Carbonic anhydrase inhibition selectively prevents amyloid b neurovascular mitochondrial toxicity

Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer’s disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid b (Ab)-mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Ab, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Ab, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Ab-induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA-approved drugs with a well-known profile of brain delivery

Evaluating the effect of aging on interference resolution with time-varying complex networks analysis

In this study we used graph theory analysis to investigate age-related reorganization of functional networks during the active maintenance of information that is interrupted by external interference. Additionally, we sought to investigate network differences before and after averaging network parameters between both maintenance and interference windows. We compared young and older adults by measuring their magnetoencephalographic recordings during an interference-based working memory task restricted to successful recognitions. Data analysis focused on the topology/temporal evolution of functional networks during both the maintenance and interference windows. We observed that: (a) Older adults require higher synchronization between cortical brain sites in order to achieve a successful recognition, (b) The main differences between age groups arise during the interference window, (c) Older adults show reduced ability to reorganize network topology when interference is introduced, and (d) Averaging network parameters leads to a loss of sensitivity to detect age differencesThis work has been supported by the Spanish MINECO under project [FIS2013-41057], as well as Fundación Carolina Doctoral Scholarship Program and Colciencias Doctoral Program 56

Evaluating the effect of aging on interference resolution with time-varying complex networks analysis

In this study we used graph theory analysis to investigate age-related reorganization of functional networks during the active maintenance of information that is interrupted by external interference. Additionally, we sought to investigate network differences before and after averaging network parameters between both maintenance and interference windows. We compared young and older adults by measuring their magnetoencephalographic recordings during an interference-based working memory task restricted to successful recognitions. Data analysis focused on the topology/temporal evolution of functional networks during both the maintenance and interference windows. We observed that: (a) Older adults require higher synchronization between cortical brain sites in order to achieve a successful recognition, (b) The main differences between age groups arise during the interference window, (c) Older adults show reduced ability to reorganize network topology when interference is introduced, and (d) Averaging network parameters leads to a loss of sensitivity to detect age differencesThis work has been supported by the Spanish MINECO under project [FIS2013-41057], as well as Fundación Carolina Doctoral Scholarship Program and Colciencias Doctoral Program 56

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson’s disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Age-Dependent Modulations of Resting State Connectivity Following Motor Practice

Recent work in young adults has demonstrated that motor learning can modulate resting state functional connectivity. However, evidence for older adults is scarce. Here, we investigated whether learning a bimanual tracking task modulates resting state functional connectivity of both inter- and intra-hemispheric regions differentially in young and older individuals, and whether this has behavioral relevance. Both age groups learned a set of complex bimanual tracking task variants over a 2-week training period. Resting-state and task-related functional magnetic resonance imaging scans were collected before and after training. Our analyses revealed that both young and older adults reached considerable performance gains. Older adults even obtained larger training-induced improvements relative to baseline, but their overall performance levels were lower than in young adults. Short-term practice resulted in a modulation of resting state functional connectivity, leading to connectivity increases in young adults, but connectivity decreases in older adults. This pattern of age differences occurred for both inter- and intra-hemispheric connections related to the motor network. Additionally, long-term training-induced increases were observed in intra-hemispheric connectivity in the right hemisphere across both age groups. Overall, at the individual level, the long-term changes in inter-hemispheric connectivity correlated with training-induced motor improvement. Our findings confirm that short-term task practice shapes spontaneous brain activity differentially in young and older individuals. Importantly, the association between changes in resting state functional connectivity and improvements in motor performance at the individual level may be indicative of how training shapes the short-term functional reorganization of the resting state motor network for improvement of behavioral performance

El Instituto Torroja, edificio histórico: Conservaciôn y características de los materiales de sus fachadas

[EN] The "Instituto de Ciencias de la Construction" building is one of the most singular engineering design done by Eduardo Torroja; it was started in 1951. This study focussed on the Institute façade-building materials has been carried out in the 100th anniversary of his birth. The analysis has revealed that the design of the original project has been of a great importance for the good conservation of the external walls. The pointing mortar characterization of its brick walls by instrumental techniques (infrared spectroscopy, X-ray diffraction, scanning electron microscopy with EDS) reveals that calcite is its main component, with gypsum presence in polluted external zones and silica compounds from the sand. The obtained results indicate a good compatibility between mortars and façade bricks.[ES] El edificio del "Instituto de Ciencias de la Construcción", construido en 1951, constituye una de las obras singulares del ingeniero Eduardo Torroja. En el centenario de su nacimiento se ha elaborado este estudio, que se centra en los materiales de construcción de las fachadas del Instituto. De su análisis se desprende la importancia del diseño del proyecto original en la buena conservación de los paramentos exteriores. La caracterización de los morteros de junta de las fábricas de ladrillo de los paramentos, mediante técnicas instrumentales (espectroscopia infrarroja, difracción de rayos X, microscopía electrónica de barrido con energías dispersivas de rayos X) revela que la calcita es el compuesto principal, con presencia de yeso -especialmente en zonas externas contaminadas- y compuestos silíceos procedentes de la arena. Los resultados sobre las fachadas reflejan una buena compatibilidad entre los morteros de cal y los ladrillos.Los autores agradecen la financiación de los estudios sobre las características de los morteros de junta en las fábricas de ladrillo, que se encuadran en el Proyecto Europeo CE-ENV4-CT98-0706 ''Maintenance of pointing in historic buildings: Decay and replacement "

Coordinative task difficulty and behavioural errors are associated with increased long-range beta band synchronization

The neural network and the task-dependence of (local) activity changes involved in bimanual coordination are well documented. However, much less is known about the functional connectivity within this neural network and its modulation according to manipulations of task complexity. Here, we assessed neural activity via high-density electroencephalography, focussing on changes of activity in the beta frequency band (~15–30 Hz) across the motor network in 26 young adult participants (19–29 years old). We investigated how network connectivity was modulated with task difficulty and errors of performance during a bimanual visuomotor movement consisting of dial rotation according to three different ratios of speed: an isofrequency movement (1:1), a non-isofrequency movement with the right hand keeping the fast pace (1:3), and the converse ratio with the left hand keeping the fast pace (3:1). To quantify functional coupling, we determined neural synchronization which might be key for the timing of the activity within brain regions during task execution. Individual source activity with realistic head models was reconstructed at seven regions of interest including frontal and parietal areas, among which we estimated phase-based connectivity. Partial least squares analysis revealed a significant modulation of connectivity with task difficulty, and significant correlations between connectivity and errors in performance, in particular between sensorimotor cortices. Our findings suggest that modulation of long-range synchronization is instrumental for coping with increasing task demands in bimanual coordination

Understanding bimanual coordination across small time scales from an electrophysiological perspective

Bimanual movement involves a variety of coordinated functions, ranging from elementary patterns that are performed automatically to complex patterns that require practice to be performed skillfully. The neural dynamics accompanying these coordination patterns are complex and rapid. By means of electro- and magneto-encephalographic approaches, it has been possible to examine these dynamics during bimanual coordination with excellent temporal resolution, which complements other neuroimaging modalities with superb spatial resolution. This review focuses on EEG/MEG studies that unravel the processes involved in movement planning and execution, motor learning, and executive functions involved in task switching and dual tasking. Evidence is presented for a spatio-temporal reorganization of the neural networks within and between hemispheres to meet increased task difficulty demands, induced or spontaneous switches in coordination mode, or training-induced neuroplastic modulation in coordination dynamics. Future theoretical developments will benefit from the integration of research techniques unraveling neural activity at different time scales. Ultimately this work will contribute to a better understanding of how the human brain orchestrates complex behavior via the implementation of inter- and intra-hemispheric coordination networks.publisher: Elsevier articletitle: Understanding bimanual coordination across small time scales from an electrophysiological perspective journaltitle: Neuroscience & Biobehavioral Reviews articlelink: http://dx.doi.org/10.1016/j.neubiorev.2014.10.003 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.status: publishe