Predicting toxicity through computers: a changing world

The computational approaches used to predict toxicity are evolving rapidly, a process hastened on by the emergence of new ways of describing chemical information. Although this trend offers many opportunities, new regulations, such as the European Community's 'Registration, Evaluation, Authorisation and Restriction of Chemicals' (REACH), demand that models be ever more robust

A Proximal Approach for a Class of Matrix Optimization Problems

In recent years, there has been a growing interest in mathematical models leading to the minimization, in a symmetric matrix space, of a Bregman divergence coupled with a regularization term. We address problems of this type within a general framework where the regularization term is split in two parts, one being a spectral function while the other is arbitrary. A Douglas-Rachford approach is proposed to address such problems and a list of proximity operators is provided allowing us to consider various choices for the fit-to-data functional and for the regularization term. Numerical experiments show the validity of this approach for solving convex optimization problems encountered in the context of sparse covariance matrix estimation. Based on our theoretical results, an algorithm is also proposed for noisy graphical lasso where a precision matrix has to be estimated in the presence of noise. The nonconvexity of the resulting objective function is dealt with a majorization-minimization approach, i.e. by building a sequence of convex surrogates and solving the inner optimization subproblems via the aforementioned Douglas-Rachford procedure. We establish conditions for the convergence of this iterative scheme and we illustrate its good numerical performance with respect to state-of-the-art approaches

Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways

An increasing body of evidence suggests that several membrane receptors – in addition to activating distinct signalling cascades – also engage in substantial crosstalk with each other, thereby adjusting their signalling outcome as a function of specific input information. However, little is known about the molecular mechanisms that control their coordination and integration of downstream signalling. A protein that is likely to have a role in this process is kinase-D-interacting substrate of 220 kDa [Kidins220, also known as ankyrin repeat-rich membrane spanning (ARMS), hereafter referred to as Kidins220/ARMS]. Kidins220/ARMS is a conserved membrane protein that is preferentially expressed in the nervous system and interacts with the microtubule and actin cytoskeleton. It interacts with neurotrophin, ephrin, vascular endothelial growth factor (VEGF) and glutamate receptors, and is a common downstream target of several trophic stimuli. Kidins220/ARMS is required for neuronal differentiation and survival, and its expression levels modulate synaptic plasticity. Kidins220/ARMS knockout mice show developmental defects mainly in the nervous and cardiovascular systems, suggesting a crucial role for this protein in modulating the cross talk between different signalling pathways. In this Commentary, we summarise existing knowledge regarding the physiological functions of Kidins220/ARMS, and highlight some interesting directions for future studies on the role of this protein in health and disease.This study was supported by research grants from: Cancer Research UK (to G.S.); the Italian Institute of Technology (to F.C. and F.B.); the Italian Ministry of University and Research [2008T4ZCNL grant number 2008T4ZCNL to F.B.]; the Compagnia di San Paolo, Torino (to F.B.); Telethon-Italy [grant number GGP09134 to F.B.] and the Spanish Ministry of Science and Innovation [grant number JCI-2008-01843 to V.N.].Peer reviewe

Synapsin I controls synaptic maturation of long-range projections in the lateral amygdala in a targeted selective fashion

The amygdala, and more precisely its lateral nucleus, is thought to attribute emotional valence to external stimuli by generating long-term plasticity changes at long-range projections to principal cells. Aversive experience has also been shown to modify pre- and post-synaptic markers in the amygdala, suggesting their possible role in the structural organization of adult amygdala networks. Here, we focused on how the maturation of cortical and thalamic long-range projections occurs on principal neurons and interneurons in the lateral amygdala (LA). We performed dual electrophysiological recordings of identified cells in juvenile and adult GAD67-GFP mice after independent stimulation of cortical and thalamic afferent systems. The results demonstrate that synaptic strengthening occurs during development at synapses projecting to LA principal neurons, but not interneurons. As synaptic strengthening underlies fear conditioning which depends, in turn, on presence and increasing expression of synapsin I, we tested if synapsin I contributes to synaptic strengthening during development. Interestingly, the physiological synaptic strengthening of cortical and thalamic synapses projecting to LA principal neurons was virtually abolished in synapsin I knockout mice, but not differences were observed in the excitatory projections to interneurons. Immunohistochemistry analysis showed that the presence of synapsin I is restricted to excitatory contacts projecting to principal neurons in LA of adult mice. These results indicate that synapsin I is a key regulator of the maturation of synaptic connectivity in this brain region and that is expression is dependent on postsynaptic identity

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

RE-1 Silencing Transcription factor (REST) controls several steps in neural development by modulating the expression of a wide range of neural genes. Alterations in REST expression have been associated with the onset of epilepsy; however, whether such alterations are deleterious or represent a protective homeostatic response remains elusive. To study the impact of REST modulation on seizure propensity, we developed a tool for its negative modulation in vivo. The tool is composed of the paired-amphipathic helix 1 (PAH1) domain, a competitive inhibitor of REST activation by mSin3, fused to the light-oxygen-voltage sensing 2 (LOV2) domain of Avena sativa phototropin 1, a molecular switch to alternatively hide or expose the PAH1 inhibitor. We employed the C450A and I539E light-independent AsLOV2 variants to mimic the closed (inactive) and open (active) states of LOV2-PAH1, respectively. Recombinant AAV1/2 viral particles (rAAVs) allowed LOV2-PAH1 expression in HEK293T cells and primary neurons, and efficiently transduced hippocampal neurons in vivo. mRNA expression analysis revealed an increased expression of several neuronal genes in the hippocampi of mice expressing the open probe. AAV-transduced mice received a single dose of kainic acid (KA), a treatment known to induce a transient increase of REST levels in the hippocampus. Remarkably, mice expressing the active variant displayed a reduced number of KA-induced seizures, which were less severe compared to mice carrying the inactive probe. These data support the validity of our tool to modulate REST activity in vivo and the potential impact of REST modulation on epileptogenesis

Magnetic signatures of domain walls in s+is and s+id superconductors: Observability and what that can tell us about the superconducting order parameter

One of the defining features of spontaneously broken time-reversal symmetry (BTRS) is the existence of domain walls, the detection of which would be strong evidence for such systems. There is keen interest in BTRS currently, in part, due to recent muon spin rotation experiments, which have pointed towards Ba1−xKxFe2As2 exhibiting a remarkable case of s-wave superconductivity with spontaneously broken time-reversal symmetry. A key question, however, is how to differentiate between the different theoretical models which describe such a state. Two particularly popular choices of model are s+is and s+id superconducting states. In this paper, we obtain solutions for domain walls in s+is and s+id systems, including the effects of lattice anisotropies. We show that, in general, both models exhibit spontaneous magnetic fields that extend along the entire length of the domain wall. We demonstrate the qualitative difference between the magnetic signatures of s+is and s+id domain walls and propose a procedure to extract the superconducting pairing symmetry from the magnetic-field response of domain walls

Integrating computational methods to predict mutagenicity of aromatic azo compounds

Azo dyes have several industrial uses. However, these azo dyes and their degradation products showed mutagenicity, inducing damage in environmental and human systems. Computational methods are proposed as cheap and rapid alternatives to predict the toxicity of azo dyes. A benchmark dataset of Ames data for 354 azo dyes was employed to develop three classification strategies using knowledge-based methods and docking simulations. Results were compared and integrated with three models from the literature, developing a series of consensus strategies. The good results confirm the usefulness of in silico methods as a support for experimental methods to predict the mutagenicity of azo compounds

Large-scale, high-resolution electrophysiological imaging of field potentials in brain slices with microelectronic multielectrode arrays

Multielectrode arrays (MEAs) are extensively used for electrophysiological studies on brain slices, but the spatial resolution and field of recording of conventional arrays are limited by the low number of electrodes available. Here, we present a large-scale array recording simultaneously from 4096 electrodes used to study propagating spontaneous and evoked network activity in acute murine cortico-hippocampal brain slices at unprecedented spatial and temporal resolution. We demonstrate that multiple chemically induced epileptiform episodes in the mouse cortex and hippocampus can be classified according to their spatio-temporal dynamics. Additionally, the large-scale and high-density features of our recording system enable the topological localization and quantification of the effects of antiepileptic drugs in local neuronal microcircuits, based on the distinct field potential propagation patterns. This novel high-resolution approach paves the way to detailed electrophysiological studies in brain circuits spanning spatial scales from single neurons up to the entire slice network

QSPR modeling for enthalpies of formation of organometallic compounds by means of SMILES-based optimal descriptors

Organometallic compounds are an important class of chemicals, because many of them have vital biochemical features. There are studies on the quantitative structure-property/activity relationships (QSPR/QSAR) for organic substances [1-5], but only a few articles have deal with QSPR for organometallic compounds Simplified molecular input line entry system (SMILES) [9-13] has been used as an alternative for molecular graphs in the QSPR/QSAR analyses SMILES-based optimal descriptors were calculated a

Fabrication of biocompatible free-standing nanopatterned films for primary neuronal cultures

Devising and constructing biocompatible devices for nervous system regeneration is an extremely challenging task. Besides tackling the issue of biocompatibility, biomaterials for neuroscience applications should mimic the complex environment of the extracellular matrix, which in vivo provides neurons with a series of cues and signals to guide cells towards their appropriate targets. In this work, a novel nanopatterned biocompatible poly-ε-caprolactone (PCL) film is realized to assist the attachment and growth of primary hippocampal neurons. Costly and time-consuming processes can be avoided using plasma-surface nanotexturing obtained by a mixed gas SF6/Ar at -5 °C. The intrinsic composition and line topography of nanopatterned PCL ensure healthy development of the neuronal network, as shown by confocal microscopy, by analysing the expression of a range of neuronal markers typical of mature cultures, as well as by scanning electron microscopy. In addition, we show that surface nanopatterning improves differentiation of neurons compared to flat PCL films, while no neural growth was observed on either flat or nanopatterned substrates in the absence of a poly-d-lysine coating. Thus, we successfully optimized a nanofabrication protocol to obtain nanostructured PCL layers endowed with several mechanical and structural characteristics that make them a promising, versatile tool for future tissue engineering studies aimed at neural tissue regeneration