The hypothalamic neuropeptide oxytocin is required for formation of the neurovascular interface of the pituitary

The hypothalamo-neurohypophyseal system (HNS) is?the neurovascular structure through which the hypothalamic neuropeptides oxytocin and arginine-vasopressin exit the brain into the bloodstream, where they go on to affect peripheral physiology. Here, we investigate the molecular cues that regulate the neurovascular contact between hypothalamic axons and neurohypophyseal capillaries of the zebrafish. We developed a transgenic system in which both hypothalamic axons and neurohypophyseal vasculature can be analyzed in?vivo. We identified the cellular organization of the zebrafish HNS as well as the dynamic processes that contribute to formation of the HNS neurovascular interface. We show that formation of this interface is regulated during development by local release of oxytocin, which affects endothelial morphogenesis. This cell communication process is essential for the establishment of a tight axovasal interface between the neurons and blood vessels of the HNS. We present a unique example of axons affecting endothelial morphogenesis through secretion of a neuropeptide.     

Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart

Heart failure is a consequence of progressive deterioration of cardiac performance. Little is known about the role of impaired oxidative phosphorylation in the progression of the disease, since previous studies of mitochondrial injuries are restricted to end-stage chronic heart failure. The present study aimed at evaluating the involvement of mitochondrial dysfunction in the development of human heart failure. We measured the control of oxidative phosphorylation with high-resolution respirometry in permeabilized myocardial fibres from donor hearts (controls), and patients with no or mild heart failure but presenting with heart disease, or chronic heart failure due to dilated or ischemic cardiomyopathy. The capacity of the phosphorylation system exerted a strong limitation on oxidative phosphorylation in the human heart, estimated at 121 pmol O(2)s(-1)mg(-1) in the healthy left ventricle. In heart disease, a specific defect of the phosphorylation system, Complex I-linked respiration, and mass-specific fatty acid oxidation were identified. These early defects were also significant in chronic heart failure, where the capacities of the oxidative phosphorylation and electron transfer systems per cardiac tissue mass were decreased with all tested substrate combinations, suggesting a decline of mitochondrial density. Oxidative phosphorylation and electron transfer system capacities were higher in ventricles compared to atria, but the impaired mitochondrial quality was identical in the four cardiac chambers of chronic heart failure patients. Coupling was preserved in heart disease and chronic heart failure, in contrast to the mitochondrial dysfunction observed after prolonged cold storage of cardiac tissue. Mitochondrial defects in the phosphorylation system, Complex I respiration and mass-specific fatty acid oxidation occurred early in the development of heart failure. Targeting these mitochondrial injuries with metabolic therapy may offer a promising approach to delay the progression of heart disease.     

High local substrate availability stabilizes a cooperative trait

Cooperative behavior is widely spread in microbial populations. An example is the expression of an extracellular protease by the lactic acid bacterium Lactococcus lactis, which degrades milk proteins into free utilizable peptides that are essential to allow growth to high cell densities in milk. Cheating, protease-negative strains can invade the population and drive the protease-positive strain to extinction. By using multiple experimental approaches, as well as modeling population dynamics, we demonstrate that the persistence of the proteolytic trait is determined by the fraction of the generated peptides that can be captured by the cell before diffusing away from it. The mechanism described is likely to be relevant for the evolutionary stability of many extracellular substrate-degrading enzymes.     

The self in social interactions: sensory attenuation of auditory action effects is stronger in interactions with others

The experience of oneself as an agent not only results from interactions with the inanimate environment, but often takes place in a social context. Interactions with other people have been suggested to play a key role in the construal of self-agency. Here, we investigated the influence of social interactions on sensory attenuation of action effects as a marker of pre-reflective self-agency. To this end, we compared the attenuation of the perceived loudness intensity of auditory action effects generated either by oneself or another person in either an individual, non-interactive or interactive action context. In line with previous research, the perceived loudness of self-generated sounds was attenuated compared to sounds generated by another person. Most importantly, this effect was strongly modulated by social interactions between self and other. Sensory attenuation of self- and other-generated sounds was increased in interactive as compared to the respective individual action contexts. This is the first experimental evidence suggesting that pre-reflective self-agency can extend to and is shaped by interactions between individuals.     

Copepod and microzooplankton grazing in mesocosms fertilised with different Si:N ratios: no overlap between food spectra and Si:N influence on zooplankton trophic level

We hypothesized that the trophic level of marine copepods should depend on the composition of the protist community. To test this hypothesis, we manipulated the phytoplankton composition in mesocosms and measured grazing rates of copepods and mesozooplankton in those mesocosms. Twelve mesocosms with Northeast Atlantic phytoplankton were fertilised with different Si:N ratios from 0:1 to 1:1. After 1 week, ten of the mesocosms were filled with natural densities of mesozooplankton, mainly calanoid copepods, while two remained as mesozooplankton-free controls. Both before and after the addition of copepods there was a positive correlation of diatom dominance with Si:N ratios. During the second phase of the experiment, copepod and microzooplankton grazing rates on different phytoplankton species were assessed by a modification of the Landry-Hassett dilution technique, where the bottles containing the different dilution treatments were replaced by dialysis bags incubated in situ. The results indicated no overlap in the food spectrum of microzooplankton (mainly ciliates) and copepods. Ciliates fed on nanoplankton, while copepods fed on large or chain-forming diatoms, naked dinoflagellates, and ciliates. The calculated trophic level of copepods showed a significantly negative but weak correlation with Si:N ratios. The strength of this response was strongly dependent on the trophic levels assumed for ciliates and mixotrophic dinoflagellates.     

A Plasmodium actin-depolymerizing factor that binds exclusively to actin monomers

ADF/cofilins (AC) are essential F- and G-actin binding proteins that modulate microfilament turnover. The genome of Plasmodium falciparum, the parasite causing malaria, contains two members of the AC family. Interestingly, P. falciparum ADF1 lacks the F-actin binding residues of the AC consensus. Reverse genetics in the rodent malaria model system suggest that ADF1 performs vital functions during the pathogenic red blood cell stages, whereas ADF2 is not present in these stages. We show that recombinant PfADF1 interacts with monomeric actin but does not bind to actin polymers. Although other AC proteins inhibit nucleotide exchange on monomeric actin, the Plasmodium ortholog stimulates nucleotide exchange. Thus, PfADF1 differs in its biochemical properties from previously known AC proteins and seems to promote turnover exclusively by interaction with actin monomers. These findings provide important insights into the low cytosolic abundance and unique turnover characteristics of actin polymers in parasites of the phylum Apicomplexa.     

Genetic dissection of the zebrafish retinal stem-cell compartment

In a large-scale forward-genetic screen, we discovered that a limited number of genes are required for the regulation of retinal stem cells after embryogenesis in zebrafish. In 18 mutants out of almost 2000 F2 families screened, the eye undergoes normal embryonic development, but fails to continue growth from the ciliary marginal zone (CMZ), the post-embryonic stem-cell niche. Class I-A mutants (5 loci) display lower amounts of proliferation in the CMZ, while nearly all cells in the retina appear differentiated. Class I-B mutants (2 loci) have a reduced CMZ with a concomitant expansion in the retinal pigmented epithelium (RPE), suggesting a common post-embryonic stem cell is the source for these neighboring cell types. Class II encompasses three distinct types of mutants (11 loci) with expanded CMZ, in which the progenitor population is arrested in the cell cycle. We also show that in at least one combination, the reduced CMZ phenotype is genetically epistatic to the expanded CMZ phenotype, suggesting that Class I genes are more likely to affect the stem cells and Class II the progenitor cells. Finally, a comparative mapping analysis demonstrates that the new genes isolated do not correspond to genes previously implicated in stem-cell regulation. Our study suggests that embryonic and post-embryonic stem cells utilize separable genetic programs in the zebrafish retina.