Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses.

α-Synuclein overexpression and aggregation are linked to Parkinson's disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal (RS) synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to an increase in endocytic intermediates and a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein, Hsc70 availability was reduced at stimulated synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 along with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the synaptic vesicle trafficking defects associated with excess α-synuclein, which may be of value for improving synaptic function in PD and other synuclein-linked diseases.

Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis.

Periodontitis (PD) is a chronic osteolytic disease that shares pathogenic inflammatory features with other conditions associated with nonresolving inflammation. A hallmark of PD is inflammation-mediated alveolar bone loss. Myeloid cells, in particular polymorphonuclear neutrophils (PMN) and macrophages (Mac), are essential players in PD by control of gingival biofilm pathogenicity, activation of adaptive immunity, as well as nonresolving inflammation and collateral tissue damage. Despite mounting evidence of significant innate immune implications to PD progression and healing after therapy, myeloid cell markers and targets for immune modulation have not been validated for clinical use. The remarkable plasticity of monocytes/Mac in response to local activation factors enables these cells to play central roles in inflammation and restoration of tissue homeostasis and provides opportunities for biomarker and therapeutic target discovery for management of chronic inflammatory conditions, including osteolytic diseases such as PD and arthritis. Along a wide spectrum of activation states ranging from proinflammatory to pro-resolving, Macs respond to environmental changes in a site-specific manner in virtually all tissues. This review summarizes the existing evidence on Mac immunomodulation therapies for osteolytic diseases in the broader context of conditions associated with nonresolving inflammation, and discusses osteoimmune implications of Macs in PD.

Resveratrol derivative-rich melinjo seed extract induces healing in a murine model of established periodontitis.

BACKGROUND: Products of internal defense systems, like pro-inflammatory cytokines, reactive oxygen species, and leukocytes, are released which attack periodontal bacteria in periodontitis, but at the same time, lead to tissue destruction as well. We hypothesize that resveratrol derivative-rich melinjo seed extract (MSE), an edible plant extract that has antioxidant properties, should promote healing of periodontal bone loss and modulating immune-inflammatory systems that leads periodontal tissue destruction. METHODS: We used an experimentally induced periodontitis (EP) model in mice. Ligatures were placed first for development of EP (15 days). MSE was intraperitoneally administrated (0.001% (w/w)) to reverse bone loss that had already occurred in established EP and mice were then sacrificed (day 17, 20 and 22). RESULTS: Morphometric outcomes revealed lower bone-loss in the MSE groups compared to control. Immunohistochemistry assays demonstrated lower oxidative stress in MSE groups. MSE also inhibited M-CSF/sRANKL mediated osteoclast formation and down-regulated osteoclast activity. CONCLUSIONS: Treatment with MSE in EP actually caused healing of bone, and these effects are probably related to decreases in local oxidative damage and osteoclast activity. Given MSE's positive effects on osteodifferentiation as well, these findings suggest that MSE could be a useful therapeutic agent for the management of periodontitis.

Adseverin plays a role in osteoclast differentiation and periodontal disease-mediated bone loss.

Osteoclast differentiation and function are highly dependent on the assembly and turnover of actin filaments, but little is known about the roles of actin binding proteins in these processes. Adseverin (Ads), a member of the gelsolin superfamily of actin capping and severing proteins, regulates actin filament turnover and can regulate the turnover of cortical actin filaments of chromaffin cells during exocytosis. Using a conditional Ads knockout mouse model, we confirmed our previous finding in cultured cells that Ads plays a role in osteoclastogenesis (OCG) and actin cytoskeletal organization in osteoclasts. Here we show that Ads is required for osteoclast formation and that when alveolar bone resorption is experimentally induced in mice, genetic deletion of Ads prevents osteoclast-mediated bone loss. Further, when Ads-null osteoclasts are cultured, they exhibit defective OCG, disorganized podosome-based actin filament superstructures, and decreased bone resorption. Reintroduction of Ads into Ads-null osteoclast precursor cells restored these osteoclast defects. Collectively, these data demonstrate a unique and osteoclast-specific role for Ads in OCG and osteoclast function.

Eco-evo-devo: the time has come.

The major goal of ecological evolutionary developmental biology, also known as "eco-evo-devo," is to uncover the rules that underlie the interactions between an organism's environment, genes, and development and to incorporate these rules into evolutionary theory. In this chapter, we discuss some key and emerging concepts within eco-evo-devo. These concepts show that the environment is a source and inducer of genotypic and phenotypic variation at multiple levels of biological organization, while development acts as a regulator that can mask, release, or create new combinations of variation. Natural selection can subsequently fix this variation, giving rise to novel phenotypes. Combining the approaches of eco-evo-devo and ecological genomics will mutually enrich these fields in a way that will not only enhance our understanding of evolution, but also of the genetic mechanisms underlying the responses of organisms to their natural environments.

Shifts in developmental timing, and not increased levels of experience-dependent neuronal activity, promote barrel expansion in the primary somatosensory cortex of rats enucleated at birth.

Birth-enucleated rodents display enlarged representations of whiskers (i.e., barrels of the posteromedial subfield) in the primary somatosensory cortex. Although the historical view maintains that barrel expansion is due to incremental increases in neuronal activity along the trigeminal pathway during postnatal development, recent evidence obtained in experimental models of intramodal plasticity challenges this view. Here, we re-evaluate the role of experience-dependent neuronal activity on barrel expansion in birth-enucleated rats by combining various anatomical methods and sensory deprivation paradigms. We show that barrels in birth-enucleated rats were already enlarged by the end of the first week of life and had levels of metabolic activity comparable to those in control rats at different ages. Dewhiskering after the postnatal period of barrel formation did not prevent barrel expansion in adult, birth-enucleated rats. Further, dark rearing and enucleation after barrel formation did not lead to expanded barrels in adult brains. Because incremental increases of somatosensory experience did not promote barrel expansion in birth-enucleated rats, we explored whether shifts of the developmental timing could better explain barrel expansion during the first week of life. Accordingly, birth-enucleated rats show earlier formation of barrels, accelerated growth of somatosensory thalamocortical afferents, and an earlier H4 deacetylation. Interestingly, when H4 deacetylation was prevented with a histone deacetylases inhibitor (valproic acid), barrel specification timing returned to normal and barrel expansion did not occur. Thus, we provide evidence supporting that shifts in developmental timing modulated through epigenetic mechanisms, and not increased levels of experience dependent neuronal activity, promote barrel expansion in the primary somatosensory cortex of rats enucleated at birth.

Draft genome of the globally widespread and invasive Argentine ant (Linepithema humile).

Ants are some of the most abundant and familiar animals on Earth, and they play vital roles in most terrestrial ecosystems. Although all ants are eusocial, and display a variety of complex and fascinating behaviors, few genomic resources exist for them. Here, we report the draft genome sequence of a particularly widespread and well-studied species, the invasive Argentine ant (Linepithema humile), which was accomplished using a combination of 454 (Roche) and Illumina sequencing and community-based funding rather than federal grant support. Manual annotation of >1,000 genes from a variety of different gene families and functional classes reveals unique features of the Argentine ant's biology, as well as similarities to Apis mellifera and Nasonia vitripennis. Distinctive features of the Argentine ant genome include remarkable expansions of gustatory (116 genes) and odorant receptors (367 genes), an abundance of cytochrome P450 genes (>110), lineage-specific expansions of yellow/major royal jelly proteins and desaturases, and complete CpG DNA methylation and RNAi toolkits. The Argentine ant genome contains fewer immune genes than Drosophila and Tribolium, which may reflect the prominent role played by behavioral and chemical suppression of pathogens. Analysis of the ratio of observed to expected CpG nucleotides for genes in the reproductive development and apoptosis pathways suggests higher levels of methylation than in the genome overall. The resources provided by this genome sequence will offer an abundance of tools for researchers seeking to illuminate the fascinating biology of this emerging model organism.

Draft genome of the red harvester ant Pogonomyrmex barbatus.

We report the draft genome sequence of the red harvester ant, Pogonomyrmex barbatus. The genome was sequenced using 454 pyrosequencing, and the current assembly and annotation were completed in less than 1 y. Analyses of conserved gene groups (more than 1,200 manually annotated genes to date) suggest a high-quality assembly and annotation comparable to recently sequenced insect genomes using Sanger sequencing. The red harvester ant is a model for studying reproductive division of labor, phenotypic plasticity, and sociogenomics. Although the genome of P. barbatus is similar to other sequenced hymenopterans (Apis mellifera and Nasonia vitripennis) in GC content and compositional organization, and possesses a complete CpG methylation toolkit, its predicted genomic CpG content differs markedly from the other hymenopterans. Gene networks involved in generating key differences between the queen and worker castes (e.g., wings and ovaries) show signatures of increased methylation and suggest that ants and bees may have independently co-opted the same gene regulatory mechanisms for reproductive division of labor. Gene family expansions (e.g., 344 functional odorant receptors) and pseudogene accumulation in chemoreception and P450 genes compared with A. mellifera and N. vitripennis are consistent with major life-history changes during the adaptive radiation of Pogonomyrmex spp., perhaps in parallel with the development of the North American deserts.

Portrait of human tapeworms.

The tapeworms of the genus Taenia that infect human beings are T. solium, T. saginata and T. saginata asiatica. Taenia solium and T. saginata exhibit unequivocal features that characterize them; in contrast, only recent DNA studies, morphological characteristics, and epidemiological and sanitary aspects indicate that T. saginata asiatica is a subspecies of T. saginata. These 3 tapeworms occur in humans in their adult stage, and the intermediate hosts are pigs for T. solium and T. saginata asiatica and cows for T. saginata. Their identification is crucial considering the migratory increase from Asia to the Western Hemisphere and the fact that these tapeworms coexist in the same environment in Asia; furthermore, it is estimated that movement in both directions across the United States-Mexico border exceeds 200 million persons per yr, and thus, opportunities for acquiring and transporting T. solium infections are multiplied. It is not easy to distinguish among these tapeworms; therefore, a comparative diagram of the 3 parasites is shown in this article, which will facilitate their identification. All morphological features, some of which allow for identification, are clear and can be easily distinguished among the 3 tapeworms.