An Analysis of Music Therapy on Improving Social and Communication Skills in Children with Autism Spectrum Disorder

Autism, a diagnosis that has skyrocketed and is worrisome to parents, teachers, clinicians and researchers. Over the past four decades, the rate of children suffering from Autism Spectrum Disorder has grown 10 times and is the fastest growing disability in the US.1,2 Currently, 1 in 68 births are affected by Autism.1 Due to the high prevalence of this disability, researchers are searching for ways to treat the symptoms of this incurable disorder. Music therapy is gaining popularity as an intervention strategy for children with Autism Spectrum Disorder (ASD).3 This paper will analyze the benefits music therapy has on the improvement of social skills and communication in children with ASD

Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.

SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins

Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins

None of the 28 identified point mutations in tafazzin (Taz1p), which is the mutant gene product associated with Barth syndrome (BTHS), has a biochemical explanation. In this study, endogenous Taz1p was localized to mitochondria in association with both the inner and outer mitochondrial membranes facing the intermembrane space (IMS). Unexpectedly, Taz1p does not contain transmembrane (TM) segments. Instead, Taz1p membrane association involves a segment that integrates into, but not through, the membrane bilayer. Residues 215–232, which were predicted to be a TM domain, were identified as the interfacial membrane anchor by modeling four distinct BTHS mutations that occur at conserved residues within this segment. Each Taz1p mutant exhibits altered membrane association and is nonfunctional. However, the basis for Taz1p dysfunction falls into the following two categories: (1) mistargeting to the mitochondrial matrix or (2) correct localization associated with aberrant complex assembly. Thus, BTHS can be caused by mutations that alter Taz1p sorting and assembly within the mitochondrion, indicating that the lipid target of Taz1p is resident to IMS-facing leaflets

On a Feasible–Infeasible Two-Population (FI-2Pop) Genetic Algorithm for Constrained Optimization: Distance Tracing and no Free Lunch

We explore data-driven methods for gaining insight into the dynamics of a two-population genetic algorithm (GA), which has been effective in tests on constrained optimization problems. We track and compare one population of feasible solutions and another population of infeasible solutions. Feasible solutions are selected and bred to improve their objective function values. Infeasible solutions are selected and bred to reduce their constraint violations. Interbreeding between populations is completely indirect, that is, only through their offspring that happen to migrate to the other population. We introduce an empirical measure of distance, and apply it between individuals and between population centroids to monitor the progress of evolution. We find that the centroids of the two populations approach each other and stabilize. This is a valuable characterization of convergence. We find the infeasible population influences, and sometimes dominates, the genetic material of the optimum solution. Since the infeasible population is not evaluated by the objective function, it is free to explore boundary regions, where the optimum is likely to be found. Roughly speaking, the No Free Lunch theorems for optimization show that all blackbox algorithms (such as Genetic Algorithms) have the same average performance over the set of all problems. As such, our algorithm would, on average, be no better than random search or any other blackbox search method. However, we provide two general theorems that give conditions that render null the No Free Lunch results for the constrained optimization problem class we study. The approach taken here thereby escapes the No Free Lunch implications, per se

Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane

Defined mutations in the mitochondrial ADP/ATP carrier (AAC) are associated with certain types of progressive external ophthalmoplegia. AAC is required for oxidative phosphorylation (OXPHOS), and dysregulation of AAC has been implicated in apoptosis. Little is known about the AAC interactome, aside from a known requirement for the phospholipid cardiolipin (CL) and that it is thought to function as a homodimer. Using a newly developed dual affinity tag, we demonstrate that yeast AAC2 physically participates in several protein complexes of distinct size and composition. The respiratory supercomplex and several smaller AAC2-containing complexes, including other members of the mitochondrial carrier family, are identified here. In the absence of CL, most of the defined interactions are destabilized or undetectable. The absence of CL and/or AAC2 results in distinct yet additive alterations in respiratory supercomplex structure and respiratory function. Thus, a single lipid can significantly alter the functional interactome of an individual protein

Energy Expenditure following Acute Cold Exposure

TACSM Abstract - Energy Expenditure following Acute Cold Exposure Stelly S, Bravo D, Hines N, Koehler L, Levi M and Fogt D Exercise Biochemistry & Metabolism Laboratory; Department of Kinesiology, Health & Nutrition; The University of Texas at San Antonio; San Antonio, TX Category: Masters Advisor / Mentor: Fogt, Donovan ([email protected]) ABSTRACT Whole body energy expenditure (i.e., RMR) increases during acute cold exposure. Whether this increase in energy expenditure persists in the post-cold term in humans due to non-shivering thermogenesis has not yet been evaluated. Therefore we tested the hypothesis that RMR would be different directly following acute cold exposure. RMR (kcal•min-1) was assessed via indirect calorimetry on eight (8) males and seven (7) females at six time points: prior to cold exposure (T1), at the end of 30 minutes of cold exposure (T2), immediately post-cold-post-shivering (T3), at 35 minutes post-cold (T4), at 75 minutes post-cold (T5), and at 115 minutes post-cold (T6). This RMR data for the aforementioned time points was analyzed using paired, dependent t-tests and one way ANOVA; the significance level was placed at p \u3c 0.05. The RMR data for each time point was as follows: T1 (1.19±0.21), T2 (2.30±0.94), T3 (1.37±0.25), T4 (1.12±0.19), T5 (1.14±0.22), and T6 (1.14±0.22). The analysis of the RMR data showed a significant difference between the cold (T2) data and all other time points (T1, T3, T4, T5, and T6). Additionally there was a significant difference between the pre-cold (T1) and the immediately post-cold (T3) data. However there was no significant difference between the pre-cold (T1) data when compared with the remaining post-cold data (T4 – T6). These results suggest that the human body is capable of returning RMR to baseline levels relatively immediately following the cessation of acute cold exposure

Tim54p connects inner membrane assembly and proteolytic pathways in the mitochondrion

Tim54p, a component of the inner membrane TIM22 complex, does not directly mediate the import of inner membrane substrates but is required for assembly/stability of the 300-kD TIM22 complex. In addition, Δtim54 yeast exhibit a petite-negative phenotype (also observed in yeast harboring mutations in the F1Fo ATPase, the ADP/ATP carrier, mitochondrial morphology components, or the i–AAA protease, Yme1p). Interestingly, other import mutants in our strain background are not petite-negative. We report that Tim54p is not involved in maintenance of mitochondrial DNA or mitochondrial morphology. Rather, Tim54p mediates assembly of an active Yme1p complex, after Yme1p is imported via the TIM23 pathway. Defective Yme1p assembly is likely the major contributing factor for the petite-negativity in strains lacking functional Tim54p. Thus, Tim54p has two independent functions: scaffolding/stability for the TIM22 membrane complex and assembly of Yme1p into a proteolytically active complex. As such, Tim54p links protein import, assembly, and turnover pathways in the mitochondrion

Repair of giant paraesophageal hernias routinely produces improvement in respiratory function

ObjectiveAssessment of the clinical impact of giant paraesophageal hernias have historically focused on upper gastrointestinal symptoms. This study assesses the effect of paraesophageal hernia repair on respiratory function.MethodsAll patients undergoing repair of giant paraesophageal hernia were prospectively entered into a database approved by the institutional review board. Patients had symptoms documented preoperatively, including dyspnea. Pulmonary function tests (PFTs) were done preoperatively and repeated a median of 106 days after repair (range, 16-660 days).ResultsPreoperative and postoperative PFTs were obtained in 120 unselected patients treated for paraesophageal hernia between 2000 and 2010. Patients’ median age was 74 years (range, 45-91 years), 74 (62%) were female, and median body mass index was 28.0 (range, 16.8-46.6). Median length of stay was 4 days (range, 3-10 days), and perioperative mortality was zero. Hernias were classified as type II in 3 (3%) patients, III in 92 (77%), and IV in 25 (21%). Percent of intrathoracic stomach was assigned from preoperative contrast studies and grouped as less than 50% (n = 6; 5%), 50% to 74% (n = 35; 29%), 75% to 99% (n = 29; 24%), and 100% (n = 50; 42%). Preoperative symptoms included heartburn 71 (59%), early satiety 65 (54%), dyspnea 63 (52%), chest pain 48 (40%), dysphagia 56 (47%), regurgitation 47 (39%), and anemia 44 (37%). PFTs significantly improved after paraesophageal hernia repair (mean volume change, percent reference change): forced vital capacity +0.30 L,+10.3%pred; FEV1 +0.23 L,+10.4%pred (all P < .001); diffusion capacity of the lung for carbon monoxide +0.58 mL · mm Hg−1 · min−1 (P = .004), and +2.9%pred (P = .002). Greater improvements were documented in older patients with significant subjective respiratory symptoms and higher percent of intrathoracic stomach (P < .01).ConclusionsParaesophageal hernia has a significant effect on respiratory function, which is largely underappreciated. This study demonstrates that these repairs can be done safely and supports routine consideration for elective repair; older patients with borderline respiratory function may achieve substantial improvements in their respiratory status and quality of life

Defining functional classes of Barth syndrome mutation in humans

The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ