The molecular basis and biologic significance of the β-dystroglycan-emerin interaction

β-dystroglycan (β-DG) assembles with lamins A/C and B1 and emerin at the nuclear envelope (NE) to maintain proper nuclear architecture and function. To provide insight into the nuclear function of β-DG, we characterized the interaction between β-DG and emerin at the molecular level. Emerin is a major NE protein that regulates multiple nuclear processes and whose deficiency results in Emery–Dreifuss muscular dystrophy (EDMD). Using truncated variants of β-DG and emerin, via a series of in vitro and in vivo binding experiments and a tailored computational analysis, we determined that the β-DG–emerin interaction is mediated at least in part by their respective transmembrane domains (TM). Using surface plasmon resonance assays we showed that emerin binds to β-DG with high affinity (KD in the nanomolar range). Remarkably, the analysis of cells in which DG was knocked out demonstrated that loss of β-DG resulted in a decreased emerin stability and impairment of emerin-mediated processes. β-DG and emerin are reciprocally required for their optimal targeting within the NE, as shown by immunofluorescence, western blotting and immunoprecipitation assays using emerin variants with mutations in the TM domain and B-lymphocytes of a patient with EDMD. In summary, we demonstrated that β-DG plays a role as an emerin interacting partner modulating its stability and function

XVI International Congress of Control Electronics and Telecommunications: "Techno-scientific considerations for a post-pandemic world intensive in knowledge, innovation and sustainable local development"

Este título, sugestivo por los impactos durante la situación de la Covid 19 en el mundo, y que en Colombia lastimosamente han sido muy críticos, permiten asumir la obligada superación de tensiones sociales, políticas, y económicas; pero sobre todo científicas y tecnológicas. Inicialmente, esto supone la existencia de una capacidad de la sociedad colombiana por recuperar su estado inicial después de que haya cesado la perturbación a la que fue sometida por la catastrófica pandemia, y superar ese anterior estado de cosas ya que se encontraban -y aún se encuentran- muchos problemas locales mal resueltos, medianamente resueltos, y muchos sin resolver: es decir, habrá que rediseñar y fortalecer una probada resiliencia social existente - producto del prolongado conflicto social colombiano superado parcialmente por un proceso de paz exitoso - desde la tecnociencia local; como lo indicaba Markus Brunnermeier - economista alemán y catedrático de economía de la Universidad de Princeton- en su libro The Resilient Society…La cuestión no es preveerlo todo sino poder reaccionar…aprender a recuperarse rápido.This title, suggestive of the impacts during the Covid 19 situation in the world, and which have unfortunately been very critical in Colombia, allows us to assume the obligatory overcoming of social, political, and economic tensions; but above all scientific and technological. Initially, this supposes the existence of a capacity of Colombian society to recover its initial state after the disturbance to which it was subjected by the catastrophic pandemic has ceased, and to overcome that previous state of affairs since it was found -and still is find - many local problems poorly resolved, moderately resolved, and many unresolved: that is, an existing social resilience test will have to be redesigned and strengthened - product of the prolonged Colombian social conflict partially overcome by a successful peace process - from local technoscience; As Markus Brunnermeier - German economist and professor of economics at Princeton University - indicates in his book The Resilient Society...The question is not to foresee everything but to be able to react...learn to recover quickly.Bogot

Consenso para el diagnóstico, tratamiento y seguimiento del paciente con distrofia muscular de Duchenne.

Duchenne muscular dystrophy (DMD) is the most common myopathy in children, with a worldwide prevalence of approximately 0.5 cases per 10,000 male births. It is characterised by a progressive muscular weakness manifesting in early childhood, with the subsequent appearance of musculoskeletal, respiratory, and cardiac complications, causing disability, dependence, and premature death. Currently, DMD is mainly managed with multidisciplinary symptomatic treatment, with favourable results in terms of the progression of the disease. It is therefore crucial to establish clear, up-to-date guidelines enabling early detection, appropriate treatment, and monitoring of possible complications. We performed a literature search of the main biomedical databases for articles published in the last 10years in order to obtain an overview of the issues addressed by current guidelines and to identify relevant issues for which no consensus has yet been established. The degree of evidence and level of recommendation of the information obtained were classified and ordered according to the criteria of the American Academy of Neurology. DMD management should be multidisciplinary and adapted to the patient's profile and the stage of clinical progression. In addition to corticotherapy, treatment targeting gastrointestinal, respiratory, cardiac, and orthopaedic problems, as well as physiotherapy, should be provided with a view to improving patients' quality of life. Genetic studies play a key role in the management of the disease, both in detecting cases and potential carriers and in characterising the mutation involved and developing new therapies

Evaluation of an exercise-enabling control interface for powered wheelchair users: a feasibility study with Duchenne muscular dystrophy

Background: Powered wheelchairs are an essential technology to support mobility, yet their use is associated with a high level of sedentarism that can have negative health effects for their users. People with Duchenne muscular dystrophy (DMD) start using a powered wheelchair in their early teens due to the loss of strength in their legs and arms. There is evidence that low-intensity exercise can help preserve the functional abilities of people with DMD, but options for exercise when sitting in a powered wheelchair are limited. Methods: In this paper, we present the design and the feasibility study of a new version of the MOVit device that allows powered-wheelchair users to exercise while driving the chair. Instead of using a joystick to drive the wheelchair, users move their arms through a cyclical motion using two powered, mobile arm supports that provide controller inputs to the chair. The feasibility study was carried out with a group of five individuals with DMD and five unimpaired individuals. Participants performed a series of driving tasks in a wheelchair simulator and on a real driving course with a standard joystick and with the MOVit 2.0 device. Results: We found that driving speed and accuracy were significantly lowered for both groups when driving with MOVit compared to the joystick, but the decreases were small (speed was 0.26 m/s less and maximum path error was 0.1 m greater). Driving with MOVit produced a significant increase in heart rate (7.5 bpm) compared to the joystick condition. Individuals with DMD reported a high level of satisfaction with their performance and comfort in using MOVit. Conclusions: These results show for the first time that individuals with DMD can easily transition to driving a powered wheelchair using cyclical arm motions, achieving a reasonable driving performance with a short period of training. Driving in this way elicits cardiopulmonary exercise at an intensity found previously to produce health-related benefits in DMD.This research has been partially supported by Grant 17.008 funded by Duchenne Parent Project Netherlands, and by the Juan de la Cierva Formación postdoctoral fellowship FJCI-2017-31754, which is funded by the Spanish Ministry of Science and Innovation (MCI)-Agencia Estatal de Investigación (AEI) along with the European Regional Development Fund (ERDF)

Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus).

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA

Consenso Delphi de las recomendaciones para el tratamiento de los pacientes con atrofia muscular espinal en España (consenso RET-AME)

Introducción La atrofia muscular espinal (AME) es una enfermedad neurodegenerativa, causada por una mutación bialélica del gen 5q SMN1, que afecta predominantemente a las neuronas motoras del asta anterior medular causando una progresiva debilidad y atrofia muscular. La aparición de tratamientos modificadores del curso de la enfermedad está cambiando considerablemente la historia natural de la AME, pero existe todavía incertidumbre sobre qué pacientes se pueden beneficiar de estos tratamientos y cómo se debería medir ese beneficio. Metodología Un grupo de expertos especialistas en neurología, neuropediatría y rehabilitación, y de la asociación de pacientes con AME de España, analizaron, siguiendo la metodología Delphi, 5 apartados relacionados con el uso de los nuevos tratamientos: aspectos generales; objetivos del tratamiento; herramientas de medición de resultados; requisitos de los centros tratantes; y regulación de su uso. Se definió como consenso cuando una respuesta recibió al menos el 80% de los votos. Resultados Los protocolos de tratamiento son útiles para regular el uso de medicamentos de alto impacto y deben constituir una guía para aquel, pero se deben actualizar regularmente para recoger la evidencia más reciente disponible y su implementación se debe valorar de forma individualizada. La edad, la funcionalidad basal y, en el caso de los niños, el tipo de AME y el número de copias de SMN2 son características que se deben tener en cuenta a la hora de establecer los objetivos terapéuticos, las herramientas de medición y el uso de dichos tratamientos. El aspecto más determinante del coste-efectividad de estos tratamientos en la edad pediátrica es su inicio precoz, por lo que se recomienda la instauración de un cribado neonatal. Conclusiones Las recomendaciones del consenso RET-AME proporcionan un marco de referencia para el uso adecuado de tratamientos modificadores de la enfermedad en pacientes con AME

The molecular basis and biologic significance of the β-dystroglycan-emerin interaction

β-dystroglycan (β-DG) assembles with lamins A/C and B1 and emerin at the nuclear envelope (NE) to maintain proper nuclear architecture and function. To provide insight into the nuclear function of β-DG, we characterized the interaction between β-DG and emerin at the molecular level. Emerin is a major NE protein that regulates multiple nuclear processes and whose deficiency results in Emery–Dreifuss muscular dystrophy (EDMD). Using truncated variants of β-DG and emerin, via a series of in vitro and in vivo binding experiments and a tailored computational analysis, we determined that the β-DG–emerin interaction is mediated at least in part by their respective transmembrane domains (TM). Using surface plasmon resonance assays we showed that emerin binds to β-DG with high affinity (KD in the nanomolar range). Remarkably, the analysis of cells in which DG was knocked out demonstrated that loss of β-DG resulted in a decreased emerin stability and impairment of emerin-mediated processes. β-DG and emerin are reciprocally required for their optimal targeting within the NE, as shown by immunofluorescence, western blotting and immunoprecipitation assays using emerin variants with mutations in the TM domain and B-lymphocytes of a patient with EDMD. In summary, we demonstrated that β-DG plays a role as an emerin interacting partner modulating its stability and function

Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and –0·19 (–1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group). Interpretation: Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2–25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam. Funding: F Hoffmann-La Roche