Duchenne muscular dystrophy: From diagnosis to therapy

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options

A comprehensive approach to establish the impact of worksites air emissions

Worksite activities are time-limited events associated with continuous releases of airborne pollutants, such as carbon monoxide, particulate matter, and NOx, and they impact potentially vast areas. The side-effects on the environment can be severe, and they are subject of literature studies, with the final aim of proposing solutions that may improve the management of air emissions. No general assessment method or approach is yet available to estimate their effects on the environment and workers’ health. In this work, a general procedure that can be potentially applied to every type of worksite is proposed (i.e., construction sites, upgrading of chemical plants, road sites, etc..). The approach involves a detailed assessment of emissions and their expected pollutant concentrations. A dedicated mathematical model has been defined to assess pollutant emissions over time, consistent with all the different phases of foreseen activities. Emissions are defined on base of the GANTT descriptions of the activities and air pollutant dispersion is simulated with a dedicated model. Finally, the obtained results are evaluated against air quality thresholds as defined by laws and conditioning the human health risks for workers and citizens potentially exposed to pollutants

Delivering COBie data - Focus on curtain walls and building envelopes

COBie is a standard data framework whose main purpose is to transmit useful, reliable and us-able information collected throughout the whole building process and to be consumed in order to properly maintain the facility. Focusing on Facility Management information exchanges and considering the UK BIM policies and requirements, this paper shows the results obtained applying COBie to complex products such as curtain walls. Two Information Delivery Manuals (IDMs) were also developed, in order to provide a com-monly known and standardized framework, which can regulate the COBie-based information exchanges. Fu-ture developments of this study could concern the application of the developed IDMs to different case studies in order to overtake that specificity characterizing each single project and verify the validity of the proposal

Trilingual conversations: a window into multicompetence

A recurrent theme in the literature on trilingual language use is the question of whether there is a specific “trilingual competence.” In this paper we consider this question in the light of codeswitching patterns in two dyadic trilingual conversations between a mother and daughter conducted in (Lebanese) Arabic, French, and English. Quantitative and qualitative analysis of codeswitching in both conversants shows that, despite the fact that both subjects are fluent in all three languages, uses of switching are significantly different for mother and daughter across a number of features, including relative frequency of different switch types, and the incidence of hybrid constructions involving items from two or more languages. The subjects appear to display qualitatively distinct profiles of competence in the trilingual mode. This in turn leads to the conclusion that the facts of trilingual language use are best characterized in terms of “multicompetence” (Cook, 1991). The paper concludes with some further reflections on the uniqueness of trilingual language use (an “old chestnut” in trilingualism research, cf. Klein, 1995)

Assumptions behind grammatical approaches to code-switching: when the blueprint is a red herring

Many of the so-called ‘grammars’ of code-switching are based on various underlying assumptions, e.g. that informal speech can be adequately or appropriately described in terms of ‘‘grammar’’; that deep, rather than surface, structures are involved in code-switching; that one ‘language’ is the ‘base’ or ‘matrix’; and that constraints derived from existing data are universal and predictive. We question these assumptions on several grounds. First, ‘grammar’ is arguably distinct from the processes driving speech production. Second, the role of grammar is mediated by the variable, poly-idiolectal repertoires of bilingual speakers. Third, in many instances of CS the notion of a ‘base’ system is either irrelevant, or fails to explain the facts. Fourth, sociolinguistic factors frequently override ‘grammatical’ factors, as evidence from the same language pairs in different settings has shown. No principles proposed to date account for all the facts, and it seems unlikely that ‘grammar’, as conventionally conceived, can provide definitive answers. We conclude that rather than seeking universal, predictive grammatical rules, research on CS should focus on the variability of bilingual grammars

A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation

n/

Biocompatibility and toxicity of graphene quantum dots for potential application in photodynamic therapy

This is the author accepted manuscript. The final version is available from Future Medicine via the DOI in this recordAim: Achieving reliably high production of reactive oxygen species (ROS) in photodynamic therapy (PDT) remains challenging. Graphene quantum dots (GQD) hold great promise for PDT. However, the photochemical processes leading to GQD-derived ROS generation have not yet been fully elucidated. Materials & methods: Physicochemical characteristics of GQDs were comprehensively investigated, including electron paramagnetic resonance analysis of singlet oxygen production. Dark toxicity was assessed in vitro and in vivo. Results: GQDs demonstrated excellent photo-luminescent features, corrosion resistance, high water solubility, high photo/pH-stability, in vitro and in vivo biocompatibility and very efficient singlet oxygen/ROS generation. Conclusion: The enhanced ROS generation, combined with good biocompatibility and minimal toxicity in vitro and in vivo support the potential of GQDs for future PDT application.This work was supported by the EPSRC Centre for Doctoral Training in Metamaterials, XM2 (grant number EP/L015331/1

Operationalising and measuring language dominance

The paper offers a new way to measure language ability in bilinguals, based on measures of lexical richness. The validity of proposed approach is tested in a variety of ways

The Rg1 allele as a valuable tool for genetic transformation of the tomato 'Micro-Tom' model system.

Artigo número 23

Serotonin syndrome:pathophysiology, clinical features, management, and potential future directions

Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS