Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion

Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases—OPA1 and the mitofusins Mfn1 and Mfn2—are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast

Accelerating Chemical Discovery with Machine Learning: Simulated Evolution of Spin Crossover Complexes with an Artificial Neural Network

Machine learning (ML) has emerged as a powerful complement to simulation for materials discovery by reducing time for evaluation of energies and properties at accuracy competitive with first-principles methods. We use genetic algorithm (GA) optimization to discover unconventional spin-crossover complexes in combination with efficient scoring from an artificial neural network (ANN) that predicts spin-state splitting of inorganic complexes. We explore a compound space of over 5600 candidate materials derived from eight metal/oxidation state combinations and a 32-ligand pool. We introduce a strategy for error-aware ML-driven discovery by limiting how far the GA travels away from the nearest ANN training points while maximizing property (i.e., spin-splitting) fitness, leading to discovery of 80% of the leads from full chemical space enumeration. Over a 51-complex subset, average unsigned errors (4.5 kcal/mol) are close to the ANN's baseline 3 kcal/mol error. By obtaining leads from the trained ANN within seconds rather than days from a DFT-driven GA, this strategy demonstrates the power of ML for accelerating inorganic material discovery.United States. Office of Naval Research (Grant N00014-17-1-2956)United States. Department of Energy (Grant DE-SC0018096)National Science Foundation (U.S.) (Grant CBET-1704266

Supply-Chain Synchronization: Lessons from Hyundai Motor Company

One of the challenges of supply-chain management is developing ways to effectively integrate activities across organizations on the supply chain. Hyundai Motor Company developed mechanisms to coordinate production planning and scheduling activities among supply-chain members. Hyundai Motor\u27s production-and-sales-control (P/SC) department uses regularly scheduled cross-functional meetings and scheduling policies to coordinate supply-chain activities. When implementing this process, the P/SC department overcame structural, environ mental, and behavioral problems. Although Hyundai manage ment concedes that the process is not perfect, communication among supply-chain members has improved, and the P/SC group has successfully promoted mutual understanding and respect among functional areas. The primary benefit, ultimately, is improved customer satisfaction through better integration of functional activities

Introduction: Domestic Violence and Access to Justice within the Family Law and Intersecting Legal Systems

The articles in this collection explore the access to justice issues that arise for survivors of domestic violence in their encounters with Canada’s family law system. While family law and family dispute resolution processes are the central focus of the articles, three contributions also address family law\u27s intersections with other legal domains (civil restraining orders, child welfare, and immigration). Common across the contributions is a desire to carefully interrogate the potential of law and legal processes to enhance—or conversely to undermine—the safety and well-being of survivors and their children

Introduction: Domestic Violence and Access to Justice within the Family Law and Intersecting Legal Systems

The articles in this collection explore the access to justice issues that arise for survivors of domestic violence in their encounters with Canada’s family law system. While family law and family dispute resolution processes are the central focus of the articles, three contributions also address family law\u27s intersections with other legal domains (civil restraining orders, child welfare, and immigration). Common across the contributions is a desire to carefully interrogate the potential of law and legal processes to enhance—or conversely to undermine—the safety and well-being of survivors and their children

Volumetric facial contour changes of immediately placed implants with and without immediate provisionalization

BackgroundWhether immediate provisionalization can preserve facial tissue contour remains undetermined. The goal of this 12- month randomized controlled clinical trial was to compare three- dimensional (3D) ridge changes after immediate implant placement with and without immediate provisionalization.MethodsForty participants with an unrestorable maxillary anterior or premolar tooth were randomized to receive either a provisional crown (test) or standard healing abutment (control) after immediate implant placement. In each participant, three digital models taken before implant surgery, final crown delivery (4 months), and final follow- up (12 months) were registered to analyze linear deviation in 3D and volume changes of ridge contour at the implant site.ResultsThe mean value of mid- facial linear 3D spatial resorption ranged from 0.1 to 0.7 mm. Significant difference of linear changes of facial contour was noted over time and not between the groups. Facial volume changes at 12 months remained significantly higher in the control group than in the test group (17.4% versus 11.9%, P = 0.04).ConclusionsLinear changes of facial soft- tissue resorption at immediately placed implants were independent of immediate provisionalization. However, immediate provisionalization showed better volume preservation at the esthetic concern area (mid- facial margin and 2 to 6 mm above) at the final 12- month follow- up.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156220/2/jper10486_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156220/1/jper10486.pd

Academic Resilience: A Retrospective Study of Adults With Learning Difficulties

This article reports qualitative analyses of two sets of retrospective interviews with adults with learning difficulties. The purpose of the study was to examine the high school experiences of these adults from a holistic perspective to understand possible factors that contributed to one group staying in school and the other group leaving school early. One set of interviews was conducted with adults who had returned to complete high school at an adult learning center (the late successful group). The second set of interviews was conducted with the early successful group, adults who had completed high school during adolescence. Interview questions focused on interests, friends, and general aspects of the high school experience. Analyses yielded three themes: intrapersonal support, interpersonal support, and institutional support. These data suggest that schools might act in a number of ways to counter the high rate of early leaving by adolescents with learning disabilities, including building strong teacher-student relationships, using students' interests to develop curricula and structured activities, and fostering a sense of purpose.Cet article expose deux analyses qualitatives de deux séries d'entrevues rétrospectives auprès d'adultes présentant des difficultés d'apprentissage. Le but de l'étude consistait à examiner, dans une perspective holistique, les expériences qu'avaient vécues ces adultes quand ils étaient au secondaire, pour ensuite déterminer si des facteurs avaient influencé le fait que certaines personnes étaient restées à l'école alors que d'autres avaient décroché. Une série d'entrevues a été effectuée auprès d'adultes qui avaient repris leurs études secondaires dans un institut d'apprentissage pour adultes (le groupe de diplômés tardifs). La deuxième série d'entrevues a eu lieu auprès d'adultes ayant terminé l'école secondaire alors qu'ils étaient adolescents dégroupe de diplômés précoces). Les questions d'entrevues portaient sur les intérêts, les amis et les aspects généraux de leur expérience à l'école secondaire. Trois thèmes sont ressortis des analyses: l'appui intrapersonnel, l'appui interpersonnel et l'appui institutionnel. Ces données donnent à penser que les écoles pourraient intervenir de diverses façons pour contrer le taux élevé de décrochage chez les adolescents ayant des difficultés d'apprentissage. Parmi ces stratégies notons la création de rapports solides entre les enseignants et les élèves, le développement de programmes d'études et d'activités structurées basés sur les intérêts des élèves et le fait de favoriser des buts bien précis

mab-31 and the TGF-β pathway act in the ray lineage to pattern C. elegans male sensory rays

<p>Abstract</p> <p>Background</p> <p><it>C. elegans </it>TGF-β-like Sma/Mab signaling pathway regulates both body size and sensory ray patterning. Most of the components in this pathway were initially identified by genetic screens based on the small body phenotype, and many of these mutants display sensory ray patterning defect. At the cellular level, little is known about how and where these components work although ray structural cell has been implicated as one of the targets. Based on the specific ray patterning abnormality, we aim to identify by RNAi approach additional components that function specifically in the ray lineage to elucidate the regulatory role of TGF-β signaling in ray differentiation.</p> <p>Result</p> <p>We report here the characterization of a new member of the Sma/Mab pathway, <it>mab-31</it>, recovered from a genome-wide RNAi screen. <it>mab-31 </it>mutants showed ray cell cluster patterning defect and mis-specification of the ray identity. <it>mab-31 </it>encodes a nuclear protein expressed in descendants of ray precursor cells impacting on the ray cell's clustering properties, orientation of cell division plane, and fusion of structural cells. Genetic experiments also establish its relationship with other Sma/Mab pathway components and transcription factors acting upstream and downstream of the signaling event.</p> <p>Conclusion</p> <p><it>mab-31 </it>function is indispensable in Sma/Mab signal recipient cells during sensory rays specification. Both <it>mab-31 </it>and <it>sma-6 </it>are required in ray lineage at the late larval stages. They act upstream of <it>C. elegans Pax-6 </it>homolog and repress its function. These findings suggested <it>mab-31 </it>is a key factor that can integrate TFG-β signals in male sensory ray lineage to define organ identity.</p