scholarly journals Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease

2017 ◽  
Vol 474 (23) ◽  
pp. 4019-4034 ◽  
Author(s):  
Juvid Aryaman ◽  
Iain G. Johnston ◽  
Nick S. Jones
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cell Volume ◽  
Large Scale ◽  
Deep Understanding ◽  
Interdisciplinary Approach ◽  
Threshold Effect ◽  
Progressive Increase ◽  
Mtdna Mutation ◽  
Theoretical Understanding ◽  
Demand Reduction

Mitochondrial dysfunction is involved in a wide array of devastating diseases, but the heterogeneity and complexity of the symptoms of these diseases challenges theoretical understanding of their causation. With the explosion of omics data, we have the unprecedented opportunity to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. This goal raises the outstanding need to make these complex datasets interpretable. Quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Taking an interdisciplinary approach, we use a recently published large-scale dataset and develop a descriptive and predictive mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation. The experimentally observed behaviour is surprisingly rich, but we find that our simple, biophysically motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus power demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, up-regulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here to further develop our understanding of the threshold effect and connect with rational choices for mtDNA disease therapies.

scholarly journals Mitochondrial DNA Density Homeostasis Accounts for the Threshold Effect in Human Mitochondrial Disease

2016 ◽  
Author(s):  
Juvid Aryaman ◽  
Iain G. Johnston ◽  
Nick S. Jones
Keyword(s):  
Mathematical Model ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Cell Volume ◽  
Mitochondrial Disease ◽  
Large Scale ◽  
Threshold Effect ◽  
Progressive Increase ◽  
Theoretical Understanding ◽  
Demand Reduction

AbstractMitochondrial dysfunction is involved in a wide array of devastating diseases but the heterogeneity and complexity of these diseases’ symptoms challenges theoretical understanding of their causation. With the explosion of -omics data, we have the unprecedented ability to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. However, there is also a need to make such datasets interpretable, and quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Working towards this interdisciplinary goal, we use a recently published large-scale dataset, and develop a mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation to develop a descriptive and predictive biophysical model. The experimentally observed behaviour is surprisingly rich, but we find that a simple, biophysically-motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus energy demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, upregulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density, and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here, to further develop our understanding of the threshold effect, and connect with rational choices for mtDNA disease therapies.Author SummaryMitochondria are organelles which produce the major energy currency of the cell: ATP. Mitochondrial dysfunction is associated with a multitude of devastating diseases, from Parkinson’s disease to cancer. Large volumes of data related to these diseases are being produced, but translation of these data into rational biomedical treatment is challenged by a lack of theoretical understanding. We develop a mathematical model of progressive increase of mutant load in mitochondrial DNA, for the mutation associated with MELAS (the most common mitochondrial disease), to address this. We predict that cells attempt to maintain the ratio of healthy mtDNA to cell volume by reducing their cell volume until they reach a minimum cell volume. As mutant load continues to increase, cells switch strategy by increasing their energy supply pathways. Our work accounts for large-scale experimental data and makes testable predictions about mitochondrial dysfunction. It also provides support for increasing mitochondrial content, as well as reduction in dependence upon mitochondrial metabolism via the ketogenic diet, as relevant treatments for mitochondrial disease.

Unlock imagined: arts in criminal justice

2019 ◽  
Vol 1 (2) ◽  
pp. 131-143
Author(s):  
Alison Frater
Keyword(s):  
Criminal Justice ◽  
Criminal Justice System ◽  
Justice System ◽  
Interdisciplinary Approach ◽  
Personal Perspective ◽  
Theoretical Understanding ◽  
The Arts ◽  
Optimistic Picture ◽  
The Uk ◽  
Causes Of Crime

Starting with a personal perspective this piece outlines the place and role of the arts in the criminal justice system in the UK. It paints an optimistic picture, though an unsettling one, because the imagination and reflexiveness of the arts reveals a great deal about the causes of crime and the consequences of incarceration. It raises questions about the transforming impact of the arts: how the benefits could, and should, be optimised and why evaluations of arts interventions are consistent in identifying the need for a non-coercive, more socially focused, paradigm for rehabilitation. It concludes that the deeper the arts are embedded in the criminal justice system the greater the benefits will be, that a more interdisciplinary approach would support better theoretical understanding, and that increased capacity to deliver arts in the criminal justice system is needed to offer more people a creative pathway out of crime.

scholarly journals Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 496
Author(s):  
Alessandra Maresca ◽  
Valerio Carelli
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Unmet Need ◽  
Deep Understanding ◽  
Genetic Landscape ◽  
Innovative Therapies ◽  
Energy Dependent

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

Islamic Glass in the Making

2022 ◽  
Author(s):  
Nadine Schibille
Keyword(s):  
Glass Industry ◽  
Large Scale ◽  
Interdisciplinary Approach ◽  
Islamic Period ◽  
Holistic Understanding ◽  
History Of ◽  
Early Islamic Period ◽  
Early Islamic ◽  
Plant Ash ◽  
Islamic Glass

The ancient glass industry changed dramatically towards the end of the first millennium. The Roman glassmaking tradition of mineral soda glass was increasingly supplanted by the use of plant ash as the main fluxing agent at the turn of the ninth century CE. Defining primary production groups of plant ash glass has been a challenge due to the high variability of raw materials and the smaller scale of production. Islamic Glass in the Making advocates a large-scale archaeometric approach to the history of Islamic glassmaking to trace the developments in the production, trade and consumption of vitreous materials between the eighth and twelfth centuries and to separate the norm from the exception. It proposes compositional discriminants to distinguish regional production groups, and provides insights into the organisation of the glass industry and commerce during the early Islamic period. The interdisciplinary approach leads to a holistic understanding of the development of Islamic glass; assemblages from the early Islamic period in Mesopotamia, Central Asia, Egypt, Greater Syria and Iberia are evaluated, and placed in the larger geopolitical context. In doing so, this book fills a gap in the present literature and advances a large-scale approach to the history of Islamic glass.

Robotics in Surgical Techniques Robotics in Surgical Techniques

2019 ◽  
pp. 1528-1542
Author(s):  
Vassilia Costarides ◽  
Apollon Zygomalas ◽  
Kostas Giokas ◽  
Dimitris Koutsouris
Keyword(s):  
Large Scale ◽  
Surgical Techniques ◽  
Interdisciplinary Approach ◽  
The Elderly ◽  
Cellular Level ◽  
Exciting Field ◽  
Technological Advances ◽  
Quality Of Life Indicators ◽  
The Disabled ◽  
Robotic Devices

Healthcare robotic applications are a growing trend due to rapid demographic changes that affect healthcare systems, professionals and quality of life indicators, for the elderly, the injured and the disabled. Current technological advances in robotic systems offer an exciting field for medical research, as the interdisciplinary approach of robotics in healthcare and specifically in surgery is continuously gaining ground. This chapter features a review of current applications, from external large scale robotic devices to nanoscale swarm robots programmed to interact on a cellular level.

Robotics in Surgical Techniques Robotics in Surgical Techniques

2020 ◽  
pp. 2033-2047
Author(s):  
Vassilia Costarides ◽  
Apollon Zygomalas ◽  
Kostas Giokas ◽  
Dimitris Koutsouris
Keyword(s):  
Large Scale ◽  
Surgical Techniques ◽  
Interdisciplinary Approach ◽  
The Elderly ◽  
Cellular Level ◽  
Exciting Field ◽  
Technological Advances ◽  
Quality Of Life Indicators ◽  
The Disabled ◽  
Robotic Devices

Healthcare robotic applications are a growing trend due to rapid demographic changes that affect healthcare systems, professionals and quality of life indicators, for the elderly, the injured and the disabled. Current technological advances in robotic systems offer an exciting field for medical research, as the interdisciplinary approach of robotics in healthcare and specifically in surgery is continuously gaining ground. This chapter features a review of current applications, from external large scale robotic devices to nanoscale swarm robots programmed to interact on a cellular level.

Gel-Immobilized Microarrays for the Study of Nucleic Acids and Proteins

1999 ◽  
Vol 5 (S2) ◽  
pp. 1018-1019
Author(s):  
Jordanka Zlatanova ◽  
Andrei Mirzabekov
Keyword(s):  
Large Scale ◽  
Biochemical Analysis ◽  
Computer Software ◽  
Interdisciplinary Approach ◽  
Basic Research ◽  
Single Nucleotide ◽  
Quantum Leap ◽  
Nucleotide Mutation ◽  
Agriculture And Environment ◽  
Almost All

Recently, a quantum leap has been achieved in the analysis of DNA and proteins through the advent of the biochip technology. This technology is a product of a broad interdisciplinary approach combining biochemical analysis, semiconductor manufacturing and computer software. Biochips can be defined as miniaturized ordered arrays of macro molecules or pieces thereof that are immobilized in a precise spatial manner on support media and can be used in highly automated, large-scale and high-throughput fashion to analyze biological material. The biochip can be used in a wide variety of areas related to basic research and can find versatile applications in almost all areas of human activities connected to biotechnology, medicine, agriculture, and environment monitoring and bioremediation.The power of the technology has already been demonstrated in areas like gene sequencing and proofreading, detection of single-nucleotide mutation and polymorphism, identification of genes, identification of viruses and microorganisms, gene expression analysis, analysis of sequencespecific ligands and proteins, and others.

scholarly journals No Country for Men: Searching for Late Medieval Submerged Settlements in the North-Eastern Zuiderzee Area in the Netherlands

2019 ◽  
Vol 22 (4) ◽  
pp. 567-587 ◽  
Author(s):  
Yftinus T. van Popta
Keyword(s):  
The Netherlands ◽  
Cultural Landscape ◽  
Large Scale ◽  
Interdisciplinary Approach ◽  
Economic Networks ◽  
Late Medieval ◽  
Maritime Cultural Landscape ◽  
The North ◽  
Maritime Culture ◽  
North Eastern

This article focuses on the maritime cultural landscape of the former Zuiderzee (ad 1170–1932) in the central part of the Netherlands. Since the large-scale reclamations from the sea (1932–1968), many remains have been discovered, revealing a submerged and eroded late medieval maritime culture, represented by lost islands, drowned settlements, cultivated lands, shipwrecks, and consequently socio-economic networks. Especially the north-eastern part of the region, known today as the Noordoostpolder, is testimony to the dynamic battles of the Dutch against the water. By examining physical and immaterial datasets from the region, it is possible to give a modern-day idea of this late medieval maritime cultural landscape. Spatial distribution and densities of late medieval archaeological remains are analysed and compared to historical data and remote sensing results. This interdisciplinary approach has led to the discovery of the remains of the drowned settlement of Fenehuysen.

scholarly journals Large-Scale Desynchronization During Interictal Epileptic Discharges Recorded With Intracranial EEG

2020 ◽  
Vol 11 ◽  
Author(s):  
Elie Bou Assi ◽  
Younes Zerouali ◽  
Manon Robert ◽  
Frederic Lesage ◽  
Philippe Pouliot ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Large Scale ◽  
Time Course ◽  
Deep Understanding ◽  
Epileptic Focus ◽  
Epileptogenic Focus ◽  
Intracranial Eeg ◽  
Epileptiform Discharges ◽  
Potential Biomarker ◽  
Epileptic Discharges

It is increasingly recognized that deep understanding of epileptic seizures requires both localizing and characterizing the functional network of the region where they are initiated, i. e., the epileptic focus. Previous investigations of the epileptogenic focus' functional connectivity have yielded contrasting results, reporting both pathological increases and decreases during resting periods and seizures. In this study, we shifted paradigm to investigate the time course of connectivity in relation to interictal epileptiform discharges. We recruited 35 epileptic patients undergoing intracranial EEG (iEEG) investigation as part of their presurgical evaluation. For each patient, 50 interictal epileptic discharges (IEDs) were marked and iEEG signals were epoched around those markers. Signals were narrow-band filtered and time resolved phase-locking values were computed to track the dynamics of functional connectivity during IEDs. Results show that IEDs are associated with a transient decrease in global functional connectivity, time-locked to the peak of the discharge and specific to the high range of the gamma frequency band. Disruption of the long-range connectivity between the epileptic focus and other brain areas might be an important process for the generation of epileptic activity. Transient desynchronization could be a potential biomarker of the epileptogenic focus since 1) the functional connectivity involving the focus decreases significantly more than the connectivity outside the focus and 2) patients with good surgical outcome appear to have a significantly more disconnected focus than patients with bad outcomes.

Crystal Growth of High Temperature Superconductors

MRS Bulletin ◽  
1988 ◽  
Vol 13 (10) ◽  
pp. 56-61 ◽  
Author(s):  
H.J. Scheel ◽  
F. Licci
Keyword(s):  
High Temperature ◽  
Critical Current Density ◽  
Single Crystals ◽  
Critical Current ◽  
Current Density ◽  
Large Scale ◽  
High Temperature Superconductivity ◽  
High Temperature Superconductors ◽  
Superconducting Transition ◽  
Theoretical Understanding

The discovery of high temperature superconductivity (HTSC) in oxide compounds has confronted materials scientists with many challenging problems. These include the preparation of ceramic samples with critical current density of about 106 A/cm2 at 77 K and sufficient mechanical strength for large-scale electrotechnical and magnetic applications and the preparation of epitaxial thin films of high structural perfection for electronic devices.The main interest in the growth of single crystals is for the study of physical phenomena, which will help achieve a theoretical understanding of HTSC. Theorists still do not agree on the fundamental mechanisms of HTSC, and there is a need for good data on relatively defect-free materials in order to test the many models. In addition, the study of the role of defects like twins, grain boundaries, and dislocations in single crystals is important for understanding such parameters as the critical current density. The study of HTSC with single crystals is also expected to be helpful for finding optimum materials for the various applications and hopefully achieving higher values of the superconducting transition temperature Tc than the current maximum of about 125 K. It seems unlikely at present that single crystals will be used in commercial devices, but this possibility cannot be ruled out as crystal size and quality improve.

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