Defining the Substrate Spectrum of the TIM22 Complex Identifies Pyruvate Carrier Subunits as Unconventional Cargos

Mitochondria carrier proteins, which possess six transmembrane spans (TM), are transported by the TIM22 complex. By using a quantitative proteomic approach, Gomkale and Cruz-Zaragoza et al. reveal subunits of the mitochondrial pyruvate carrier (MPC) that possess two or three TMs as unexpected substrates of the carrier pathway

Mitochondrial precursor proteins are imported through a hydrophilic membrane environment

We have analyzed how translocation intermediates of imported mitochondrial precursor proteins, which span contact sites, interact with the mitochondrial membranes. F1-ATPase subunit β(F1β) was trapped at contact sites by importing it into Neurospora mitochondria in the presence of low levels of nucleoside triphosphates. This F1β translocation intermediate could be extracted from the membranes by treatment with protein denaturants such as alkaline pH or urea. By performing import at low temperatures, the ADP/ATP carrier was accumulated in contact sites of Neurospora mitochondria and cytochrome b2 in contact sites of yeast mitochondria. These translocation intermediates were also extractable from the membranes at alkaline pH. Thus, translocation of precursor proteins across mitochondrial membranes seems to occur through an environment which is accessible to aqueous perturbants. We propose that proteinaceous structures are essential components of a translocation apparatus present in contact sites

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Non-monotonicity on a spatio-temporally defined cyclic task: evidence of two movement types?

We tested 23 healthy participants who performed rhythmic horizontal movements of the elbow. The required amplitude and frequency ranges of the movements were specified to the participants using a closed shape on a phase-plane display, showing angular velocity versus angular position, such that participants had to continuously control both the speed and the displacement of their forearm. We found that the combined accuracy in velocity and position throughout the movement was not a monotonic function of movement speed. Our findings suggest that specific combinations of required movement frequency and amplitude give rise to two distinct types of movements: one of a more rhythmic nature, and the other of a more discrete nature

A parsimonious oscillatory model of handwriting

International audienceWe propose an oscillatory model that is theoretically parsimonious, empirically efficient and biologically plausible. Building on Hollerbach’s (Biol Cybern 39:139–156, 1981) model, our Parsimonious Oscillatory Model of Handwriting (POMH) overcomes the latter’s main shortcomings by making it possible to extract its parameters from the trace itself and by reinstating symmetry between the x and y coordinates. The benefit is a capacity to autonomously generate a smooth continuous trace that reproduces the dynamics of the handwriting movements through an extremely sparse model, whose efficiency matches that of other, more computationally expensive optimizing methods. Moreover, the model applies to 2D trajectories, irrespective of their shape, size, orientation and length. It is also independent of the endeffectors mobilized and of the writing direction

A Newly Identified Essential Complex, Dre2-Tah18, Controls Mitochondria Integrity and Cell Death after Oxidative Stress in Yeast

A mutated allele of the essential gene TAH18 was previously identified in our laboratory in a genetic screen for new proteins interacting with the DNA polymerase delta in yeast [1]. The present work shows that Tah18 plays a role in response to oxidative stress. After exposure to lethal doses of H2O2, GFP-Tah18 relocalizes to the mitochondria and controls mitochondria integrity and cell death. Dre2, an essential Fe/S cluster protein and homologue of human anti-apoptotic Ciapin1, was identified as a molecular partner of Tah18 in the absence of stress. Moreover, Ciapin1 is able to replace yeast Dre2 in vivo and physically interacts with Tah18. Our results are in favour of an oxidative stress-induced cell death in yeast that involves mitochondria and is controlled by the newly identified Dre2-Tah18 complex

The Manipulative Complexity of Lower Paleolithic Stone Toolmaking

Early stone tools provide direct evidence of human cognitive and behavioral evolution that is otherwise unavailable. Proper interpretation of these data requires a robust interpretive framework linking archaeological evidence to specific behavioral and cognitive actions.Here we employ a data glove to record manual joint angles in a modern experimental toolmaker (the 4(th) author) replicating ancient tool forms in order to characterize and compare the manipulative complexity of two major Lower Paleolithic technologies (Oldowan and Acheulean). To this end we used a principled and general measure of behavioral complexity based on the statistics of joint movements.This allowed us to confirm that previously observed differences in brain activation associated with Oldowan versus Acheulean technologies reflect higher-level behavior organization rather than lower-level differences in manipulative complexity. This conclusion is consistent with a scenario in which the earliest stages of human technological evolution depended on novel perceptual-motor capacities (such as the control of joint stiffness) whereas later developments increasingly relied on enhanced mechanisms for cognitive control. This further suggests possible links between toolmaking and language evolution

Nanotools for Neuroscience and Brain Activity Mapping

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function