Immune gene variability influences roe deer natal dispersal

Dispersal is a key life‐history trait governing the response of individuals, populations and species to changing environmental conditions. In the context of global change, it is therefore essential to better understand the respective role of condition‐, phenotype‐ and genetic‐dependent drivers of dispersal behaviour. Although the importance of immune function and pathogen infestation in determining patterns of dispersal is increasingly recognised, no study to our knowledge has yet investigated the influence of immune gene variability on dispersal behaviour. Here, we filled this knowledge gap by assessing whether individual heterozygosity at five immune gene loci (one from the Major histocompatibility complex and four from encoding Toll‐like receptors) influences roe deer natal dispersal. We found that dispersal propensity was affected by immune gene diversity, suggesting potential pathogen‐mediated selection through over‐dominance. However, the direction of this effect differed between high and low quality individuals, suggesting that dispersal propensity is driven by two different mechanisms. In support of the condition‐dependent dispersal hypothesis, dispersal propensity increased with increasing body mass and, among high quality individuals only (standardized body mass > 18 kg), with increasing immune gene diversity. However, among poor quality individuals, we observed the opposite pattern such that dispersal propensity was higher for individuals with lower immune gene diversity. We suggest that these poor quality individuals expressed an emergency dispersal tactic in an attempt to escape a heavily infested environment associated with poor fitness prospects. Our results have potentially important consequences in terms of population genetics and demography, as well as host–pathogen evolution.     

The concerted conformational changes during human rhinovirus 2 uncoating

Delivery of the rhinovirus genome into the cytoplasm involves a cooperative structural modification of the viral capsid. We have studied this phenomenon for human rhinovirus serotype 2 (HRV2). The structure of the empty capsid has been determined to a resolution of better than 15 A by cryo-electron microscopy, and the atomic structure of native HRV2 was used to examine conformational changes of the capsid. The two proteins around the 5-fold axes make an iris type of movement to open a 10 A diameter channel which allows the RNA genome to exit, and the N terminus of VP1 exits the capsid at the pseudo 3-fold axis. A remarkable modification occurs at the 2-fold axes where the N-terminal loop of VP2 bends inward, probably to detach the RNA.     

Dietary antioxidants as inhibitors of the heme-induced peroxidation of linoleic acid: mechanism of action and synergism

In this work, a quantitative kinetic model for investigating the heme-induced peroxidation of linoleic acid and its inhibition by two important dietary antioxidants, quercetin and alpha-tocopherol, is developed. The main conclusions of this work are: (1) The time dependence of the lipid hydroperoxide concentration is critically dependent on the rate constant for lipid hydroperoxide cleavage, initial fraction of lipid hydroperoxides among the pool of conjugated dienes, and rate of heme degradation. (2) The lipophilic antioxidant alpha-tocopherol acts as a chain-breaking antioxidant that quickly reduces 1-2 eq of lipid peroxyl radicals (inhibition of propagation), whereas the more hydrophilic antioxidant quercetin is only marginally chain-breaking but capable of reducing 4-5 eq of iron-oxo initiator (inhibition of initiation). (3) Based on comparisons between experimental peroxidation curves and simulated curves assuming additivity, it can be concluded that combinations of alpha-tocopherol and quercetin are generally synergistic. The kinetic analysis and HPLC titrations of the antioxidants both suggest that synergism mainly arises from a capacity of alpha-tocopherol to regenerate some quercetin oxidation products still endowed with a reducing activity.     

Alcohol Consumption in Midlife and Cognitive Performance Assessed 13 Years Later in the SU.VI.MAX 2 Cohort

Background

Associations between alcohol consumption and cognitive function are discordant and data focusing on midlife exposure are scarce.

Objective

To estimate the association between midlife alcohol consumption and cognitive performance assessed 13 y later while accounting for comorbidities and diet.

Methods

3,088 French middle-aged adults included in the SU.VI.MAX (1994) study with available neuropsychological evaluation 13 y later. Data on alcohol consumption were obtained from repeated 24h dietary records collected in 1994–1996. Cognitive performance was assessed in 2007–2009 via a battery of 6 neuropsychological tests. A composite score was built as the mean of the standardized individual test scores (mean = 50, SD = 10). ANCOVA were performed to estimate mean differences in cognitive performance and 95% confidence intervals (CI).

Results

In women, abstainers displayed lower cognitive scores than did low-to-moderate alcohol drinkers (1 to 2 drinks/day) (mean difference = −1.77; 95% CI: −3.29, −0.25). In men, heavy drinkers (>3 drinks/day) had higher cognitive scores than did low-to-moderate (1 to 3 drinks/day) (mean difference = 1.05; 95% CI: 0.10, 1.99). However, a lower composite cognitive score was detected in male drinkers consuming ≥90 g/d (≈8 drinks/d). A higher proportion of alcohol intake from beer was also associated with lower cognitive scores. These associations remained significant after adjustment for diet, comorbidities and sociodemographic factors.

Conclusion

In men, heavy but not extreme drinking was associated with higher global cognitive scores. Given the known harmful effects of alcohol even in low doses regarding risk of cancer, the study does not provide a basis for modifying current public health messages.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00272428","term_id":"NCT00272428"}}NCT00272428     

Candidate Luminal B Breast Cancer Genes Identified by Genome,Gene Expression and DNA Methylation Profiling

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.     

The wobble nucleotide-excising anticodon nuclease RloC is governed by the zinc-hook and DNA-dependent ATPase of its Rad50-like region

The conserved bacterial anticodon nuclease (ACNase) RloC and its phage-excluding homolog PrrC comprise respective ABC-adenosine triphosphatase (ATPase) and ACNase N- and C-domains but differ in three key attributes. First, prrC is always linked to an ACNase silencing, DNA restriction-modification (R-M) locus while rloC rarely features such linkage. Second, RloC excises its substrate's wobble nucleotide, a lesion expected to impede damage reversal by phage transfer RNA (tRNA) repair enzymes that counteract the nick inflicted by PrrC. Third, a distinct coiled-coil/zinc-hook (CC/ZH) insert likens RloC's N-region to the universal DNA damage checkpoint/repair protein Rad50. Previous work revealed that ZH mutations activate RloC's ACNase. Data shown here suggest that RloC has an internal ACNase silencing/activating switch comprising its ZH and DNA-break-responsive ATPase. The existence of this control may explain the lateral transfer of rloC without an external silencer and supports the proposed role of RloC as an antiviral contingency acting when DNA restriction is alleviated under genotoxic stress. We also discuss RloC's possible evolution from a PrrC-like ancestor.     

Leukemia: beneficial actions of retinoids and rexinoids

Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is the prototype of a cancer that can be cured by differentiation therapy using combined retinoic acid (RA) and chemotherapy. Acute promyelocytic leukemia is caused by chromosomal translocations, which in the large majority of cases generate the prototypic promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARalpha) an oncogenic fusion protein formed from the retinoic-acid receptor alpha and the so-called PML protein. The fusion protein leads to the deregulation of wild type PML and RARalpha function, thus inducing the differentiation block and an altered survival capacity of promyelocytes of affected patients. A plethora of studies have revealed molecular details that account for the oncogenic properties of acute promyelocytic leukemia fusion proteins and the events that contribute to the therapy-induced differentiation and apoptosis of patients' blasts. Illustrating the beneficial mechanisms of action of retinoids for acute promyelocytic leukemia patients this review goes on to discuss a plethora of recently recognized molecular paradigms by which retinoids and rexinoids, alone or in combination with other compounds, regulate growth, differentiation and apoptosis also in non-acute promyelocytic leukemia cells, highlighting their potential as drugs for cancer therapy and prevention.