Targeted kinase inhibition relieves slowness and tremor in a Drosophila model of LRRK2 Parkinson’s disease

Disease models: A reflex reaction A simple reflex in flies can be used to test the effectiveness of therapies that slow neurodegeneration in Parkinson’s disease (PD). Christopher Elliott and colleagues at the University of York in the United Kingdom investigated the contraction of the proboscis muscle which mediates a taste behavior response and is regulated by a single dopaminergic neuron. Flies bearing particular mutations in the PD-associated gene leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons lost their ability to feed on a sweet solution. This was due to the movement of the proboscis muscle becoming slower and stiffer, hallmark features of PD. The authors rescued the impaired reflex reaction by feeding the flies l-DOPA or LRRK2 inhibitors. These findings highlight the proboscis extension response as a useful tool to identify other PD-associated mutations and test potential therapeutic compounds

Aza-deoxycytidine induces apoptosis or differentiation via DNMT3B and targets embryonal carcinoma cells but not their differentiated derivatives

Background: Teratocarcinoma is a malignant male germ cell tumour, which contains stem cells and differentiated cancer tissues. DNMT3B has been shown to be highly expressed in human teratocarcinoma stem cells, and to mediate cytotoxicity of Aza-deoxycytidine (Aza-dC) in a pluripotent stem cell line NTERA2. Methods: We have established DNMT3B or POU5F1 (hereafter referred to as OCT4) knockdown in teratocarcinoma stem cells N2102Ep and TERA1 and in the pluripotent NTERA2 by a doxycycline-inducible system, and tested the cytotoxicity induced by Aza-dC. Results: Silencing of DNMT3B led to apoptosis of human teratocarcinoma stem cells N2102Ep and TERA1. Further, we found that induction of apoptosis or differentiation in NTERA2 and human embryonic stem cells by Aza-dC requires DNMT3B. To test whether Aza-dC inhibits proliferation of differentiated teratocarcinoma cells, we depleted OCT4 expression in N2102Ep and TERA1 cells treated with Aza-dC. Treatment with Aza-dC reduced cell number of differentiated cells to a lesser extent than their undifferentiated parental stem cells. Moreover, in contrast to the stem cells, Aza-dC failed to induce apoptosis of differentiated cells. Conclusions: Our finding suggests that DNMT3B acts as an antiapoptotic gene in teratocarcinoma stem cells, and mediates apoptosis and differentiation of human pluripotent stem cells induced by Aza-dC, and that Aza-dC specifically induces apoptosis of teratocarcinoma stem cells

Oral Rabies Vaccination in North America: Opportunities, Complexities, and Challenges

Steps to facilitate inter-jurisdictional collaboration nationally and continentally have been critical for implementing and conducting coordinated wildlife rabies management programs that rely heavily on oral rabies vaccination (ORV). Formation of a national rabies management team has been pivotal for coordinated ORV programs in the United States of America. The signing of the North American Rabies Management Plan extended a collaborative framework for coordination of surveillance, control, and research in border areas among Canada, Mexico, and the US. Advances in enhanced surveillance have facilitated sampling of greater scope and intensity near ORV zones for improved rabies management decision-making in real time. The value of enhanced surveillance as a complement to public health surveillance was best illustrated in Ohio during 2007, where 19 rabies cases were detected that were critical for the formulation of focused contingency actions for controlling rabies in this strategically key area. Diverse complexities and challenges are commonplace when applying ORV to control rabies in wild meso-carnivores. Nevertheless, intervention has resulted in notable successes, including the elimination of an arctic fox (Vulpes lagopus) rabies virus variant in most of southern Ontario, Canada, with ancillary benefits of elimination extending into Quebec and the northeastern US. Progress continues with ORV toward preventing the spread and working toward elimination of a unique variant of gray fox (Urocyon cinereoargenteus) rabies in west central Texas. Elimination of rabies in coyotes (Canis latrans) through ORV contributed to the US being declared free of canine rabies in 2007. Raccoon (Procyon lotor) rabies control continues to present the greatest challenges among meso-carnivore rabies reservoirs, yet to date intervention has prevented this variant from gaining a broad geographic foothold beyond ORV zones designed to prevent its spread from the eastern US. Progress continues toward the development and testing of new bait-vaccine combinations that increase the chance for improved delivery and performance in the diverse meso-carnivore rabies reservoir complex in the US

Fabry disease: recent advances in pathology, diagnosis, treatment and monitoring

<p>Abstract</p> <p>Background</p> <p>In Fabry disease (α-galactosidase A deficiency) accumulation of Globotriaosylceramide (Gb3) leads to progressive organ failure and premature death. The introduction of enzyme replacement therapy (ERT) was the beginning of a new era in this disorder, and has prompted a broad range of research activities. This review aims to summarize recent developments and progress with high impact for Fabry disease.</p> <p>Methods</p> <p>A Pubmed analysis was performed using the search terms "Fabry disease", "Anderson-Fabry disease", "alpha-galactosidase A" and "Gb3". Of the given publications by 31st January 2009 only original articles recently published in peer reviewed journals were included for this review. Case reports were included only when they comprised a new aspect. In addition we included relevant conference abstracts when the results had not already been published as original articles.</p> <p>Results</p> <p>Apart from Gb3-accumulation cellular and organ specific damages may be related also to inflammatory and immunological consequences. It will be interesting whether this may lead to new therapeutic strategies in the treatment of Fabry disease. Since newborn screening is still difficult in Fabry disease, detection of patients in populations at risk is of great importance. Undiagnosed patients with Fabry disease may still be found in cohorts of subjects with renal diseases, cardiomyopathy and TIA or stroke. Efforts should be undertaken to identify these individuals and initialise ERT in order to hault disease progression. It has also been demonstrated that Gb3-accumulation leads to pre-clinical damages and it is believed that early treatment may be the only possibility so far to prevent irreversible organ damage.</p

Assessing anti-rabies baiting – what happens on the ground?

BACKGROUND: Rabies is one of the most hazardous zoonoses in the world. Oral mass vaccination has developed into the most effective management method to control fox rabies. The future need to control the disease in large countries (i.e. Eastern Europe and the Americas) forces cost-benefit discussions. The 'Increase bait density' option refers to the usual management assumption that more baits per km(2 )could compensate for high fox abundance and override the imperfect supply of bait pieces to the individual fox. METHODS: We use a spatial simulation, which combines explicitly fox space use (tessellation polygons) and aeroplane flight lines (straight lines). The number of baits actually falling into each polygon is measured. The manager's strategic options are converted into changes of the resulting bait distribution on the ground. The comparison enables the rating of the options with respect to the management aim (i.e. accessibility of baits). RESULTS: Above 5% (approx. 10%) of all fox groups without any bait (at most 5 baits) relate to the baiting strategy applied in the field (1 km spaced parallel flight lines, 20 baits per km(2 )distributed) under habitat conditions comparable to middle and western Europe (fox group home-range 1 km(2), 2.5 adults; reference strategy). Increasing the bait density on the same flight-line pattern neither reduces the number of under-baited fox group home-ranges, nor improves the management outcome and hence wastes resources. However, reducing the flight line distance provides a more even bait distribution and thus compensates for missed fox groups or extra high fox density. The reference strategy's bait density can be reduced when accounting for the missed fox groups. The management result with the proper strategy is likely the same but with reduced costs. CONCLUSION: There is no overall optimal strategy for the bait distribution in large areas. For major parts of the landscape, the reference strategy will be more competitive. In situations where set backs are attributed to non-homogeneous bait accessibility the distribution scheme has to be refined zone-based (i.e. increase of the flight line length per unit area). However, increase in bait density above the reference strategy appears inappropriate at least for non-urban abundance conditions of the red fox

Mutualism and Adaptive Divergence: Co-Invasion of a Heterogeneous Grassland by an Exotic Legume-Rhizobium Symbiosis

Species interactions play a critical role in biological invasions. For example, exotic plant and microbe mutualists can facilitate each other's spread as they co-invade novel ranges. Environmental context may influence the effect of mutualisms on invasions in heterogeneous environments, however these effects are poorly understood. We examined the mutualism between the legume, Medicago polymorpha, and the rhizobium, Ensifer medicae, which have both invaded California grasslands. Many of these invaded grasslands are composed of a patchwork of harsh serpentine and relatively benign non-serpentine soils. We grew legume genotypes collected from serpentine or non-serpentine soil in both types of soil in combination with rhizobium genotypes from serpentine or non-serpentine soils and in the absence of rhizobia. Legumes invested more strongly in the mutualism in the home soil type and trends in fitness suggested that this ecotypic divergence was adaptive. Serpentine legumes had greater allocation to symbiotic root nodules in serpentine soil than did non-serpentine legumes and non-serpentine legumes had greater allocation to nodules in non-serpentine soil than did serpentine legumes. Therefore, this invasive legume has undergone the rapid evolution of divergence for soil-specific investment in the mutualism. Contrary to theoretical expectations, the mutualism was less beneficial for legumes grown on the stressful serpentine soil than on the non-serpentine soil, possibly due to the inhibitory effects of serpentine on the benefits derived from the interaction. The soil-specific ability to allocate to a robust microbial mutualism may be a critical, and previously overlooked, adaptation for plants adapting to heterogeneous environments during invasion

The Influence of cis-Regulatory Elements on DNA Methylation Fidelity

It is now established that, as compared to normal cells, the cancer cell genome has an overall inverse distribution of DNA methylation (“methylome”), i.e., predominant hypomethylation and localized hypermethylation, within “CpG islands” (CGIs). Moreover, although cancer cells have reduced methylation “fidelity” and genomic instability, accurate maintenance of aberrant methylomes that underlie malignant phenotypes remains necessary. However, the mechanism(s) of cancer methylome maintenance remains largely unknown. Here, we assessed CGI methylation patterns propagated over 1, 3, and 5 divisions of A2780 ovarian cancer cells, concurrent with exposure to the DNA cross-linking chemotherapeutic cisplatin, and observed cell generation-successive increases in total hyper- and hypo-methylated CGIs. Empirical Bayesian modeling revealed five distinct modes of methylation propagation: (1) heritable (i.e., unchanged) high- methylation (1186 probe loci in CGI microarray); (2) heritable (i.e., unchanged) low-methylation (286 loci); (3) stochastic hypermethylation (i.e., progressively increased, 243 loci); (4) stochastic hypomethylation (i.e., progressively decreased, 247 loci); and (5) considerable “random” methylation (582 loci). These results support a “stochastic model” of DNA methylation equilibrium deriving from the efficiency of two distinct processes, methylation maintenance and de novo methylation. A role for cis-regulatory elements in methylation fidelity was also demonstrated by highly significant (p<2.2×10−5) enrichment of transcription factor binding sites in CGI probe loci showing heritably high (118 elements) and low (47 elements) methylation, and also in loci demonstrating stochastic hyper-(30 elements) and hypo-(31 elements) methylation. Notably, loci having “random” methylation heritability displayed nearly no enrichment. These results demonstrate an influence of cis-regulatory elements on the nonrandom propagation of both strictly heritable and stochastically heritable CGIs

GaSbBi alloys and heterostructures: fabrication and properties

International audienceDilute bismuth (Bi) III-V alloys have recently attracted great attention, due to their properties of band-gap reduction and spin-orbit splitting. The incorporation of Bi into antimonide based III-V semiconductors is very attractive for the development of new optoelectronic devices working in the mid-infrared range (2-5 µm). However, due to its large size, Bi does not readily incorporate into III-V alloys and the epitaxy of III-V dilute bismides is thus very challenging. This book chapter presents the most recent developments in the epitaxy and characterization of GaSbBi alloys and heterostructures

Network, degeneracy and bow tie. Integrating paradigms and architectures to grasp the complexity of the immune system

Recently, the network paradigm, an application of graph theory to biology, has proven to be a powerful approach to gaining insights into biological complexity, and has catalyzed the advancement of systems biology. In this perspective and focusing on the immune system, we propose here a more comprehensive view to go beyond the concept of network. We start from the concept of degeneracy, one of the most prominent characteristic of biological complexity, defined as the ability of structurally different elements to perform the same function, and we show that degeneracy is highly intertwined with another recently-proposed organizational principle, i.e. 'bow tie architecture'. The simultaneous consideration of concepts such as degeneracy, bow tie architecture and network results in a powerful new interpretative tool that takes into account the constructive role of noise (stochastic fluctuations) and is able to grasp the major characteristics of biological complexity, i.e. the capacity to turn an apparently chaotic and highly dynamic set of signals into functional information