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Recent animal studies, as well as quantitative sodium MRI observations on humans demonstrated that remarkable amounts of sodium can be stored in the skin. It is also known that excess sodium in the tissues leads to inflammation in various organs, but its role in dermal pathophysiology has not been elucidated. Therefore, our aim was to study the effect of dietary salt loading on inflammatory process and related extracellular matrix (ECM) remodeling in the skin. To investigate the effect of high salt consumption on inflammation and ECM production in the skin mice were kept on normal (NSD) or high salt (HSD) diet and then dermatitis was induced with imiquimod (IMQ) treatment. The effect of high salt concentration on dermal fibroblasts (DF) and peripheral blood mononuclear cells (PBMC) was also investigated in vitro. The HSD resulted in increased sodium content in the skin of mice. Inflammatory cytokine Il17 expression was elevated in the skin of HSD mice. Expression of anti-inflammatory Il10 and Il13 decreased in the skin of HSD or HSD IMQ mice. The fibroblast marker Acta2 and ECM component Fn and Col1a1 decreased in HSD IMQ mice. Expression of ECM remodeling related Pdgfb and activation phosphorylated (p)-SMAD2/3 was lower in HSD IMQ mice. In PBMCs, production of IL10, IL13 and PDGFB was reduced due to high salt loading. In cultured DFs high salt concentration resulted in decreased cell motility and ECM production, as well. Our results demonstrate that high dietary salt intake is associated with increased dermal pro-inflammatory status. Interestingly, although inflammation induces the synthesis of ECM in most organs, the expression of ECM decreased in the inflamed skin of mice on high salt diet. Our data suggest that salt intake may alter the process of skin remodeling.

Previous studies targeting inter-individual differences in pain processing in migraine mainly focused on the perception of pain. Our main aim was to disentangle pain anticipation and perception using a classical fear conditioning task, and investigate how migraine frequency and pre-scan cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio as an index of neurobiological stress response would relate to neural activation in these two phases. Functional Magnetic Resonance Imaging (fMRI) data of 23 participants (18 females; mean age: 27.61± 5.36) with episodic migraine without aura were analysed. We found that migraine frequency was significantly associated with pain anticipation in brain regions comprising the midcingulate and caudate, whereas pre-scan cortisol-to DHEA-S ratio was related to pain perception in the pre-supplementary motor area (pre-SMA). Both results suggest exaggerated preparatory responses to pain or more general to stressors, which may contribute to the allostatic load caused by stressors and migraine attacks on the brain.

Glucocorticoid (GC) hormones are significant regulators of homeostasis. The physiological effects of GCs critically depend on the time of exposure (short vs. long) as well as on their circulating levels (baseline vs. stress-induced). Previous experiments, in which chronic and high elevation of GC levels was induced, indicate that GCs impair both the activity of the immune system and the oxidative balance. Nonetheless, our knowledge on how mildly elevated GC levels, a situation much more common in nature, might influence homeostasis is limited. Therefore, we studied whether an increase in GC level within the baseline range suppresses or enhances condition (body mass, hematocrit and coccidian infestation) and physiological state (humoral innate immune system activity and oxidative balance). We implanted captive house sparrows Passer domesticus with either 60 days release corticosterone (CORT) or control pellets. CORT-treated birds had elevated baseline CORT levels one week after the implantation, but following this CORT returned to its pre-treatment level and the experimental groups had similar CORT levels one and two months following the implantation. The mass of tail feathers grown during the initial phase of treatment was smaller in treated than in control birds. CORT implantation had a transient negative effect on body mass and hematocrit, but both of these traits resumed the pre-treatment values by one month post-treatment. CORT treatment lowered oxidative damage to lipids (malondialdehyde) and enhanced constitutive innate immunity at one week and one month post-implantation. Our findings suggest that a relatively short-term (i.e. few days) elevation of baseline CORT might have a positive and stimulatory effect on animal physiology.

It has been widely accepted that the Finno-Ugric Hungarian language, originated from proto Uralic people, was brought into the Carpathian Basin by the conquering Hungarians. From the middle of the 19th century this view prevailed against the deep-rooted Hungarian Hun tradition, maintained in folk memory as well as in Hungarian and foreign written medieval sources, which claimed that Hungarians were kinsfolk of the Huns. In order to shed light on the genetic origin of the Conquerors we sequenced 102 mitogenomes from early Conqueror cemeteries and compared them to sequences of all available databases. We applied novel population genetic algorithms, named Shared Haplogroup Distance and MITOMIX, to reveal past admixture of maternal lineages. Our results show that the Conquerors assembled from various nomadic groups of the Eurasian steppe. Population genetic results indicate that they had closest connection to the Onogur-Bulgar ancestors of Volga Tatars. Phylogenetic results reveal that more than one third of the Conqueror maternal lineages were derived from Central-Inner Asia and their most probable ultimate sources were the Asian Scythians and Asian Huns, giving support to the Hungarian Hun tradition. The rest of the lineages most likely originated from the Bronze Age Potapovka-Poltavka-Srubnaya cultures of the Pontic-Caspian steppe. Available data imply that the Conquerors did not have a major contribution to the gene pool of the Carpathian Basin.

The development of farming was a catalyst for the evolution of the human diet from the varied subsistence practices of hunter-gatherers to the more globalised food economy we depend upon today. Although there has been considerable research into the dietary changes associated with the initial spread of farming, less attention has been given to how dietary choices continued to develop during subsequent millennia. A paleogenomic time transect for 5 millennia of human occupation in the Great Hungarian Plain spanning from the advent of the Neolithic to the Iron Age, showed major genomic turnovers. Here we assess where these genetic turnovers are associated with corresponding dietary shifts, by examining the carbon and nitrogen stable isotope ratios of 52 individuals. Results provide evidence that early Neolithic individuals, which were genetically characterised as Mesolithic hunter-gatherers, relied on wild resources to a greater extent than those whose genomic attributes were of typical Neolithic European farmers. Other Neolithic individuals and those from the Copper Age to Bronze Age periods relied mostly on terrestrial C3 plant resources. We also report a carbon isotopic ratio typical of C4 plants, which may indicate millet consumption in the Late Bronze Age, despite suggestions of the crop's earlier arrival in Europe during the Neolithic.

Mutations of the Adenomatous polyposis coli (APC) gene are common and strongly associated with the development of colorectal adenomas and carcinomas. While extensively studied in modern populations, reports on visceral tumors in ancient populations are scarce. To the best of our knowledge, genetic characterization of mutations associated with colorectal cancer in ancient specimens has not yet been described. In this study we have sequenced hotspots for mutations in the APC gene isolated from 18th century naturally preserved human Hungarian mummies. While wild type APC sequences were found in two mummies, we discovered the E1317Q missense mutation, known to be a colorectal cancer predisposing mutation, in a large intestine tissue of an 18th century mummy. Our data suggests that this genetic predisposition to cancer already existed in the pre-industrialization era. This study calls for similar investigations of ancient specimens from different periods and geographical locations to be conducted and shared for the purpose of obtaining a larger scale analysis that will shed light on past cancer epidemiology and on cancer evolution.

Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.Our study is cross-sectional and applies self-report questionnaires.Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.

Understanding why host species differ so much in symbiont loads and how this depends on ecological host and symbiont traits is a major issue in the ecology of symbiosis. A first step in this inquiry is to know whether observed differences among host species are species-specific traits or more related with host-symbiont environmental conditions. Here we analysed the repeatability (R) of the intensity and the prevalence of feather mites to partition within- and among-host species variance components. We compiled the largest dataset so far available: 119 Paleartic passerine bird species, 75,944 individual birds, ca. 1.8 million mites, seven countries, 23 study years. Several analyses and approaches were made to estimate R and adjusted repeatability (R(adj)) after controlling for potential confounding factors (breeding period, weather, habitat, spatial autocorrelation and researcher identity). The prevalence of feather mites was moderately repeatable (R = 0.26-0.53; R(adj) = 0.32-0.57); smaller values were found for intensity (R = 0.19-0.30; R(adj )= 0.18-0.30). These moderate repeatabilities show that prevalence and intensity of feather mites differ among species, but also that the high variation within species leads to considerable overlap among bird species. Differences in the prevalence and intensity of feather mites within bird species were small among habitats, suggesting that local factors are playing a secondary role. However, effects of local climatic conditions were partially observed for intensity.

STUDY OBJECTIVES: Millions suffer from sleep disorders that often accompany severe illnesses such as major depression; a leading psychiatric disorder characterized by appetite and rapid eye movement sleep (REMS) abnormalities. Melanin-concentrating hormone (MCH) and nesfatin-1/NUCB2 (nesfatin) are strongly co - expressed in the hypothalamus and are involved both in food intake regulation and depression. Since MCH was recognized earlier as a hypnogenic factor, we analyzed the potential role of nesfatin on vigilance. DESIGN: We subjected rats to a 72 h-long REMS deprivation using the classic flower pot method, followed by a 3 h-long 'rebound sleep'. Nesfatin mRNA and protein expressions as well as neuronal activity (Fos) were measured by quantitative in situ hybridization technique, ELISA and immunohistochemistry, respectively, in 'deprived' and 'rebound' groups, relative to controls sacrificed at the same time. We also analyzed electroencephalogram of rats treated by intracerebroventricularly administered nesfatin-1, or saline. RESULTS: REMS deprivation downregulated the expression of nesfatin (mRNA and protein), however, enhanced REMS during 'rebound' reversed this to control levels. Additionally, increased transcriptional activity (Fos) was demonstrated in nesfatin neurons during 'rebound'. Centrally administered nesfatin-1 at light on reduced REMS and intermediate stage of sleep, while increased passive wake for several hours and also caused a short-term increase in light slow wave sleep. CONCLUSIONS: The data designate nesfatin as a potential new factor in sleep regulation, which fact can also be relevant in the better understanding of the role of nesfatin in the pathomechanism of depression.

BACKGROUND: The matrix metalloproteinases (MMPs) and their endogenous regulators, the tissue inhibitor of metalloproteinases (TIMPs 1-4) are responsible for the physiological remodeling of the extracellular matrix (ECM). Among all TIMPs, TIMP3 appears to play a unique role since TIMP3 is a secreted protein and, unlike the other TIMP family members, is tightly bound to the ECM. Moreover TIMP3 has been shown to be able to induce apoptotic cell death. As little is known about the underlying mechanisms, we set out to investigate the pro-apoptotic effect of TIMP3 in human mesenchymal cells. METHODOLOGY/PRINCIPAL FINDINGS: Lentiviral overexpression of TIMP3 in mesenchymal cells led to a strong dose-dependent induction of ligand-independent apoptosis as reflected by a five-fold increase in caspase 3 and 7 activity compared to control (pLenti6/V5-GW/lacZ) or uninfected cells, whereas exogenous TIMP3 failed to induce apoptosis. Concordantly, increased cleavage of death substrate PARP and the caspases 3 and 7 was observed in TIMP3 overexpressing cultures. Notably, activation of caspase-8 but not caspase-9 was observed in TIMP3-overexpressing cells, indicating a death receptor-dependent mechanism. Moreover, overexpression of TIMP3 led to a further induction of apoptosis after stimulation with TNF-alpha, FasL and TRAIL. Most interestingly, TIMP3-overexpression was associated with a decrease in phosphorylation of cRaf, extracellular signal-regulated protein kinase (Erk1/2), ribosomal S6 kinase (RSK1) and Akt and serum deprivation of TIMP3-overexpressing cells resulted in a distinct enhancement of apoptosis, pointing to an impaired signaling of serum-derived survival factors. Finally, heparinase treatment of heparan sulfate proteoglycans led to the release of TIMP3 from the surface of overexpressing cells and to a significant decrease in apoptosis indicating that the binding of TIMP3 is necessary for apoptosis induction. CONCLUSION: The results demonstrate that exclusively cell surface-bound endogenous TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival signaling pathways.

Climate change potentially has important effects on distribution, abundance, transmission and virulence of parasites in wild populations of animals.Here we analyzed paired information on 89 parasite populations for 24 species of bird hosts some years ago and again in 2010 with an average interval of 10 years. The parasite taxa included protozoa, feather parasites, diptera, ticks, mites and fleas. We investigated whether change in abundance and prevalence of parasites was related to change in body condition, reproduction and population size of hosts. We conducted analyses based on the entire dataset, but also on a restricted dataset with intervals between study years being 5-15 years. Parasite abundance increased over time when restricting the analyses to datasets with an interval of 5-15 years, with no significant effect of changes in temperature at the time of breeding among study sites. Changes in host body condition and clutch size were related to change in temperature between first and second study year. In addition, changes in clutch size, brood size and body condition of hosts were correlated with change in abundance of parasites. Finally, changes in population size of hosts were not significantly related to changes in abundance of parasites or their prevalence.Climate change is associated with a general increase in parasite abundance. Variation in laying date depended on locality and was associated with latitude while body condition of hosts was associated with a change in temperature. Because clutch size, brood size and body condition were associated with change in parasitism, these results suggest that parasites, perhaps mediated through the indirect effects of temperature, may affect fecundity and condition of their hosts. The conclusions were particularly in accordance with predictions when the restricted dataset with intervals of 5-15 years was used, suggesting that short intervals may bias findings.

The trade-off between current and residual reproductive values is central to life history theory, although the possible mechanisms underlying this trade-off are largely unknown. The 'molt constraint' hypothesis suggests that molt and plumage functionality are compromised by the preceding breeding event, yet this candidate mechanism remains insufficiently explored.The seasonal change in photoperiod was manipulated to accelerate the molt rate. This treatment simulates the case of naturally late-breeding birds. House sparrows Passer domesticus experiencing accelerated molt developed shorter flight feathers with more fault bars and body feathers with supposedly lower insulation capacity (i.e. shorter, smaller, with a higher barbule density and fewer plumulaceous barbs). However, the wing, tail and primary feather lengths were shorter in fast-molting birds if they had an inferior body condition, which has been largely overlooked in previous studies. The rachis width of flight feathers was not affected by the treatment, but it was still condition-dependent.This study shows that sedentary birds might face evolutionary costs because of the molt rate-feather quality conflict. This is the first study to experimentally demonstrate that (1) molt rate affects several aspects of body feathers as well as flight feathers and (2) the costly effects of rapid molt are condition-specific. We conclude that molt rate and its association with feather quality might be a major mediator of life history trade-offs. Our findings also suggest a novel advantage of early breeding, i.e. the facilitation of slower molt and the condition-dependent regulation of feather growth.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA) the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF). Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important for developing intracellular acting drugs used in inflammatory diseases.

Invasive species can displace natives, and thus identifying the traits that make aliens successful is crucial for predicting and preventing biodiversity loss. Pathogens may play an important role in the invasive process, facilitating colonization of their hosts in new continents and islands. According to the Novel Weapon Hypothesis, colonizers may out-compete local native species by bringing with them novel pathogens to which native species are not adapted. In contrast, the Enemy Release Hypothesis suggests that flourishing colonizers are successful because they have left their pathogens behind. To assess the role of avian malaria and related haemosporidian parasites in the global spread of a common invasive bird, we examined the prevalence and genetic diversity of haemosporidian parasites (order Haemosporida, genera Plasmodium and Haemoproteus) infecting house sparrows (Passer domesticus). We sampled house sparrows (N = 1820) from 58 locations on 6 continents. All the samples were tested using PCR-based methods; blood films from the PCR-positive birds were examined microscopically to identify parasite species. The results show that haemosporidian parasites in the house sparrows' native range are replaced by species from local host-generalist parasite fauna in the alien environments of North and South America. Furthermore, sparrows in colonized regions displayed a lower diversity and prevalence of parasite infections. Because the house sparrow lost its native parasites when colonizing the American continents, the release from these natural enemies may have facilitated its invasion in the last two centuries. Our findings therefore reject the Novel Weapon Hypothesis and are concordant with the Enemy Release Hypothesis.

Many animals display colorful signals in their integument which convey information about the quality of their bearer. Theoretically, these ornaments incur differential production and/or maintenance costs that enforce their honesty. However, the proximate mechanisms of production costs are poorly understood and contentious in cases of non-carotenoid-based plumage ornaments like the melanin-based badge and depigmented white wing-bar in house sparrows Passer domesticus. Costly life-history events are adaptively separated in time, thus, when reproduction is extended, the time available for molt is curtailed and, in turn, molt rate is accelerated.We experimentally accelerated the molt rate by shortening the photoperiod in order to test whether this environmental constraint is mirrored in the expression of plumage ornaments. Sparrows which had undergone an accelerated molt developed smaller badges and less bright wing-bars compared to conspecifics that molted at a natural rate being held at natural-like photoperiod. There was no difference in the brightness of the badge or the size of the wing-bar.These results indicate that the time available for molt and thus the rate at which molt occurs may constrain the expression of melanin-based and depigmented plumage advertisements. This mechanism may lead to the evolution of honest signaling if the onset of molt is condition-dependent through the timing of and/or trade-off between breeding and molt.

Background: The trade-off between current and residual reproductive values is central to life history theory, although the possible mechanisms underlying this trade-off are largely unknown. The 'molt constraint' hypothesis suggests that molt and plumage functionality are compromised by the preceding breeding event, yet this candidate mechanism remains insufficiently explored. Methodology/Principal Findings: The seasonal change in photoperiod was manipulated to accelerate the molt rate. This treatment simulates the case of naturally late-breeding birds. House sparrows Passer domesticus experiencing accelerated molt developed shorter flight feathers with more fault bars and body feathers with supposedly lower insulation capacity (i.e. shorter, smaller, with a higher barbule density and fewer plumulaceous barbs). However, the wing, tail and primary feather lengths were shorter in fast-molting birds if they had an inferior body condition, which has been largely overlooked in previous studies. The rachis width of flight feathers was not affected by the treatment, but it was still condition-dependent. Conclusions/Significance: This study shows that sedentary birds might face evolutionary costs because of the molt rate- feather quality conflict. This is the first study to experimentally demonstrate that (1) molt rate affects several aspects of body feathers as well as flight feathers and (2) the costly effects of rapid molt are condition-specific. We conclude that molt rate and its association with feather quality might be a major mediator of life history trade-offs. Our findings also suggest a novel advantage of early breeding, i.e. the facilitation of slower molt and the condition-dependent regulation of feather growth. [ABSTRACT FROM AUTHOR]

[This corrects the article DOI: 10.1371/journal.pone.0205920.].

Sexual selection and aerodynamic forces affecting structural properties of the flight feathers of birds are poorly understood. Here, we compared the structural features of the innermost primary wing feather (P1) and the sexually dimorphic outermost (Ta6) and monomorphic second outermost (Ta5) tail feathers of barn swallows (Hirundo rustica) from a Romanian population to investigate how sexual selection and resistance to aerodynamic forces affect structural differences among these feathers. Furthermore, we compared structural properties of Ta6 of barn swallows from six European populations. Finally, we determined the relationship between feather growth bars width (GBW) and the structural properties of tail feathers. The structure of P1 indicates strong resistance against aerodynamic forces, while the narrow rachis, low vane density and low bending stiffness of tail feathers suggest reduced resistance against airflow. The highly elongated Ta6 is characterized by structural modifications such as large rachis width and increased barbule density in relation to the less elongated Ta5, which can be explained by increased length and/or high aerodynamic forces acting at the leading tail edge. However, these changes in Ta6 structure do not allow for full compensation of elongation, as reflected by the reduced bending stiffness of Ta6. Ta6 elongation in males resulted in feathers with reduced resistance, as shown by the low barb density and reduced bending stiffness compared to females. The inconsistency in sexual dimorphism and in change in quality traits of Ta6 among six European populations shows that multiple factors may contribute to shaping population differences. In general, the difference in quality traits between tail feathers cannot be explained by the GBW of feathers. Our results show that the material and structural properties of wing and tail feathers of barn swallows change as a result of aerodynamic forces and sexual selection, although the result of these changes can be contrasting.