Population origins in Mongolia: genetic structure analysis of ancient and modern DNA

In the present study, nuclear (autosomal and Y-chromosome short tandem repeats) and mitochondrial (hypervariable region I) ancient DNA data previously obtained from a 2,300-year-old Xiongnu population of the Egyin Gol Valley (south of Lake Baikal in northern Mongolia) (Keyser-Tracqui et al. 2003 Am. J. Hum. Genet. 73:247-260) were compared with data from two contemporary Mongolian populations: one from the same location (Egyin Gol Valley plus a perimeter of less than 100 km around the valley), and one from the whole of Mongolia. The principal objective of this comparative analysis was to assess the likelihood that genetic continuity exists between ancient and present-day Mongolian populations. Since the ancient Xiongnu sample might have been composed of some of the ancestors of the present-day Yakuts, data from a present-day Yakut population, as well as published data from Turkish populations, were also included in the comparative analysis. The main result of our study was the genetic similarity observed among Mongolian samples from different periods and geographic areas. This result supports the hypothesis that the succession over time of different Turkic and Mongolian tribes in the current territory of Mongolia resulted in cultural rather than genetic exchanges. Furthermore, it appears that the Yakuts probably did not find their origin among the Xiongnu tribes, as we previously hypothesized.     

An experimental manipulation of life-history trajectories and resistance to oxidative stress

Optimal investment into life-history traits depends on the environmental conditions that organisms are likely to experience during their life. Evolutionary theory tells us that optimal investment in reproduction versus maintenance is likely to shape the pattern of age-associated decline in performance, also known as aging. The currency that is traded against different vital functions is, however, still debated. Here, we took advantage of a phenotypic manipulation of individual quality in early life to explore (1) long-term consequences on life-history trajectories, and (2) the possible physiological mechanism underlying the life-history adjustments. We manipulated phenotypic quality of a cohort of captive zebra finches (Taeniopygia guttata) by assigning breeding pairs to either an enlarged or a reduced brood. Nestlings raised in enlarged broods were in poorer condition than nestlings raised in reduced broods. Interestingly, the effect of environmental conditions experienced during early life extended to the age at first reproduction. Birds from enlarged broods delayed reproduction. Birds that delayed reproduction produced less offspring but lived longer, although neither fecundity nor longevity were directly affected by the experimental brood size. Using the framework of the life-table response experiment modeling, we also explored the effect of early environmental condition on population growth rate and aging. Birds raised in reduced broods tended to have a higher population growth rate, and a steeper decrease of reproductive value with age than birds reared in enlarged broods. Metabolic resources necessary to fight off the damaging effect of reactive oxygen species (ROS) could be the mechanism underlying the observed results, as (1) birds that engaged in a higher number of breeding events had a weaker red blood cell resistance to oxidative stress, (2) red blood cell resistance to oxidative stress predicted short-term mortality (but not longevity), and (3) was related with a parabolic function to age. Overall, these results highlight that early condition can have long-term effects on life-history trajectories by affecting key life-history traits such as age at first reproduction, and suggest that the trade-off between reproduction and self-maintenance might be mediated by the cumulative deleterious effect of ROS.     

Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection

Dendritic cells (DC) are potent inducers of immune responses. DC have been shown to infiltrate tumors, but very little is known about the functional status of these naturally occurring tumor-infiltrating DC (TIDC). In this study, the status and function of TIDC from several types of mouse melanoma were investigated in detail. CD11c+/MHC II+ cells, consistent with a DC phenotype, were found in all of transplantable or spontaneous melanomas studied. These TIDC were predominantly myeloid (CD11c+/CD8alpha-/B220-) in nature with small numbers of plasmacytoid (CD11c+/B220+). TIDC had an intermediate maturation phenotype with some expression of costimulatory molecules and the capacity to take up particles. Upon culture overnight ex vivo, the TIDC markedly up-regulated the expression of costimulatory molecules and also increased IL-12 production. Importantly, such ex vivo-matured TIDC pulsed with OVA were able to migrate to lymph nodes, to activate naive OVA-specific CD4+ and CD8+ T cells, and to confer protection against a challenge with OVA-expressing tumor cells. In conclusion, melanomas are infiltrated by functional DC that can act as fully competent APC. These APC have the potential to be manipulated and may therefore represent a promising target for cancer immunotherapy.     

Multiplex degenerate PCR coupled with an oligo sorbent array for human endogenous retrovirus expression profiling

Human endogenous retroviruses (HERVs) can be divided into distinct families of tens to thousands of paralogous loci. The expression of HERV elements has been detected in all tissues tested to date, particularly germ cells, embryonic tissues and neoplastic tissues. Hence, the study of HERV expression could represent added value in cancer diagnosis. We developed a quantitative assay combining a multiplex degenerate PCR (MD-PCR) amplification, based on the relative conservation of the pol genes, and a colorimetric Oligo Sorbent Array (OLISA^®). Nine HERV families were selected and amplification primers and capture probes were designed for each family. The features required to achieve efficient amplification of most of the elements of each HERV family and balanced co-amplification of all HERV families were analyzed. We found that MD-PCR reliability, i.e. equivalence of amplification and dose-effect relationship, relied on the adjustment of three critical parameters: the primer degeneracy, the relative concentration of each primer and the total amount of primers in the amplification mixture. The analysis of tumoral versus normal tissues suggests that this assay could prove useful in tumor phenotyping.     

Solid-phase microextraction of volatile compounds from flowers of two Brunfelsia species

Two plant species belonging to the genus Brunfelsia, commonly known as “Yesterday-Today-and-Tomorrow”, are closely related, however, differ by their flower fragrance. Flowers of Brunfelsia australis present a pleasant fragrance, whereas flowers of Brunfelsia pauciflora are scentless. SPME/GC/MS analysis on flower samples of both species of Brunfelsia indicated that flowers of B. australis emitted a fresh flowery fragrance, essentially comprising two monoterpenic compounds (linalool and (E)-ocimene). B. pauciflora, on the other hand, produced only a few sesquiterpenoids. These results are considered in an ecological and evolutionary context.     

Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1

Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPKalpha1/alpha2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPKalpha2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPKalpha2 at the site of LKB1 phosphorylation (Thr172) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPKalpha2, significant basal activity of AMPKalpha1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPKalpha1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPKalpha2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPKalpha1 in cardiac muscle.     

Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis

Hypokalemic periodic paralysis type 2 (hypoPP2) is an inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the alpha subunit of the skeletal muscle Na+ channel (Nav1.4). All hypoPP2 mutations reported so far target an arginine residue of the voltage sensor S4 of domain II (R672/G/H/S). We identified a novel hypoPP2 mutation that neutralizes an arginine residue in DIII-S4 (R1132Q), and studied its functional consequences in HEK cells transfected with the human SCN4A cDNA. Whole-cell current recordings revealed an enhancement of both fast and slow inactivation, as well as a depolarizing shift of the activation curve. The unitary Na+ conductance remained normal in R1132Q and in R672S mutants, and cannot therefore account for the reduction of Na+ current presumed in hypoPP2. Altogether, our results provide a clear evidence for the role of R1132 in channel activation and inactivation, and confirm loss of function effects of hypoPP2 mutations leading to muscle hypoexcitability.     

Generalization of conditioned food aversions in grazing sheep and its implications for food categorization

When grazing on heterogeneous pastures, herbivores may rely on food item generalization and categorization processes for reducing information processing while selecting their diet. The objective of this study was to assess the generalization of an aversion by grazing sheep for items differing by one or two criteria from an item against which they were negatively conditioned. Four items cultivated in pots were offered to the animals, resulting from the combination of an intrinsic criterion, i.e. grass species (ryegrass and fescue) and a transitory criterion, i.e. sward height (tall and short). We assessed the generalization process by comparing binary choices between the initially preferred tall ryegrass and the three other items, before and after animals had been partially conditioned against tall ryegrass. This method proved useful in assessing the generalization of an aversion. Sheep did not generalize their aversion on the basis of sward height but rather on species: they increased their preference for tall fescue and decreased their instantaneous preference for short ryegrass after having been conditioned against tall ryegrass. The generalization of an aversion through different states of a same species could indicate the possibility of a species-based categorization by grazing herbivores.