Multiple exon skipping strategies to by-pass dystrophin mutations.

Manipulation of dystrophin pre-mRNA processing offers the potential to overcome mutations in the dystrophin gene that would otherwise lead to Duchenne muscular dystrophy. Dystrophin mutations will require the removal of one or more exons to restore the reading frame and in some cases, multiple exon skipping strategies exist to restore dystrophin expression. However, for some small intra-exonic mutations, a third strategy, not applicable to whole exon deletions, may be possible. The removal of only one frame-shifting exon flanking the mutation-carrying exon may restore the reading frame and allow synthesis of a functional dystrophin isoform, providing that no premature termination codons are encountered. For these mutations, the removal of only one exon offers a simpler, cheaper and more feasible alternative approach to the dual exon skipping that would otherwise be considered. We present strategies to by-pass intra-exonic dystrophin mutations that clearly demonstrate the importance of tailoring exon skipping strategies to specific patient mutations

Spatio-temporal and risk factor analysis of alleles related to Scrapie resistance in sheep in Great Britain before, during and after a national breeding program

Certain genotypes of sheep have been identified to increase their susceptibility (the VRQ allele) or resistance (the ARR allele) to classical scrapie. This study’s aim was to assess the spatio-temporal pattern of the ARR and VRQ alleles in GB and to explore the risk factors associated to their presence. Data was collected from the GB scrapie active surveillance program, the sheep and goat inventory survey (GB census survey) and the agricultural survey for the period 2002-2015. Spatio-temporal trends of genotypes were assessed through the use of choropleth maps, spatial cluster and linear regression analyses. Multivariable mix-effect logistic regression analyses were performed to investigate the association between the resistant or susceptible genotypes, and breeds, farm purpose, animal purpose, surveillance stream, country location and herd size. The results show a significant upward trend in the frequency of most resistant ARR alleles (1.15% per year, 95%CI: 0.76-1.53) and significant downward trend of most susceptible VRQ alleles (-0.40% per year; 95%CI: -0.69 to -0.10]. The trend continues after the termination of the national scrapie plan in 2009. Breeds such as Herdwick (OR = 0,26; 95%CI: 0.14-0.46), Shetland (OR = 0.22; 95%CI: 0.13-0.39), Swaledale (OR = 0.58; 95%CI: 0.47-0.73), Scottish blackface (OR = 0.54; 95%CI: 0.41-0.71) and Welsh Montain (OR: 0.59; 95%CI: 0.44-0.79) were identified with lower odds ratios of having the resistant ARR allele, while Beulah speckled face (OR = 1.58; 95%CI: 1.04-2.41), Jacob (OR = 2.91; 95%CI: 1.33-6.40), Lleyn (OR = 2.94; 95%CI: 1.28-6.74) and Suffolk (OR = 2.19; 95%CI: 1.69-2.84) had higher odds ratios of having the ARR allele. Other risk factors associated to presence of ARR allele were finishing farms (OR = 1.15; 95%CI: 1.06-1.24) and farms in Scotland (OR = 0,78; 95%CI: 0.73-0.83) and in Lowland grazing areas (OR = 1.53; 95%CI: 1.39-1.67). Factors associated with presence the VRQ genotype were farms in Scotland (OR = 0,85; 95%CI: 0.77-0.93) and breeds such as Herdwick (OR = 2.2; 95%CI: 1.08-4.97), Shetland (OR = 4.12; 95%CI: 2.20-7.73) and Sweledale (OR = 1.51; 95%CI: 1.10-2.09). For the most resistant genotype, two significant spatial clusters were identified: a high-risk cluster in the south-west of GB (RR = 1.51, p < 0.001) and a low-risk cluster in northern GB (RR = 0.65, p < 0.001). For the most susceptible genotypes, one significant high-risk cluster was identified in Wales (RR = 2.89 and p = 0.013). Surveillance for classical scrapie could be improved with a risk-based approach by focussing on those areas and farm types identified to have higher frequency of VRQ alleles and less frequency of ARR alleles. Scrapie control strategies could focus on developing breeding programs on farms with Shetland, Herdwick and Swaledale breeds

Molybdenum oxide on Fe2O3 Core-Shell catalysts: Probing the nature of the structural motifs responsible for methanol oxidation catalysis

A series of MoOx-modified Fe2O3 catalysts have been prepared in an attempt to make core–shell oxidic materials of the type MoOx/Fe2O3. It is conclusively shown that for three monolayers of Mo dosed, the Mo stays in the surface region, even after annealing to high temperature. It is only when the material is annealed above 400 °C that it reacts with the iron oxide. We show by a combination of methods, and especially by XAFS, that at temperatures above 400 °C, most of the Mo converts to Fe2(MoO4)3, with Mo in a tetrahedral structure, whereas below that temperature, nanocrystalline MoO3 is present in the sample; however, the active catalysts have an octahedral MoOx layer at the surface even after calcination to 600 °C. This surface layer appears to be present at all temperatures between 300 and 600 °C, and it is the nanoparticles of MoO3 that are present at the lower temperature that react to form ferric molybdate, which underlies this surface layer. It is the MoOx layer on the Fe2(MoO4)3 underlayer that makes the surface active and selective for formaldehyde synthesis, whereas the iron oxide surface itself is a combustor. The material is both activated and improved in selectivity due to the dominance of the methoxy species on the Mo-doped material, as opposed to the much more stable formate, which is the main intermediate on Fe2O3

Freezing of gait and fall detection in Parkinson’s disease using wearable sensors:a systematic review

Despite the large number of studies that have investigated the use of wearable sensors to detect gait disturbances such as Freezing of gait (FOG) and falls, there is little consensus regarding appropriate methodologies for how to optimally apply such devices. Here, an overview of the use of wearable systems to assess FOG and falls in Parkinson’s disease (PD) and validation performance is presented. A systematic search in the PubMed and Web of Science databases was performed using a group of concept key words. The final search was performed in January 2017, and articles were selected based upon a set of eligibility criteria. In total, 27 articles were selected. Of those, 23 related to FOG and 4 to falls. FOG studies were performed in either laboratory or home settings, with sample sizes ranging from 1 PD up to 48 PD presenting Hoehn and Yahr stage from 2 to 4. The shin was the most common sensor location and accelerometer was the most frequently used sensor type. Validity measures ranged from 73–100% for sensitivity and 67–100% for specificity. Falls and fall risk studies were all home-based, including samples sizes of 1 PD up to 107 PD, mostly using one sensor containing accelerometers, worn at various body locations. Despite the promising validation initiatives reported in these studies, they were all performed in relatively small sample sizes, and there was a significant variability in outcomes measured and results reported. Given these limitations, the validation of sensor-derived assessments of PD features would benefit from more focused research efforts, increased collaboration among researchers, aligning data collection protocols, and sharing data sets

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics

Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies

Passive fear

“Passive fear” denotes a certain type of response to a perceived threat; what is distinctive about the state of passive fear is that its behavioral outlook appears to qualify the emotional experience. I distinguish between two cases of passive fear: one is that of freezing in fear; the other is that of fear-involved tonic immobility. I reconstruct the explanatory strategy that is commonly employed in the field of emotion science, and argue that it leaves certain questions about the nature of passive fear unanswered. I subsequently propose an account of passive fear that builds upon a phenomenological theory of emotions, placing emphasis on the interpretation of current research into human tonic immobility. © 2014, Springer Science+Business Media Dordrecht