Health-Related Quality of Life in Children with DuchenneMuscular Dystrophy: A Review

In pediatric chronic illness, improving health-related quality of life (HRQOL) has become one of the most important goals of disease management. Duchenne muscular dystrophy (DMD) is a debilitating, progressive and chronic neuromuscular disorder affecting boys. The purpose of this review is to provide an overview of published research on HRQOL in the pediatric DMD population, describe the instruments used and summarize the study findings. The databases searched were Medline, Embase and PsycInfo. The literature search yielded 167 articles, of which 19 were included in this review. The studies were published between 2005 and 2013 across nine countries. Thirteen different generic and disease-specific measures were used, the most common being the Pediatric Quality of Life 4.0 Generic Core module. HRQOL in boys with DMD is worse than that of healthy peers and children with other chronic illnesses, especially in the physical domains. Boys who are at a more severe stage of the disease reported worse physical HRQOL but not necessarily psychosocial HRQOL than boys at a less severe stage. Traditional clinical outcome measures correlated well only with physical HRQOL. Parents\u27 proxy-reports of their sons\u27 HRQOL and the boys\u27 self-reports had poor concordance. More research is needed to assess trends in HRQOL over time and to elucidate factors that affect HRQOL

Steric regulation of tandem calponin homology domain actin-binding affinity.

Tandem calponin homology (CH1-CH2) domains are common actin-binding domains in proteins that interact with and organize the actin cytoskeleton. Despite regions of high sequence similarity, CH1-CH2 domains can have remarkably different actin-binding properties, with disease-associated point mutants known to increase as well as decrease affinity for F-actin. To investigate features that affect CH1-CH2 affinity for F-actin in cells and in vitro, we perturbed the utrophin actin-binding domain by making point mutations at the CH1-CH2 interface, replacing the linker domain, and adding a polyethylene glycol (PEG) polymer to CH2. Consistent with a previous model describing CH2 as a steric negative regulator of actin binding, we find that utrophin CH1-CH2 affinity is both increased and decreased by modifications that change the effective "openness" of CH1 and CH2 in solution. We also identified interface mutations that caused a large increase in affinity without changing solution "openness," suggesting additional influences on affinity. Interestingly, we also observe nonuniform subcellular localization of utrophin CH1-CH2 that depends on the N-terminal flanking region but not on bulk affinity. These observations provide new insights into how small sequence changes, such as those found in diseases, can affect CH1-CH2 binding properties

Conditional Generation of Paired Antibody Chain Sequences through Encoder-Decoder Language Model

Protein language models (LMs) have been successful in sequence, structural and functional predictions. However, currently, protein LMs are limited to encoder- or decoder-only architectures for single sequences while many biological contexts involve protein-protein interactions. Here, we introduce pAbT5, which models antibody chain pairing as forward- and back-translations using a T5-based architecture. We show that pAbT5 accurately reflects chain pairing through sequence generation. Our protein LM generates variable-length sequences and its next-word prediction probability agrees with position-specific scoring matrix from sequence alignment. Like other works in protein LM, pAbT5 performs state-of-the-art unsupervised prediction on experimental measurements. To the best of our knowledge, pAbT5 is the first generative encoder-decoder protein LM for protein-protein interactions

CCN6 Knockdown Disrupts Acinar Organization of Breast Cells in Three-dimensional Cultures through Up-regulation of Type III TGF-β Receptor

AbstractWhile normal cells in the human breast are organized into acinar structures, disruption of the acinar architecture is a hallmark of cancer. In a three-dimensional model of morphogenesis, we show that down-regulation of the matrix-associated tumor suppressor protein CCN6 (WNT1-inducible-signaling pathway protein 3) disrupts breast epithelial cell polarity and organization into acini through up-regulation of the type III transforming growth factor-β receptor (TβRIII or betaglycan). Down-regulation of CCN6 in benign breast cells led to loss of tissue polarity and resulted in cellular disorganization with loss of α6 integrin-rich basement membrane and the basolateral polarity protein E-cadherin. Silencing of TβRIII with shRNA and siRNA rescued the ability of breast epithelial cells to form polarized acinar structures with reduced matrix invasion and restored the correct expression of α6 integrin and E-cadherin. Conversely, CCN6 overexpression in aggressive breast cancer cells reduced TβRIII in vitro and in a xenograft model of CCN6 overexpression. The relevance of our studies to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely associated with TβRIII protein in 64%of invasive breast carcinomas. These results reveal a novel function of the matricellular protein CCN6 and establish a mechanistic link between CCN6 and TβRIII in maintaining acinar organization in the breast

WHICH ASPECTS OF THE ENGLISH LANGUAGE DO DISTANCE LEARNERS FIND DIFFICULT?

This study reports the findings of a research carried out on distance learners at the School of Distance Education (SDE), University Sains Malaysia (USM). The study was explorative in nature with the purpose identifying the aspects of the English language which distance learners found difficult to learn. A quantitative survey questionnaire design was adopted. The sample consisted of 512 students out of 1028 students who enrolled in the JUE300 English II course responded. The data were analyzed using SPSS IBM version 19.0. The distance learners reported facing difficulties in the aspects of speaking, vocabulary, grammar, writing, spelling, pronunciation, reading and listening in descending order. In the case of the SDE distance learners, their level of proficiency prior to this course, their commitment and hours spent on studying the English language may have affected their perceptions and achievement in the course

Fatigue in young people with Duchenne muscular dystrophy

AIM: To describe fatigue in Duchenne muscular dystrophy (DMD) from patients\u27 and parents\u27 perspectives and to explore risk factors for fatigue in children and adolescents with DMD. METHOD: A multicentre, cross-sectional study design was used. Seventy-one patients (all males; median age 12y, age range 5-17y) identified via the Canadian Neuromuscular Disease Registry, and their parents completed questionnaires. Subjective fatigue was assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale by child self-report and parent proxy-report. RESULTS: Patients with DMD across ages and disease stages experienced greater fatigue compared to typically developing controls from published data. Sleep disturbance symptoms were associated with greater fatigue by child self-report (ρ=-0.42; p=0.003) and parent proxy-report (ρ=-0.51; p INTERPRETATION: In paediatric DMD, sleep disturbance symptoms and depressive symptoms are potentially modifiable factors associated with fatigue, warranting additional investigation to facilitate the development of therapeutic strategies to reduce fatigue. WHAT THIS PAPER ADDS: Fatigue is a major issue in paediatric Duchenne muscular dystrophy (DMD) across ages and disease stages. Sleep disturbance and depressive symptoms are significantly associated with fatigue in paediatric DMD

Evidence of Non-Thermal Particles in Coronal Loops Heated Impulsively by Nanoflares

The physical processes causing energy exchange between the Sun's hot corona and its cool lower atmosphere remain poorly understood. The chromosphere and transition region (TR) form an interface region between the surface and the corona that is highly sensitive to the coronal heating mechanism. High resolution observations with the Interface Region Imaging Spectrograph (IRIS) reveal rapid variability (about 20 to 60 seconds) of intensity and velocity on small spatial scales at the footpoints of hot dynamic coronal loops. The observations are consistent with numerical simulations of heating by beams of non-thermal electrons, which are generated in small impulsive heating events called "coronal nanoflares". The accelerated electrons deposit a sizable fraction of their energy in the chromosphere and TR. Our analysis provides tight constraints on the properties of such electron beams and new diagnostics for their presence in the nonflaring corona.Comment: Published in Science on October 17: http://www.sciencemag.org/content/346/6207/1255724 . 26 pages, 10 figures. Movies are available at: http://www.lmsal.com/~ptesta/iris_science_mov

Independent Planning System and Public Administration in Metropolitan Development: Agglomeration Strategies of Greater Chaoshan in Southern China

This paper examines independent planning system as a means of public administration in regional economic development. It proposes a new strategy based on the theories of public administrative resources, to agglomerate and unify the cities of Shantou, Jieyang, and Chaozhou into a new administrative entity as a metropolis with the status of independent planning and the preferred policies of a Special Economic Region to lead regional development. The optimal allocation of public administrative resources has played a key role in the fundamental economic development in China in recent years. The new administrative system of large cities (metropolises) with independent planning has become an innovative format to utilize the renewable soft resources of administration, which in fact is a new attempt to reform the economic system by the Chinese government. The greater Chaoshan area needs to be agglomerated and unified to further develop the regional economy with the implementation of independent planning system. The current research conducted from a practical and political point of view is of significant value to the overall planning and strategic layout of the economic and social development of the whole eastern Guangdong region