Inositol 1,4,5- Trisphosphate Receptor Function in Drosophila Insulin Producing Cells

The Inositol 1,4,5- trisphosphate receptor (InsP3R) is an intracellular ligand gated channel that releases calcium from intracellular stores in response to extracellular signals. To identify and understand physiological processes and behavior that depends on the InsP3 signaling pathway at a systemic level, we are studying Drosophila mutants for the InsP3R (itpr) gene. Here, we show that growth defects precede larval lethality and both are a consequence of the inability to feed normally. Moreover, restoring InsP3R function in insulin producing cells (IPCs) in the larval brain rescues the feeding deficit, growth and lethality in the itpr mutants to a significant extent. We have previously demonstrated a critical requirement for InsP3R activity in neuronal cells, specifically in aminergic interneurons, for larval viability. Processes from the IPCs and aminergic domain are closely apposed in the third instar larval brain with no visible cellular overlap. Ubiquitous depletion of itpr by dsRNA results in feeding deficits leading to larval lethality similar to the itpr mutant phenotype. However, when itpr is depleted specifically in IPCs or aminergic neurons, the larvae are viable. These data support a model where InsP3R activity in non-overlapping neuronal domains independently rescues larval itpr phenotypes by non-cell autonomous mechanisms

Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43.

Phosphorylation and lipidation provide posttranslational mechanisms that contribute to the distribution of cytosolic proteins in growing nerve cells. The growth-associated protein GAP43 is susceptible to both phosphorylation and S-palmitoylation and is enriched in the tips of extending neurites. However, how phosphorylation and lipidation interplay to mediate sorting of GAP43 is unclear. Using a combination of biochemical, genetic, and imaging approaches, we show that palmitoylation is required for membrane association and that phosphorylation at Ser-41 directs palmitoylated GAP43 to the plasma membrane. Plasma membrane association decreased the diffusion constant fourfold in neuritic shafts. Sorting to the neuritic tip required palmitoylation and active transport and was increased by phosphorylation-mediated plasma membrane interaction. Vesicle tracking revealed transient association of a fraction of GAP43 with exocytic vesicles and motion at a fast axonal transport rate. Simulations confirmed that a combination of diffusion, dynamic plasma membrane interaction and active transport of a small fraction of GAP43 suffices for efficient sorting to growth cones. Our data demonstrate a complex interplay between phosphorylation and lipidation in mediating the localization of GAP43 in neuronal cells. Palmitoylation tags GAP43 for global sorting by piggybacking on exocytic vesicles, whereas phosphorylation locally regulates protein mobility and plasma membrane targeting of palmitoylated GAP43

The highly potent AhR agonist picoberin modulates Hh-dependent osteoblast differentiation

Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation. Global transcriptome and proteome profiling revealed the aryl hydrocarbon receptor (AhR) as the molecular target of this compound and identified a cross talk between Hh and AhR signaling during osteoblast differentiation

Semantics in Support of Biodiversity Knowledge Discovery: An Introduction to the Biological Collections Ontology and Related Ontologies

The study of biodiversity spans many disciplines and includes data pertaining to species distributions and abundances, genetic sequences, trait measurements, and ecological niches, complemented by information on collection and measurement protocols. A review of the current landscape of metadata standards and ontologies in biodiversity science suggests that existing standards such as the Darwin Core terminology are inadequate for describing biodiversity data in a semantically meaningful and computationally useful way. Existing ontologies, such as the Gene Ontology and others in the Open Biological and Biomedical Ontologies (OBO) Foundry library, provide a semantic structure but lack many of the necessary terms to describe biodiversity data in all its dimensions. In this paper, we describe the motivation for and ongoing development of a new Biological Collections Ontology, the Environment Ontology, and the Population and Community Ontology. These ontologies share the aim of improving data aggregation and integration across the biodiversity domain and can be used to describe physical samples and sampling processes (for example, collection, extraction, and preservation techniques), as well as biodiversity observations that involve no physical sampling. Together they encompass studies of: 1) individual organisms, including voucher specimens from ecological studies and museum specimens, 2) bulk or environmental samples (e.g., gut contents, soil, water) that include DNA, other molecules, and potentially many organisms, especially microbes, and 3) survey-based ecological observations. We discuss how these ontologies can be applied to biodiversity use cases that span genetic, organismal, and ecosystem levels of organization. We argue that if adopted as a standard and rigorously applied and enriched by the biodiversity community, these ontologies would significantly reduce barriers to data discovery, integration, and exchange among biodiversity resources and researchers

Propagation of Tau aggregates.

Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighbouring cells. In mice, the intracerebral injection of Tau inclusions induced the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Short fibrils constituted the major species of seed-competent Tau. The existence of several human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist

Zooterapia amazônica: uso de gordura de sucuri ( Eunectes murinus ) como cicatrizante natural

Zootherapy (the use of the therapeutic potential of animals) is at least 6,000 years old, and has been kept active throughout generations until modern days. Animal fat is commonly used in the zootherapeutic folk medicine from South America, specially the green anaconda's fat, which is widely promoted as a natural medicine to treat wounds, even though there is no scientific evidence showing its efficacy. In this study we compared the total healing time and the proportional daily reduction of dorsal epithelial incisions in adult male Wistar rats treated with nitrofural (a commercial cicatrizing ointment) and with anaconda fat. We applied the treatments every two days and measured the incision diameter daily, during ten consecutive days. Differences among the groups in the total healing time and in the proportional daily reduction of the incision consistently showed that the fat-based treatment resulted in a faster healing process compared to the commercial ointment tested. The literature suggests that the efficacy of animal fat on healing may be primarily related to the presence of fatty acids, which have been widely demonstrated to be important for biochemical reactions involved in healing processes. Our findings are widely socially relevant, considering that traditional Amazonian communities that use anaconda fat in folk medicine do not have easy access to pharmacies and hospitals.Práticas ancestrais de zooterapia (uso das potencialidades terapêuticas da fauna) existem há pelo menos 6000 anos, e têm sido mantidas ao longo de gerações até os tempos modernos. Gordura de animais é comumente utilizada na zooterapia tradicional da América do Sul, e a gordura de serpentes sucuris é amplamente comercializada como cicatrizante natural, embora não existam evidências científicas que mostrem sua eficácia terapêutica. Neste estudo comparamos o tempo de cicatrização epitelial total e a redução proporcional diária de uma incisão dorsal em ratos Wistar machos adultos, entre um grupo controle, um grupo tratado com nitrofural (uma pomada cicatrizante comercial) e um grupo tratado com gordura de sucuri. Nós aplicamos os tratamentos a cada dois dias e medimos o diâmetro da incisão diariamente por dez dias consecutivos. Diferenças entre os grupos no tempo de cicatrização total e na redução proporcional diária da incisão consistentemente mostraram que gordura de sucuri teve ação cicatrizante mais eficiente que a pomada comercial testada. A literatura sugere que a eficácia de gordura animal em processos de cicatrização pode estar principalmente relacionada à presença de ácidos graxos, os quais têm sido amplamente demonstrados como importantes para reações bioquímicas envolvidas em processos de cicatrização. Os resultados têm ampla relevância social, considerando que as comunidades tradicionais amazônicas que utilizam a gordura de sucuris como zooterápico não têm acesso fácil a farmácias e hospitais