Reshaping the preterm heart: shifting cardiac renin-angiotensin system towards cardioprotection in rats exposed to neonatal high-oxygen stress

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O2) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O2-induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1–7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O2 exposure. Methods: Sprague-Dawley pups were exposed to room air or 80% O2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry. Results: At P10, high O2-exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin–Angio-(1–7) significantly improved LV function in the O2-exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin–Angio-(1–7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O2-exposed rats at P10 and P28. Conclusions: Our findings demonstrate LV remodeling changes induced by O2-stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm

Loop Quantum Gravity a la Aharonov-Bohm

The state space of Loop Quantum Gravity admits a decomposition into orthogonal subspaces associated to diffeomorphism equivalence classes of spin-network graphs. In this paper I investigate the possibility of obtaining this state space from the quantization of a topological field theory with many degrees of freedom. The starting point is a 3-manifold with a network of defect-lines. A locally-flat connection on this manifold can have non-trivial holonomy around non-contractible loops. This is in fact the mathematical origin of the Aharonov-Bohm effect. I quantize this theory using standard field theoretical methods. The functional integral defining the scalar product is shown to reduce to a finite dimensional integral over moduli space. A non-trivial measure given by the Faddeev-Popov determinant is derived. I argue that the scalar product obtained coincides with the one used in Loop Quantum Gravity. I provide an explicit derivation in the case of a single defect-line, corresponding to a single loop in Loop Quantum Gravity. Moreover, I discuss the relation with spin-networks as used in the context of spin foam models.Comment: 19 pages, 1 figure; v2: corrected typos, section 4 expanded

A Niche-Based Framework to Assess Current Monitoring of European Forest Birds and Guide Indicator Species' Selection

Concern that European forest biodiversity is depleted and declining has provoked widespread efforts to improve management practices. To gauge the success of these actions, appropriate monitoring of forest ecosystems is paramount. Multi-species indicators are frequently used to assess the state of biodiversity and its response to implemented management, but generally applicable and objective methodologies for species' selection are lacking. Here we use a niche-based approach, underpinned by coarse quantification of species' resource use, to objectively select species for inclusion in a pan-European forest bird indicator. We identify both the minimum number of species required to deliver full resource coverage and the most sensitive species' combination, and explore the trade-off between two key characteristics, sensitivity and redundancy, associated with indicators comprising different numbers of species. We compare our indicator to an existing forest bird indicator selected on the basis of expert opinion and show it is more representative of the wider community. We also present alternative indicators for regional and forest type specific monitoring and show that species' choice can have a significant impact on the indicator and consequent projections about the state of the biodiversity it represents. Furthermore, by comparing indicator sets drawn from currently monitored species and the full forest bird community, we identify gaps in the coverage of the current monitoring scheme. We believe that adopting this niche-based framework for species' selection supports the objective development of multi-species indicators and that it has good potential to be extended to a range of habitats and taxa

Quantization of Midisuperspace Models

We give a comprehensive review of the quantization of midisuperspace models. Though the main focus of the paper is on quantum aspects, we also provide an introduction to several classical points related to the definition of these models. We cover some important issues, in particular, the use of the principle of symmetric criticality as a very useful tool to obtain the required Hamiltonian formulations. Two main types of reductions are discussed: those involving metrics with two Killing vector fields and spherically symmetric models. We also review the more general models obtained by coupling matter fields to these systems. Throughout the paper we give separate discussions for standard quantizations using geometrodynamical variables and those relying on loop quantum gravity inspired methods.Comment: To appear in Living Review in Relativit

Mechanism of subunit interaction at ketosynthase-dehydratase junctions in trans-AT polyketide synthases

Modular polyketide synthases (PKSs) produce numerous structurally complex natural products with diverse applications in medicine and agriculture. They typically consist of several multienzyme subunits that utilize structurally-defined docking domains (DDs) at their N- and C-termini to ensure correct assembly into functional multi-protein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-AT modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This involves direct interaction of a largely unstructured docking domain (DD) at the C-terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based cross-linking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene foot-printing and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity

Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects

Atypical development of the executive attention network in children with chromosome 22q11.2 deletion syndrome

Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue × flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS

Predicting Coral Species Richness: The Effect of Input Variables, Diversity and Scale

Coral reefs are facing a biodiversity crisis due to increasing human impacts, consequently, one third of reef-building corals have an elevated risk of extinction. Logistic challenges prevent broad-scale species-level monitoring of hard corals; hence it has become critical that effective proxy indicators of species richness are established. This study tests how accurately three potential proxy indicators (generic richness on belt transects, generic richness on point-intercept transects and percent live hard coral cover on point-intercept transects) predict coral species richness at three different locations and two analytical scales. Generic richness (measured on a belt transect) was found to be the most effective predictor variable, with significant positive linear relationships across locations and scales. Percent live hard coral cover consistently performed poorly as anindicator of coral species richness. This study advances the practical framework for optimizing coral reef monitoring programs and empirically demonstrates that generic richness offers an effective way to predict coral species richness with a moderate level of precision. While the accuracy of species richness estimates will decrease in communities dominated byspecies-rich genera (e.g. Acropora), generic richness provides a useful measure of phylogenetic diversity and incorporating this metric into monitoring programs will increase the likelihood that changes in coral species diversity can be detected

Performance and Consistency of Indicator Groups in Two Biodiversity Hotspots

In a world limited by data availability and limited funds for conservation, scientists and practitioners must use indicator groups to define spatial conservation priorities. Several studies have evaluated the effectiveness of indicator groups, but still little is known about the consistency in performance of these groups in different regions, which would allow their a priori selection.We systematically examined the effectiveness and the consistency of nine indicator groups in representing mammal species in two top-ranked Biodiversity Hotspots (BH): the Brazilian Cerrado and the Atlantic Forest. To test for group effectiveness we first found the best sets of sites able to maximize the representation of each indicator group in the BH and then calculated the average representation of different target species by the indicator groups in the BH. We considered consistent indicator groups whose representation of target species was not statistically different between BH. We called effective those groups that outperformed the target-species representation achieved by random sets of species. Effective indicator groups required the selection of less than 2% of the BH area for representing target species. Restricted-range species were the most effective indicators for the representation of all mammal diversity as well as target species. It was also the only group with high consistency.We show that several indicator groups could be applied as shortcuts for representing mammal species in the Cerrado and the Atlantic Forest to develop conservation plans, however, only restricted-range species consistently held as the most effective indicator group for such a task. This group is of particular importance in conservation planning as it captures high diversity of endemic and endangered species