Efficient cellular release of Rift Valley fever virus requires genomic RNA

The Rift Valley fever virus is responsible for periodic, explosive epizootics throughout sub-Saharan Africa. The development of therapeutics targeting this virus is difficult due to a limited understanding of the viral replicative cycle. Utilizing a virus-like particle system, we have established roles for each of the viral structural components in assembly, release, and virus infectivity. The envelope glycoprotein, Gn, was discovered to be necessary and sufficient for packaging of the genome, nucleocapsid protein and the RNA-dependent RNA polymerase into virus particles. Additionally, packaging of the genome was found to be necessary for the efficient release of particles, revealing a novel mechanism for the efficient generation of infectious virus. Our results identify possible conserved targets for development of anti-phlebovirus therapies.     

Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.     

Comprehensive analysis of 5-aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead

Background

Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.

Methods

The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.

Results

The adjusted risk associated with the ALAD variant rs8177796^CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (^GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; ^GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (p_int = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435^(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.

Conclusion

A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.     

Human rhinovirus infections in rural Thailand: epidemiological evidence for rhinovirus as both pathogen and bystander

Background

We describe human rhinovirus (HRV) detections in SaKaeo province, Thailand.

Methods

From September 1, 2003–August 31, 2005, we tested hospitalized patients with acute lower respiratory illness and outpatient controls without fever or respiratory symptoms for HRVs with polymerase chain reaction and molecularly-typed select HRVs. We compared HRV detection among hospitalized patients and controls and estimated enrollment adjusted incidence.

Results

HRVs were detected in 315 (16%) of 1919 hospitalized patients and 27 (9.6%) of 280 controls. Children had the highest frequency of HRV detections (hospitalized: <1 year: 29%, 1–4 year: 29%, ≥65 years: 9%; controls: <1 year: 24%, 1–4 year: 14%, ≥65 years: 2.8%). Enrollment adjusted hospitalized HRV detection rates were highest among persons aged <1 year (1038/100,000 persons/year), 1–4 years (457), and ≥65 years (71). All three HRV species were identified, HRV-A was the most common species in most age groups including children aged <1 year (61%) and all adult age groups. HRV-C was the most common species in the 1–4 year (51%) and 5–19 year age groups (54%). Compared to controls, hospitalized adults (≥19 years) and children were more likely to have HRV detections (odds ratio [OR]: 4.8, 95% confidence interval [CI]: 1.5, 15.8; OR: 2.0, CI: 1.2, 3.3, respectively) and hospitalized children were more likely to have HRV-A (OR 1.7, CI: 0.8, 3.5) or HVR-C (OR 2.7, CI: 1.2, 5.9) detection.

Conclusions

HRV rates were high among hospitalized children and the elderly but asymptomatic children also had substantial HRV detection. HRV (all species), and HRV-A and HRV-C detections were epidemiologically-associated with hospitalized illness. Treatment or prevention modalities effective against HRV could reduce hospitalizations due to HRV in Thailand.     

1H, 15N, and 13C assignments of the N-terminal activation domain of Dictyostelium discoideum Formin C

Dictyostelium discoideum Formin C (ForC) plays an important role in the fruiting body formation during the multicellular stages of the slime mold. Formins are multidomain proteins that are known to regulate the actin cytoskeleton. Here, we report the assignments of the ¹H, ¹⁵N, and ¹³C nuclei of the N-terminal activation domain (residues 1–100) of ForC. Chemical shifts have been deposited at the BioMagResBank under the BMRB accession number 17,029. The N-terminal region of the 131 kDa ForC protein is supposed to form a GTPase-binding domain required for activation of the formin.     

Body temperature patterns and rhythmicity in free-ranging subterranean Damaraland mole-rats, Fukomys damarensis

Body temperature (T(b)) is an important physiological component that affects endotherms from the cellular to whole organism level, but measurements of T(b) in the field have been noticeably skewed towards heterothermic species and seasonal comparisons are largely lacking. Thus, we investigated patterns of T(b) patterns in a homeothermic, free-ranging small mammal, the Damaraland mole-rat (Fukomys damarensis) during both the summer and winter. Variation in T(b) was significantly greater during winter than summer, and greater among males than females. Interestingly, body mass had only a small effect on variation in T(b) and there was no consistent pattern relating ambient temperature to variation in T(b). Generally speaking, it appears that variation in T(b) patterns varies between seasons in much the same way as in heterothermic species, just to a lesser degree. Both cosinor analysis and Fast Fourier Transform analysis revealed substantial individual variation in T(b) rhythms, even within a single colony. Some individuals had no T(b) rhythms, while others appeared to exhibit multiple rhythms. These data corroborate previous laboratory work showing multiplicity of rhythms in mole-rats and suggest the variation seen in the laboratory is a true indicator of the variation seen in the wild.     

On the time course of vocal emotion recognition

How quickly do listeners recognize emotions from a speaker''s voice, and does the time course for recognition vary by emotion type? To address these questions, we adapted the auditory gating paradigm to estimate how much vocal information is needed for listeners to categorize five basic emotions (anger, disgust, fear, sadness, happiness) and neutral utterances produced by male and female speakers of English. Semantically-anomalous pseudo-utterances (e.g., The rivix jolled the silling) conveying each emotion were divided into seven gate intervals according to the number of syllables that listeners heard from sentence onset. Participants (n = 48) judged the emotional meaning of stimuli presented at each gate duration interval, in a successive, blocked presentation format. Analyses looked at how recognition of each emotion evolves as an utterance unfolds and estimated the “identification point” for each emotion. Results showed that anger, sadness, fear, and neutral expressions are recognized more accurately at short gate intervals than happiness, and particularly disgust; however, as speech unfolds, recognition of happiness improves significantly towards the end of the utterance (and fear is recognized more accurately than other emotions). When the gate associated with the emotion identification point of each stimulus was calculated, data indicated that fear (M = 517 ms), sadness (M = 576 ms), and neutral (M = 510 ms) expressions were identified from shorter acoustic events than the other emotions. These data reveal differences in the underlying time course for conscious recognition of basic emotions from vocal expressions, which should be accounted for in studies of emotional speech processing.     

Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age

Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 μg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 μg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.