Therapies for Mitochondrial Disorders

Mitochondria are cytoplasmic, double-membrane organelles that synthesise adenosine triphosphate (ATP). Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is maternally inherited from the oocyte. Mitochondrial proteins are encoded by either nuclear DNA (nDNA) or mtDNA, and both code for proteins forming the mitochondrial oxidative phosphorylation (OXPHOS) complexes of the respiratory chain. These complexes form a chain that allows the passage of electrons down the electron transport chain (ETC) through a proton motive force, creating ATP from adenosine diphosphate (ADP). This study aims to explore current and prospective therapies for mitochondrial disorders (MTDS). MTDS are clinical syndromes coupled with abnormalities of the ETC and OXPHOS, caused by pathogenic variants in mtDNA or nDNA. Many MTDS emerge from either homoplasmic or heteroplasmic mutations of the DNA, and include mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Current therapies include increasing mitochondrial biogenesis, the use of antioxidants, dietary approaches, and exercise. However, these are mostly symptomatic and supportive therapies. Future therapies comprise of personalised and precision medicine approaches which include gene, mitochondrial, cell, and in utero-based therapies. Obstacles towards discovering effective therapies include the rarity of MTDS, its pathogenic complexity and lack of clinical trials. Despite the lack of current curative therapies for MTDS, emerging therapies promise exciting and clinically meaningful therapies in the future

Exile Vol. XXXVII No. 1

And It Was Sunday by Julie Gruen 1-6 Like a Lady by Grace Mulvihill 7 The Final You by Eric Franzon 8 Joseph\u27s Children by Seneca Murley 9 Ain\u27t the 1950s Anymore by Ellen Stader 10-12 Bonding Women by Shannon salser 13 Ice Man (for mami 1905-1975) by Anne Mulligan 14 The Car Salesman by Tom Ream 15 Cancelling the Bunny by Stewart Engesser 16-17 Richard Brautigan\u27s Body by Michael Payne 18-19 Dinner in Barcelona by Holly Kurtz 20 Untitled by Margaret Strachen 21 Candles by Eric Franzon 22 Summer Rules by Jim Cox 23-31 My Boat by Holly Kurtz 32 Untitled by Michael Payne 33 Half the Birds in the City by Tiffany Richardson 34-35 Down Queen Anne Hill by Julie Gruen 36-37 Your Music by Tim Emrick 38 Zephyrs by Steve Corinth 39-41 Mother by Anne Mulligan 42 As I Look to the Sky, Maize by Shannon Salser 43-45 Close Book before Striking by Sarah Verdon 46-47 Smoked by Tom Ream 48 Driving through Rain by Stewart Engesser 49-50 Contributors 51 Editorial decision is shared equally among the Editorial Board. -i 35th Yea

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Computational investigation into the mechanoregulation of osteoporosis

THESIS 8808Trabecular bone remodelling involves the continual resorption and formation of bone along the surface of a strut. Experimental studies have shown that mechanical stimuli, such as strain and damage, initiate and regulate this biological process. The aim of this thesis is to develop a mechanoregulation algorithm, based on both strain and damage stimuli, and to investigate whether such an algorithm is capable of simulating the bone remodelling cycle along a trabecular strut. Following on from this, the changes occurring to the process that lead to rapid and irreversible loss of bone, as observed in skeletal diseases such as osteoporosis, were investigated

Hepatitis C Direct Acting Antivirals and Ribavirin Modify Lipid but not Glucose Parameters

Chronic hepatitis C (HCV) infection perturbs lipid and glucose metabolism. The influenceof direct acting antiviral (DAA) treatment and ribavirin on these measures was evaluated.Furthermore, the effect of HCV cure on these parameters was assessed. Participants were allocatedto one of three 12-week treatment groups: non-cirrhotic genotype 1aparitaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) plus ribavirin; non-cirrhotic 1b-PrOD;compensated cirrhotic 1a or 1b-PrOD plus ribavirin. Fasting insulin, glucose, lipid andapolipoprotein measures were assessed at baseline, Treatment Weeks 4 and 12, and 12 and 24 weekspost-dosing. Twenty-three of 24 participants achieved SVR (PP= 23/24, 96% SVR). Overall, totalcholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels all increased intreatment and post-dosing. However, LDL-C levels decreased during treatment in ribavirinrecipients. Fasting glucose, insulin, and HOMA-IR were unchanged during treatment and 12 weekspost-treatment. By 12 weeks post-treatment, controlled attenuation parameter (CAP) scores, ameasure of steatosis, increased from baseline (mean 30.3 &plusmn; 63.5, p = 0.05). This regimen was safe andhighly effective and did not influence glucose metabolism. Ribavirin exposure may mitigate someon-treatment lipid changes. Further mechanistic studies are needed to understand how ribavirinimpacts lipid pathways, as there could be therapeutic implications. The metabolic pathophysiologyof increased CAP score with HCV treatment requires explanation

The TEAM project: Insights from investigating and enhancing assessment in science and health practical sessions with digital technologies.

In Higher Education, science and health degree programmes involve significant practical elements.  In many cases, students spend as much time in practical or clinical skill sessions each week as they do in classroom based lectures.  These hands-on sessions engage students, develop both soft and technical skills, while allowing theory to be put into practice.  However, in many cases, the design, assessment and feedback aspects of practical sessions has not received the attention warranted, with traditional approaches often persisting. This paper discusses a nationally funded, multi-institution enhancement project focused on implementing and evaluating digital technologies to enhance assessment in science and health practical sessions.  Via an initial baseline analysis, four thematic areas were identified for pilot development: [1] Pre-practical videos combined with online/app quizzes, [2] Electronic lab notebooks, [3] Digital Feedback and [4] Rubrics.  In collaboration with student partner groups, employers and academic staff, the TEAM (Technology Enhanced Assessment Methods) project designed and implemented 42 pilots in practical sessions across the four partner colleges, engaging almost 1,600 students.  In this paper, the key lessons identified during the baseline analysis which informed the project, as well as those from the subsequent survey and focus group evaluation of participants’ pilot experiences, will be presented.  Overall, the implementation of TEAM has represented a major success across the partner colleges, providing a strong foundation for continuous, iterative improvements in this field.

Guidelines on Models of Diabetic Heart Disease

Diabetes is a major risk factor for cardiovascular diseases, including diabetic cardiomyopathy, atherosclerosis, myocardial infarction, and heart failure. As cardiovascular disease represents the number one cause of death in people with diabetes, there has been a major emphasis on understanding the mechanisms by which diabetes promotes cardiovascular disease, and how antidiabetic therapies impact diabetic heart disease. With a wide array of models to study diabetes (both type 1 and type 2), the field has made major progress in answering these questions. However, each model has its own inherent limitations. Therefore, the purpose of this guidelines document is to provide the field with information on which aspects of cardiovascular disease in the human diabetic population are most accurately reproduced by the available models. This review aims to emphasize the advantages and disadvantages of each model, and to highlight the practical challenges and technical considerations involved. We will review the preclinical animal models of diabetes (based on their method of induction), appraise models of diabetes-related atherosclerosis and heart failure, and discuss in vitro models of diabetic heart disease. These guidelines will allow researchers to select the appropriate model of diabetic heart disease, depending on the specific research question being addressed

miR-223 exerts translational control of proatherogenic genes in macrophages

Background: A significant burden of atherosclerotic disease is driven by inflammation. Recently, microRNAs (miRNAs) have emerged as important factors driving and protecting from atherosclerosis. miR-223 regulates cholesterol metabolism and inflammation via targeting both cholesterol biosynthesis pathway and NFkB signaling pathways; however, its role in atherosclerosis has not been investigated. We hypothesize that miR-223 globally regulates core inflammatory pathways in macrophages in response to inflammatory and atherogenic stimuli thus limiting the progression of atherosclerosis. Methods and Results: Loss of miR-223 in macrophages decreases Abca1 gene and protein expression as well as cholesterol efflux to apoA1 (Apolipoprotein A1) and enhances proinflammatory gene expression. In contrast, overexpression of miR-223 promotes the efflux of cholesterol and macrophage polarization toward an anti-inflammatory phenotype. These beneficial effects of miR-223 are dependent on its target gene, the transcription factor Sp3. Consistent with the antiatherogenic effects of miR-223 in vitro, mice receiving miR223(-/-) bone marrow exhibit increased plaque size, lipid content, and circulating inflammatory cytokines (ie, IL-1 beta). Deficiency of miR-223 in bone marrow-derived cells also results in an increase in circulating pro-atherogenic cells (total monocytes and neutrophils) compared with control mice. Furthermore, the expression of miR-223 target gene (Sp3) and pro-inflammatory marker (Il-6) are enhanced whereas the expression of Abca1 and anti-inflammatory marker (Retnla) are reduced in aortic arches from mice lacking miR-223 in bone marrow-derived cells. In mice fed a high-cholesterol diet and in humans with unstable carotid atherosclerosis, the expression of miR-223 is increased. To further understand the molecular mechanisms underlying the effect of miR-223 on atherosclerosis in vivo, we characterized global RNA translation profile of macrophages isolated from mice receiving wild-type or miR223(-/-) bone marrow. Using ribosome profiling, we reveal a notable upregulation of inflammatory signaling and lipid metabolism at the translation level but less significant at the transcription level. Analysis of upregulated genes at the translation level reveal an enrichment of miR-223-binding sites, confirming that miR-223 exerts significant changes in target genes in atherogenic macrophages via altering their translation. Conclusions: Our study demonstrates that miR-223 can protect against atherosclerosis by acting as a global regulator of RNA translation of cholesterol efflux and inflammation pathways.No sponso