IGF-IR signaling attenuates the age-related decline of diastolic cardiac function

Insulin-like growth factor (IGF-I) signaling has been implicated to play an important role in regulation of cardiac growth, hypertrophy, and contractile function and has been linked to the development of age-related congestive heart failure. Here, we address the question to what extent cardiomyocyte-specific IGF-I signaling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF-I signaling in the adult heart without confounding effects due to IGF-I overexpression or adaptation during embryonic and early postnatal development, we inactivated the IGF-I receptor (IGF-IR) by a 4-hydroxytamoxifen-inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF-IR (iCMIGF-IRKO) as assessed by Western analysis and real-time PCR went along with reduced IGF-I-dependent Akt and GSK3β phosphorylation. Functional analysis by conductance manometry and MRI revealed no functional alterations in young adult iCMIGF-IRKO mice (age 3 mo). However, when induced in aging mice (11 mo) diastolic cardiac function was depressed. To address the question whether insulin signaling might compensate for the defective IGF-IR signaling, we inactivated β-cells by streptozotocin. However, the diabetes-associated functional depression was similar in control and iCMIGF-IRKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF-IR signaling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts.     

Discovery of novel PI3Kγ/δ inhibitors as potential agents for inflammation

Dual PI3Kγ/δ inhibitors have recently been shown to be suitable targets for inflammatory and respiratory diseases. In a recent study we described the discovery of selective PI3Kγ inhibitors based on a triazolopyridine scaffold. Herein, we describe the elaboration of this structural class into dual PI3Kγ/δ inhibitors with excellent selectivity over the other PI3K isoforms and the general kinome. Structural optimization led to the identification of two derivatives which showed significant efficacy in an acute model of lung inflammation.     

Myrigalone A inhibits Lepidium sativum seed germination by interference with gibberellin metabolism and apoplastic superoxide production required for embryo extension growth and endosperm rupture

Myrica gale L. (sweet gale) fruit leachate contains myrigalone A (MyA), a rare C-methylated dihydrochalcone and putative allelochemical, which is known to be a phytotoxin impeding seedling growth. We found that MyA inhibited Lepidium sativum L. seed germination in a dose-dependent manner. MyA did not affect testa rupture, but inhibited endosperm rupture and the transition to subsequent seedling growth. MyA inhibited micropylar endosperm cap (CAP) weakening and the increase in the growth potential of the radical/hypocotyl region (RAD) of the embryo, both being key processes required for endosperm rupture. We compared the contents of abscisic acid (ABA) and gibberellins in the tissues and found that the major bioactive forms of gibberellin in L. sativum seed tissues were GA(4) and GA(6), while GA(8) and GA(13) were abundant inactive metabolites. MyA did not appreciably affect the ABA contents, but severely interfered with gibberellin metabolism and signaling by inhibiting important steps catalyzed by GA3 oxidase, as well as by interfering with the GID1-type gibberellin signaling pathway. The hormonally and developmentally regulated formation of apoplastic superoxide radicals is important for embryo growth. Specific zones within the RAD were associated with accumulation of apoplastic superoxide radicals and endoreduplication indicative of embryo cell extension. MyA negatively affected both of these processes and acted as a scavenger of apoplastic reactive oxygen species. We propose that MyA is an allelochemical with a novel mode of action on seed germination.     

Extending the rapeseed gene pool with resynthesized <Emphasis Type="Italic">Brassica napus</Emphasis> II: Heterosis

Hybrid breeding relies on the combination of parents from two differing heterotic groups. However, the genetic diversity in adapted oilseed rape breeding material is rather limited. Therefore, the use of resynthesized Brassica napus as a distant gene pool was investigated. Hybrids were derived from crosses between 44 resynthesized lines with a diverse genetic background and two male sterile winter oilseed rape tester lines. The hybrids were evaluated together with their parents and check cultivars in 2 years and five locations in Germany. Yield, plant height, seed oil, and protein content were monitored, and genetic distances were estimated with molecular markers (127 polymorphic RFLP fragments). Resynthesized lines varied in yield between 40.9 dt/ha and 21.5 dt/ha, or between 85.1 and 44.6% of check cultivar yields. Relative to check cultivars, hybrids varied from 91.6 to 116.6% in yield and from 94.5 to 103.3% in seed oil content. Mid-parent heterosis varied from −3.5 to 47.2% for yield. The genetic distance of parental lines was not significantly correlated with heterosis or hybrid yield. Although resynthesized lines do not meet the elite rapeseed standards, they are a valuable source for hybrid breeding due to their large distance from present breeding material and their high heterosis when combined with European winter oilseed rape.     

A uniquely modern human pattern of endocranial development. Insights from a new cranial reconstruction of the Neandertal newborn from Mezmaiskaya

The globular braincase of modern humans is distinct from all fossil human species, including our closest extinct relatives, the Neandertals. Such adult shape differences must ultimately be rooted in different developmental patterns, but it is unclear at which point during ontogeny these group characteristics emerge.Here we compared internal shape changes of the braincase from birth to adulthood in Neandertals (N = 10), modern humans (N = 62), and chimpanzees (N = 62). Incomplete fossil specimens, including the two Neandertal newborns from Le Moustier 2 and Mezmaiskaya, were reconstructed using reference-based estimation methods. We used 3D geometric morphometrics to statistically compare shapes of virtual endocasts extracted from computed-tomographic scans. Throughout the analysis, we kept track of possible uncertainties due to the missing data values and small fossil sample sizes.We find that some aspects of endocranial development are shared by the three species. However, in the first year of life, modern humans depart from this presumably ancestral pattern of development. Newborn Neandertals and newborn modern humans have elongated braincases, and similar endocranial volumes. During a ‘globularization-phase’ modern human endocasts change to the globular shape that is characteristic for Homo sapiens. This phase of early development is unique to modern humans, and absent from chimpanzees and Neandertals.Our results support the notion that Neandertals and modern humans reach comparable adult brain sizes via different developmental pathways. The differences between these two human groups are most prominent directly after birth, a critical phase for cognitive development.     

The incredible ULKs

ABSTRACT: Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction.     

Spatial scales of bacterial diversity in cold-water coral reef ecosystems

Background

Cold-water coral reef ecosystems are recognized as biodiversity hotspots in the deep sea, but insights into their associated bacterial communities are still limited. Deciphering principle patterns of bacterial community variation over multiple spatial scales may however prove critical for a better understanding of factors contributing to cold-water coral reef stability and functioning.

Methodology/Principal Findings

Bacterial community structure, as determined by Automated Ribosomal Intergenic Spacer Analysis (ARISA), was investigated with respect to (i) microbial habitat type and (ii) coral species and color, as well as the three spatial components (iii) geomorphologic reef zoning, (iv) reef boundary, and (v) reef location. Communities revealed fundamental differences between coral-generated (branch surface, mucus) and ambient microbial habitats (seawater, sediments). This habitat specificity appeared pivotal for determining bacterial community shifts over all other study levels investigated. Coral-derived surfaces showed species-specific patterns, differing significantly between Lophelia pertusa and Madrepora oculata, but not between L. pertusa color types. Within the reef center, no community distinction corresponded to geomorphologic reef zoning for both coral-generated and ambient microbial habitats. Beyond the reef center, however, bacterial communities varied considerably from local to regional scales, with marked shifts toward the reef periphery as well as between different in- and offshore reef sites, suggesting significant biogeographic imprinting but weak microbe-host specificity.

Conclusions/Significance

This study presents the first multi-scale survey of bacterial diversity in cold-water coral reefs, spanning a total of five observational levels including three spatial scales. It demonstrates that bacterial communities in cold-water coral reefs are structured by multiple factors acting at different spatial scales, which has fundamental implications for the monitoring of microbial diversity and function in those ecosystems.