Chapter Biomarkers in Rare Genetic Diseases

Today, as the need of new regenerative solutions is steadily increasing, the demand for new bio-devices with smart functionality is pushing material scientists to develop new synthesis concepts. Indeed, the conventional approaches for biomaterials fail when it comes to generate nano-biocomposites with designed biomimetic composition and hierarchically organized architecture mimicking biologically relevant tissue features. In this respect, an emerging concept in material science is to draw inspiration from natural processes and products, which we may consider as the most advanced examples of smart nanotechnology. Natural processes of supramolecular assembly and mineralization of organic macromolecules, known as biomineralization, generate complex hybrid 3D constructs that are the basis of skeletons, exoskeletons, nacre and shells. On the other hand, natural structures such as woods and plants exhibit multi-scale hierarchic organization that is the source of smart and anisotropic mechanical properties associated with high porosity and lightness. The association of nature-inspired nano-technological products with smart functionalization can provide new advanced solutions to critical and still unmet clinical needs. In this respect, magnetic activation of biomaterials by the use of a recently developed biocompatible, resorbable magnetic apatite promises to represent a new safe and effective switching tool, enabling personalized applications in regenerative medicine and theranostics that so far were not feasible, due to the cytotoxicity of the currently used magnetic materials

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

In Support of the Matrix Language Frame Model: Evidence from Igbo-English Intrasentential Codeswitching

This paper explores the morphosyntactic features of mixed nominal expressions in a sample of empirical Igbo-English intrasentential codeswitching data (i.e. codeswitching within a bilingual clause) in terms of the Matrix Language Frame (MLF) model. Since both Igbo and English differ in the relative order of head and complement within the nominal argument phrase, the analysed data seem appropriate for testing the veracity of the principal assumption underpinning the MLF model: the notion that the two languages (in our case Igbo and English) participating in codeswitching do not both contribute equally to the morphosyntactic frame of a mixed constituent. As it turns out, the findings provide both empirical and quantitative support for the basic theoretical view that there is a Matrix Language (ML) versus Embedded Language (EL) hierarchy in classic codeswitching as predicted by the MLF model because both Igbo and English do not simultaneously satisfy the roles of the ML in Igbo-English codeswitching

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

The Popeye Domain Containing Genes and Their Function in Striated Muscle

The Popeye domain containing (POPDC) genes encode a novel class of cAMP effector proteins, which are abundantly expressed in heart and skeletal muscle. Here we will review their role in striated muscle as deduced from work in cell and animal models and the recent analysis of patients carrying a missense mutation in POPDC1. Evidence suggests that POPDC proteins control membrane trafficking of interacting proteins. Furthermore, we will discuss the current catalogue of established protein-protein interactions. In recent years, the number of POPDC-interacting proteins is rising and currently includes ion channels (TREK-1), sarcolemma-associated proteins serving functions in mechanical stability (Dystrophin), compartmentalization (Caveolin 3), scaffolding (ZO-1), trafficking (NDRG4, VAMP2/3) and repair (Dysferlin), or acting as a guanine nucleotide exchange factor for Rho-family GTPases (GEFT). Recent evidence suggests that POPDC proteins might also control the cellular level of the nuclear proto-oncoprotein c-Myc. These data suggests that this family of cAMP-binding proteins probably serves multiple roles in striated muscle

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)

How to handle big data for disease stratification in respiratory medicine?

This is the final version. Available from BMJ Publishing via the DOI in this record. Engineering and Physical Sciences Research Council (EPSRC)Medical Research CouncilMedical Research Counci

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

ICAM-1 and ICAM-2 Are Differentially Expressed and Up-Regulated on Inflamed Pulmonary Epithelium, but Neither ICAM-2 nor LFA-1: ICAM-1 Are Required for Neutrophil Migration Into the Airways In Vivo

Neutrophil migration into the airways is an important process to fight infection and is mediated by cell adhesion molecules. The intercellular adhesion molecules, ICAM-1 (CD54) and ICAM-2 (CD102) are known ligands for the neutrophil integrins, lymphocyte function associated antigen (LFA)-1 (αLβ2; CD11a/CD18), and macrophage-1 antigen (Mac-1;αMβ2;CD11b/CD18) and are implicated in leukocyte migration into the lung. However, it is ill-defined how neutrophils exit the lung and the role for ICAMs in trans-epithelial migration (TEpM) across the bronchial or alveolar epithelium. We found that human and murine alveolar epithelium expressed ICAM-1, whilst the bronchial epithelium expressed ICAM-2, and both were up-regulated during inflammatory stimulation in vitro and in inflammatory lung diseases such as cystic fibrosis. Although β2 integrins interacting with ICAM-1 and -2 mediated neutrophil migration across human bronchial epithelium in vitro, neither ICAM-2 nor LFA-1 binding of ICAM-1 mediated murine neutrophil migration into the lung or broncho-alveolar space during LPS-induced inflammation in vivo. Furthermore, TEpM of neutrophils themselves resulted in increased epithelial junctional permeability and reduced barrier function in vitro. This suggests that although β2 integrins interacting with ICAMs may regulate low levels of neutrophil traffic in healthy lung or early in inflammation when the epithelial barrier is intact; these interactions may be redundant later in inflammation when epithelial junctions are disrupted and no longer limit TEpM