Optogenetic perturbations reveal the dynamics of an oculomotor integrator

Many neural systems can store short-term information in persistently firing neurons. Such persistent activity is believed to be maintained by recurrent feedback among neurons. This hypothesis has been fleshed out in detail for the oculomotor integrator (OI) for which the so-called “line attractor” network model can explain a large set of observations. Here we show that there is a plethora of such models, distinguished by the relative strength of recurrent excitation and inhibition. In each model, the firing rates of the neurons relax toward the persistent activity states. The dynamics of relaxation can be quite different, however, and depend on the levels of recurrent excitation and inhibition. To identify the correct model, we directly measure these relaxation dynamics by performing optogenetic perturbations in the OI of zebrafish expressing halorhodopsin or channelrhodopsin. We show that instantaneous, inhibitory stimulations of the OI lead to persistent, centripetal eye position changes ipsilateral to the stimulation. Excitatory stimulations similarly cause centripetal eye position changes, yet only contralateral to the stimulation. These results show that the dynamics of the OI are organized around a central attractor state—the null position of the eyes—which stabilizes the system against random perturbations. Our results pose new constraints on the circuit connectivity of the system and provide new insights into the mechanisms underlying persistent activity

Mitochondria: role in ischemia, reperfusion and cell death

Recent advances in the knowledge of the biochemical basis of myocardial ischemia have enabled a better understanding of the complex sequence of events occurring in ischemic cardiomyopathy, whatever its manifestations. This has clearly highlighted the important role played by cardiac mitochondria in these events. At first only associated with energy production, mitochondria have been clearly shown to have other important functions, like the maintenance of calcium homeostasis, as well as ischemic and non-ischemic preconditioning, and also modulation of cellular life and death. The aims of this review are twofold: firstly, to review the current knowledge on mitochondrial morphology and structure, and how these can be affected by ischemia and ischemia-reperfusion; and secondly, to summarize the role of cardiac mitochondria in cardioprotection and modulation of cell death mechanisms

Paclitaxel response can be predicted with interpretable multi-variate classifiers exploiting DNA-methylation and miRNA data

To address the problem of resistance to paclitaxel treatment, we have investigated to which extent is possible to predict Breast Cancer (BC) patient response to this drug. We carried out a large-scale tumor-based prediction analysis using data from the US National Cancer Institute’s Genomic Data Commons. These data sets comprise the responses of BC patients to paclitaxel along with six molecular profiles of their tumors. We assessed 10 Machine Learning (ML) algorithms on each of these profiles and evaluated the resulting 60 classifiers on the same BC patients. DNA methylation and miRNA profiles were the most informative overall. In combination with these two profiles, ML algorithms selecting the smallest subset of molecular features generated the most predictive classifiers: a complexity-optimized XGBoost classifier based on CpG island methylation extracted a subset of molecular factors relevant to predict paclitaxel response (AUC = 0.74). A CpG site methylation-based Decision Tree (DT) combining only 2 of the 22,941 considered CpG sites (AUC = 0.89) and a miRNA expression-based DT employing just 4 of the 337 analyzed mature miRNAs (AUC = 0.72) reveal the molecular types associated to paclitaxel-sensitive and resistant BC tumors. A literature review shows that features selected by these three classifiers have been individually linked to the cytotoxic-drug sensitivities and prognosis of BC patients. Our work leads to several molecular signatures, unearthed from methylome and miRNome, able to anticipate to some extent which BC tumors respond or not to paclitaxel. These results may provide insights to optimize paclitaxel-therapies in clinical practice

Crowdsourcing Dialect Characterization through Twitter

We perform a large-scale analysis of language diatopic variation using geotagged microblogging datasets. By collecting all Twitter messages written in Spanish over more than two years, we build a corpus from which a carefully selected list of concepts allows us to characterize Spanish varieties on a global scale. A cluster analysis proves the existence of well defined macroregions sharing common lexical properties. Remarkably enough, we find that Spanish language is split into two superdialects, namely, an urban speech used across major American and Spanish citites and a diverse form that encompasses rural areas and small towns. The latter can be further clustered into smaller varieties with a stronger regional character.Comment: 10 pages, 5 figure

Sustained Activation of PV+ Interneurons in Core Auditory Cortex Enables Robust Divisive Gain Control for Complex and Naturalistic Stimuli

Sensory cortices must flexibly adapt their operations to internal states and external requirements. Sustained modulation of activity levels in different inhibitory interneuron populations may provide network-level mechanisms for adjustment of sensory cortical processing on behaviorally relevant timescales. However, understanding of the computational roles of inhibitory interneuron modulation has mostly been restricted to effects at short timescales, through the use of phasic optogenetic activation and transient stimuli. Here, we investigated how modulation of inhibitory interneurons affects cortical computation on longer timescales, by using sustained, network-wide optogenetic activation of parvalbumin-positive interneurons (the largest class of cortical inhibitory interneurons) to study modulation of auditory cortical responses to prolonged and naturalistic as well as transient stimuli. We found highly conserved spectral and temporal tuning in auditory cortical neurons, despite a profound reduction in overall network activity. This reduction was predominantly divisive, and consistent across simple, complex, and naturalistic stimuli. A recurrent network model with power-law input–output functions replicated our results. We conclude that modulation of parvalbumin-positive interneurons on timescales typical of sustained neuromodulation may provide a means for robust divisive gain control conserving stimulus representations

Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and xantine oxidase: what role in myocardial ischemia and reperfusion?

OBJECTIVES: The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system. METHODS: Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode). RESULTS: CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001). CONCLUSIONS: The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds

Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function

BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria

Discrete moving frames on lattice varieties and lattice based multispace

In this paper, we develop the theory of the discrete moving frame in two different ways. In the first half of the paper, we consider a discrete moving frame defined on a lattice variety and the equivalence classes of global syzygies that result from the first fundamental group of the variety. In the second half, we consider the continuum limit of discrete moving frames as a local lattice coalesces to a point. To achieve a well-defined limit of discrete frames, we construct multispace, a generalization of the jet bundle that also generalizes Olver’s one dimensional construction. Using interpolation to provide coordinates, we prove that it is a manifold containing the usual jet bundle as a submanifold. We show that continuity of a multispace moving frame ensures that the discrete moving frame converges to a continuous one as lattices coalesce. The smooth frame is, at the same time, the restriction of the multispace frame to the embedded jet bundle. We prove further that the discrete invariants and syzygies approximate their smooth counterparts. In effect, a frame on multispace allows smooth frames and their discretisations to be studied simultaneously. In our last chapter we discuss two important applications, one to the discrete variational calculus, and the second to discrete integrable systems. Finally, in an appendix, we discuss a more general result concerning equicontinuous families of discretisations of moving frames, which are consistent with a smooth frame