaxies with fuel that allows them to continue to
form stars over the lifetime of the Universe. Given its dramatic influence on a
galaxy's gas reservoir, gas accretion has to be largely responsible for how
galaxies form and evolve. Therefore, given the importance of gas accretion, it
is necessary to observe and quantify how these gas flows affect galaxy
evolution. However, observational data have yet to conclusively show that gas
accretion ubiquitously occurs at any epoch. Directly detecting gas accretion is
a challenging endeavor and we now have obtained a significant amount of
observational evidence to support it. This chapter reviews the current
observational evidence of gas accretion onto star-forming galaxies.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics
and Space Science Library, eds. A. J. Fox & R. Dav\'e, to be published by
Springer. This chapter includes 22 pages with 7 Figure
Not All Missed Doses Are the Same: Sustained NNRTI Treatment Interruptions Predict HIV Rebound at Low-to-Moderate Adherence Levels
Background: While the relationship between average adherence to HIV potent antiretroviral therapy is well defined, the relationship between patterns of adherence within adherence strata has not been investigated. We examined medication event monitoring system (MEMS) defined adherence patterns and their relation to subsequent virologic rebound. Methods and Results: We selected subjects with at least 3-months of previous virologic suppression on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen from two prospective cohorts in France and North America. We assessed the risk of virologic rebound, defined as HIV RNA of >400 copies/mL according to several MEMS adherence measurements. Seventy two subjects were studied, five of them experienced virologic rebound. Subjects with and without virologic rebound had similar baseline characteristics including treatment durations, regimen (efavirenz vs nevirapine), and dosing schedule. Each 10% increase in average adherence decreased the risk of virologic rebound (OR = 0.56; 95% confidence interval (CI) [0.37, 0.81], P<0.002). Each additional consecutive day off therapy for the longest treatment interruption (OR = 1.34; 95%CI [1.15, 1.68], P<0.0001) and each additional treatment interruption for more than 2 days (OR = 1.38; 95%CI [1.13, 1.77], P<0.002) increased the risk of virologic rebound. In those with low-to-moderate adherence (i.e. <80%), treatment interruption duration (16.2 days versus 6.1 days in the control group, P<0.02), but not average adherence (53.1% vs 55.9%, respectively, P = 0.65) was significantly associated with virologic rebound. Conclusions: Sustained treatment interruption may pose a greater risk of virologic rebound on NNRTI therapy than the same number of interspersed missed doses at low-to-moderate adherence
Minor Protease Inhibitor Mutations at Baseline Do Not Increase the Risk for a Virological Failure in HIV-1 Subtype B Infected Patients
BACKGROUND: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential.
METHODS: To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥ 1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs.
RESULTS: We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥ 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥ 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome.
CONCLUSIONS: The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals
Physical Habitat and Fish Assemblage Relationships with Landscape Variables at Multiple Spatial Scales in Wadeable Iowa Streams
Landscapes in Iowa and other midwestern states have been profoundly altered by conversion of native prairies to agriculture. We analyzed landscape data collected at multiple spatial scales to explore relationships with reach-scale physical habitat and fish assemblage data from 93 randomly selected sites on second- through fifth-order wadeable Iowa streams. Ordination of sites by physical habitat showed significant gradients of channel shape, habitat complexity, substrate composition, and stream size. Several landscape variables were significantly associated with the physical habitat ordination. Row crop land use was associated with fine substrates and steep bank angles, whereas wetland land cover and greater sinuosity and catchment land area were associated with complex channel and bank morphology and greater residual pool volume, woody debris, and canopy cover. Thirteen landscape variables were significant predictors of physical habitat variables in multiple linear regressions, with adjusted R 2 values ranging from 0.07 to 0.74. Inclusion of landscape variables with physical habitat variables in multiple regression models predicting fish assemblage metrics and a fish index of biotic integrity resulted in negligible improvements over models based on only physical habitat variables. Physical habitat in wadeable Iowa streams is strongly associated with landscape characteristics. Results of this study and previous studies suggest that (1) landscape factors directly influence physical habitat, (2) physical habitat directly influences fish assemblages, and (3) the influence of landscape factors on fish assemblages is primarily indirect. Understanding how landscape factors, such as human land use, influence physical habitat and fish assemblages will help managers make more informed decisions for improving Iowa\u27s wadeable streams
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