Modes of Metabolic Compensation during Mitochondrial Disease Using the Drosophila Model of ATP6 Dysfunction

Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP61 mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP61animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP61animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP61 animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues

Surface defect evolution in hot rolling of high-Si electrical steels

Surface defects on metal strip products can have their root cause created in the hot rolling process by cavities and indents entrapped scale. The initial size and aspect ratio of surface features are critical parameters that determine whether they will be eliminated by the rolling process. The present research investigates the effects of the initial cavity geometry and the evolution mechanisms in a single hot rolling pass for a high-silicon electrical steel substrate. Laboratory hot-rolling experiments were carried out on blocks with open cavities of different geometries machined into the surface. The final geometry of the longitudinal and transversal profiles of the deformed cavities was analysed from metallurgical cross-sections. For a given initial cavity width, the width of the resulting oxide-filled defect is inversely related to the initial depth of the machined cavity. It has also been observed that the depth of defects increases linearly with the original depth to width aspect ratio of the initial cavities. Cavities with a depth of less than 1 mm essentially disappeared after the rolling. The final length is only dependent on its initial length in the rolling direction. The percentage reduction of cross-sectional area of the defects is found to increase with the initial depth and width of the cavities

The Impact of Functional Bars and Adapted Physical Activity on Quality of Life in Chronic Kidney Disease: A Pilot Study

Chronic kidney disease (CKD) represents a public health problem because it is characterized by several comorbidities, including uremic sarcopenia (US), and a poor quality of life. Currently, there are no standardized treatments available to counteract the onset of US but only some possible therapeutic approaches to slow its progression. The aim of this pilot study is to collect descriptive data in order to design a clinical trial based on the power analysis and simple size. The purpose of this pilot study was to evaluate the possible beneficial action induced by the functional anti-inflammatory and antioxidant bars in combination with the adapted physical activity (APA), on the onset and progression of US and other related-CKD comorbidities. We enrolled 21 CKD patients under conservative therapy, divided into four groups: (A) the physical exercise program (PEP), three times a week, in combination with the daily consumption of the two functional bars group; (B) the PEP group; (C) the daily consumption of the two functional bars group; (D) the control group. The duration of the study protocol was 12 weeks. We observed an improvement trend of body composition, blood pressure levels, lipid metabolism, and functional test in A and B groups. These preliminary data would seem to confirm the effectiveness of APA and to demonstrate the additive role of the natural bioactive compound’s assumption in countering US and other CKD comorbidities

Finite element modelling of surface defect evolution during hot rolling of Silicon steel

Surface defects on metal strips can be generated during hot rolling from surface cavities and indents. The size and aspect ratio of the initial surface cavities present before rolling are critical parameters that determine the final configuration of the defect. The propagation of these defect through the full rolling process is detrimental to the surface quality of the end product, in particular for electrical steel where these type of defects may directly affect the magnetic properties of the final product. A finite element model was developed in the present research to simulate the evolution of surface defects in a high-silicon electrical steel subjected to a single pass hot-rolling operation. The surface defects were modelled as predefined cavities with various aspect ratios and a multi-scale approach was used to capture the large local deformation gradients at the vicinity of the initial cavities. A user-defined subroutine was developed to describe the material constitutive behaviour at different strain rates and temperatures based on the Sellars-Tegart model in ABAQUS/standard finite element package. The modelling results were validated by laboratory scale hot rolling experiments with respect to the measured rolling forces and the plastic deformation of the initial cavities. This study shows that buckling of the lateral sides and bulging of the floor of the initial cavities are the main mechanisms involved in the formation of sub-surface defects. The developed model can be used to predict the evolution of surface cavities and to optimise the rolling parameters in order to minimise the detrimental effect of these defects in the final stages of the hot rolling process

Stimulus information guides the emergence of behavior-related signals in primary somatosensory cortex during learning

Neurons in the primary cortex carry sensory- and behavior-related information, but it remains an open question how this information emerges and intersects together during learning. Current evidence points to two possible learning-related changes: sensory information increases in the primary cortex or sensory information remains stable, but its readout efficiency in association cortices increases. We investigated this question by imaging neuronal activity in mouse primary somatosensory cortex before, during, and after learning of an object localization task. We quantified sensory- and behavior-related information and estimated how much sensory information was used to instruct perceptual choices as learning progressed. We find that sensory information increases from the start of training, while choice information is mostly present in the later stages of learning. Additionally, the readout of sensory information becomes more efficient with learning as early as in the primary sensory cortex. Together, our results highlight the importance of primary cortical neurons in perceptual learning

Damage in dual phase steel DP1000 investigated using digital image correlation and microstructure simulation

Microstructure failure mechanisms and void nucleation in dual-phase (DP) steels during deformation have been studied using a combination of in situ tensile testing in a scanning electron microscope (SEM), digital image correlation (DIC) and finite element (FE) modelling. SEM images acquired during in situ tests were used to follow the evolution of damage within the microstructure of a DP1000 steel. From these images, strain maps were generated using DIC and used as boundary conditions for a FE model to investigate the stress state of martensite and ferrite before the onset of the martensite phase cracking. Based on the simulation results, a maximum principal stress of about 1700 MPa has been estimated for crack initiation in the martensite of the investigated DP1000 steel. The SEM image observations in combination with the FE analyses provide new insights for the development of physically-based damage models for DP-steels

An information-theoretic quantification of the content of communication between brain regions

Quantifying the amount, content and direction of communication between brain regions is key to understanding brain function. Traditional methods to analyze brain activity based on the Wiener-Granger causality principle quantify the overall information propagated by neural activity between simultaneously recorded brain regions, but do not reveal the information flow about specific features of interest (such as sensory stimuli). Here, we develop a new information theoretic measure termed Feature-specific Information Transfer (FIT), quantifying how much information about a specific feature flows between two regions. FIT merges the Wiener-Granger causality principle with information-content specificity. We first derive FIT and prove analytically its key properties. We then illustrate and test them with simulations of neural activity, demonstrating that FIT identifies, within the total information propagated between regions, the information that is transmitted about specific features. We then analyze three neural datasets obtained with different recording methods, magneto- and electro-encephalography, and spiking activity, to demonstrate the ability of FIT to uncover the content and direction of information flow between brain regions beyond what can be discerned with traditional analytical methods. FIT can improve our understanding of how brain regions communicate by uncovering previously unaddressed feature-specific information flow

Deformation-induced microstructural banding in TRIP steels

Microstructure inhomogeneities can strongly influence the mechanical properties of advanced high-strength steels in a detrimental manner. This study of a transformation-induced plasticity (TRIP) steel investigates the effect of pre-existing contiguous grain boundary networks (CGBNs) of hard second-phases and shows how these develop into bands during tensile testing using in situ observations in conjunction with digital image correlation (DIC). The bands form by the lateral contraction of the soft ferrite matrix, which rotates and displaces the CGBNs of second-phases and the individual features within them to become aligned with the loading direction. The more extensive pre-existing CGBNs that were before the deformation already aligned with the loading direction are the most critical microstructural feature for damage initiation and propagation. They induce micro-void formation between the hard second-phases along them, which coalesce and develop into long macroscopic fissures. The hard phases, retained austenite and martensite, were not differentiated as it was found that the individual phases do not play a role in the formation of these bands. It is suggested that minimizing the presence of CGBNs of hard second-phases in the initial microstructure will increase the formability

Simple model systems: a challenge for Alzheimer's disease

The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age-related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD), one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds