Inhibition of hyaluronan export attenuates cell migration and metastasis of human melanoma

When secreted from malignant cells, hyaluronan facilitates tumor invasion and metastasis, as inhibition of its export by zaprinast inhibited metastasis formation in mice. However, the precise steps of the metastatic cascade, which were influenced by zaprinast, have not been identified as yet. Here we analyzed the cell biological effects of the inhibitor on three human melanoma cell lines that differed in their hyaluronan production and their metastatic capability when xenografted into SCID mice. We measured the influence of zaprinast on cellular hyaluronan export, surface coat formation, proliferation, random migration, colony formation in soft agar, adhesion, and transepithelial resistance. Concentrations of zaprinast not affecting cell proliferation, adhesion and transepithelial resistance, nevertheless reduced hyaluronan export by 50%, surface coat formation, random migration, and colony formation in soft agar. These results indicate that hyaluronan enhances metastasis formation primarily in those steps of the metastatic cascade, which involves tumor cell migration.     

Phenotypic differences in behavior, physiology and neurochemistry between rats selected for tameness and for defensive aggression towards humans

To better understand the biology of tameness, i.e. tolerance of human presence and handling, we analyzed two lines of wild-derived rats (Rattus norvegicus) artificially selected for tameness and defensive aggression towards humans. In response to a gloved human hand, tame rats tolerated handling, whereas aggressive rats attacked. Cross-fostering showed that these behavioral differences are not caused by postnatal maternal effects. Tame rats were more active and explorative and exhibited fewer anxiety-related behaviors. They also had smaller adrenal glands, larger spleens and lower levels of serum corticosterone. Blood glucose levels were lower in tame rats, whereas the concentrations of nine amino acids were higher. In the brain, tame rats had lower serotonin and higher taurine levels than aggressive rats. Our findings reinforce the notion that tameness is correlated with differences in stress response and will facilitate future efforts to uncover the genetic basis for animal tameness.     

Morphological, physiological and behavioural evaluation of a ‘Mice in Space’ housing system

Environmental conditions likely affect physiology and behaviour of mice used for life sciences research on Earth or in Space. Here, we analysed the effects of cage confinement on the weightbearing musculoskeletal system, behaviour and stress of wild-type mice (C57BL/6JRj, 30 g b.wt., total n = 24) housed for 25 days in a prototypical ground-based and fully automated life support habitat device called “Mice in Space” (MIS). Compared with control housing (individually ventilated cages) the MIS mice revealed no significant changes in soleus muscle size and myofiber distribution (type I vs. II) and quality of bone (3-D microarchitecture and mineralisation of calvaria, spine and femur) determined by confocal and micro-computed tomography. Corticosterone metabolism measured non-invasively (faeces) monitored elevated adrenocortical activity at only start of the MIS cage confinement (day 1). Behavioural tests (i.e., grip strength, rotarod, L/D box, elevated plus-maze, open field, aggressiveness) performed subsequently revealed only minor changes in motor performance (MIS vs. controls). The MIS habitat will not, on its own, produce major effects that could confound interpretation of data induced by microgravity exposure during spaceflight. Our results may be even more helpful in developing multidisciplinary protocols with adequate scenarios addressing molecular to systems levels using mice of various genetic phenotypes in many laboratories. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Testing the threat-sensitive predator avoidance hypothesis: physiological responses and predator pressure in wild rabbits

Predation is a strong selective force with both direct and indirect effects on an animal’s fitness. In order to increase the chances of survival, animals have developed different antipredator strategies. However, these strategies have associated costs, so animals should assess their actual risk of predation and shape their antipredator effort accordingly. Under a stressful situation, such as the presence of predators, animals display a physiological stress response that might be proportional to the risk perceived. We tested this hypothesis in wild European rabbits (Oryctolagus cuniculus), subjected to different predator pressures, in Doñana National Park (Spain). We measured the concentrations of fecal corticosterone metabolites (FCM) in 20 rabbit populations. By means of track censuses we obtained indexes of mammalian predator presence for each rabbit population. Other factors that could modify the physiological stress response, such as breeding status, food availability and rabbit density, were also considered. Model selection based on information theory showed that predator pressure was the main factor triggering the glucocorticoid release and that the physiological stress response was positively correlated with the indexes of the presence of mammalian carnivore predators. Other factors, such as food availability and density of rabbits, were considerably less important. We conclude that rabbits are able to assess their actual risk of predation and show a threat-sensitive physiological response.     

Records of the gadoid fish <Emphasis Type="Italic">Arctogadus glacialis</Emphasis> (Peters, 1874) in the European Arctic

The Arctogadus glacialis is endemic to the Arctic Ocean and its apparently disjunct circumpolar distribution range from the Siberian coast through the Chukchi Sea and the Canadian Arctic to the shelf off NE Greenland. Records of A. glacialis are scarce in the European Arctic and here we present all available and reliable records of the species in the area. Altogether, 296 specimens of A. glacialis are reported from 53 positions in the European Arctic during the period 1976–2008. The specimens were registered off Iceland and the Jan Mayen Island, northwest and northeast of Svalbard, northeast in the Barents Sea, and south and east off Franz Josef Land. The additional records show that A. glacialis display a circumpolar and more continuous distribution than described before. In the European Arctic, A. glacialis has been caught at 155–741 m depth with the highest abundance at 300–400 m. We therefore suggest that A. glacialis is more associated to the continental shelves surrounding the Arctic Ocean than previously thought. The length–weight relation of A. glacialis is similar across the European Arctic.     

Effects of urban noise on song and response behaviour in great tits

Acoustic communication is fundamental in avian territory defence and mate attraction. In urban environments where sound transmissions are more likely to be masked by low-frequency anthropogenic noise, acoustic adaptations may be advantageous. However, minor modifications to a signal could affect its efficacy. While recent research has shown that there is divergence between songs from noisy and quiet areas, it is unknown whether these differences affect the response to the signal by its receivers. Here, we show that there is a difference in spectral aspects of rural and urban song in a common passerine, the great tit Parus major, at 20 sites across the UK. We also provide, to our knowledge, the first demonstration that such environmentally induced differences in song influence the response of male territory holders. Males from quiet territories exhibited a significantly stronger response when hearing song from another territory holder with low background noise than from those with high background noise. The opposite distinction in response intensity to homotypic versus heterotypic song was observed in males from noisy territories. This behavioural difference may intensify further signal divergence between urban and rural populations and raises important questions concerning signal evolution.     

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural,Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Background

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.

Methodology/Principle Findings

In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.

Conclusion/Significance

Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD.     

Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells

Background

Human multipotent mesenchymal stromal cells (MSC) can be isolated from various tissues including bone marrow. Here, MSC participate as bone lining cells in the formation of the hematopoietic stem cell niche. In this compartment, the oxygen tension is low and oxygen partial pressure is estimated to range from 1% to 7%. We analyzed the effect of low oxygen tensions on human MSC cultured with platelet-lysate supplemented media and assessed proliferation, morphology, chromosomal stability, immunophenotype and plasticity.

Results

After transferring MSC from atmospheric oxygen levels of 21% to 1%, HIF-1α expression was induced, indicating efficient oxygen reduction. Simultaneously, MSC exhibited a significantly different morphology with shorter extensions and broader cell bodies. MSC did not proliferate as rapidly as under 21% oxygen and accumulated in G₁ phase. The immunophenotype, however, was unaffected. Hypoxic stress as well as free oxygen radicals may affect chromosomal stability. However, no chromosomal abnormalities in human MSC under either culture condition were detected using high-resolution matrix-based comparative genomic hybridization. Reduced oxygen tension severely impaired adipogenic and osteogenic differentiation of human MSC. Elevation of oxygen from 1% to 3% restored osteogenic differentiation.

Conclusion

Physiologic oxygen tension during in vitro culture of human MSC slows down cell cycle progression and differentiation. Under physiological conditions this may keep a proportion of MSC in a resting state. Further studies are needed to analyze these aspects of MSC in tissue regeneration.     

Disturbances catalyze the adaptation of forest ecosystems to changing climate conditions

The rates of anthropogenic climate change substantially exceed those at which forest ecosystems – dominated by immobile, long‐lived organisms – are able to adapt. The resulting maladaptation of forests has potentially detrimental effects on ecosystem functioning. Furthermore, as many forest‐dwelling species are highly dependent on the prevailing tree species, a delayed response of the latter to a changing climate can contribute to an extinction debt and mask climate‐induced biodiversity loss. However, climate change will likely also intensify forest disturbances. Here, we tested the hypothesis that disturbances foster the reorganization of ecosystems and catalyze the adaptation of forest composition to climate change. Our specific objectives were (i) to quantify the rate of autonomous forest adaptation to climate change, (ii) examine the role of disturbance in the adaptation process, and (iii) investigate spatial differences in climate‐induced species turnover in an unmanaged mountain forest landscape (Kalkalpen National Park, Austria). Simulations with a process‐based forest landscape model were performed for 36 unique combinations of climate and disturbance scenarios over 1000 years. We found that climate change strongly favored European beech and oak species (currently prevailing in mid‐ to low‐elevation areas), with novel species associations emerging on the landscape. Yet, it took between 357 and 706 years before the landscape attained a dynamic equilibrium with the climate system. Disturbances generally catalyzed adaptation and decreased the time needed to attain equilibrium by up to 211 years. However, while increasing disturbance frequency and severity accelerated adaptation, increasing disturbance size had the opposite effect. Spatial analyses suggest that particularly the lowest and highest elevation areas will be hotspots of future species change. We conclude that the growing maladaptation of forests to climate and the long lead times of autonomous adaptation need to be considered more explicitly in the ongoing efforts to safeguard biodiversity and ecosystem services provisioning.     

Nesting behavior of greater eelpout (Lycodes esmarkii), identified through a predation event by spotted wolffish (Anarhichas minor)

The stomach of a spotted wolffish (Anarhichas minor) caught in Icelandic waters was found to contain ~727 greater eelpout larvae (Lycodes esmarkii). All the larvae were of similar size and at a similar state of digestion, indicating they were all consumed together. The likely explanation for this observation is that greater eelpout lay their eggs in a nest, with the larvae remaining in the nest for a short period after hatching. The larvae were then predated upon by the spotted wolffish while still in the nest. This study sheds new light on greater eelpout in Icelandic waters, with recently hatched larvae being present in March, breeding at a depth of ~200–250 m, and likely exhibiting nesting behavior, which has not previously been documented.