When the optimal is not the best: parameter estimation in complex biological models

Background: The vast computational resources that became available during the past decade enabled the development and simulation of increasingly complex mathematical models of cancer growth. These models typically involve many free parameters whose determination is a substantial obstacle to model development. Direct measurement of biochemical parameters in vivo is often difficult and sometimes impracticable, while fitting them under data-poor conditions may result in biologically implausible values. Results: We discuss different methodological approaches to estimate parameters in complex biological models. We make use of the high computational power of the Blue Gene technology to perform an extensive study of the parameter space in a model of avascular tumor growth. We explicitly show that the landscape of the cost function used to optimize the model to the data has a very rugged surface in parameter space. This cost function has many local minima with unrealistic solutions, including the global minimum corresponding to the best fit. Conclusions: The case studied in this paper shows one example in which model parameters that optimally fit the data are not necessarily the best ones from a biological point of view. To avoid force-fitting a model to a dataset, we propose that the best model parameters should be found by choosing, among suboptimal parameters, those that match criteria other than the ones used to fit the model. We also conclude that the model, data and optimization approach form a new complex system, and point to the need of a theory that addresses this problem more generally

Imagetic and affective measures of memory reverberation diverge at sleep onset in association with theta rhythm

The ‘day residue’ - the presence of waking memories into dreams - is a century-old concept that remains controver- sial in neuroscience. Even at the psychological level, it remains unclear how waking imagery cedes into dreams. Are visual and affective residues enhanced, modified, or erased at sleep onset? Are they linked, or dissociated? What are the neural correlates of these transformations? To address these questions we combined quantitative se- mantics, sleep EEG markers, visual stimulation, and multiple awakenings to investigate visual and affect residues in hypnagogic imagery at sleep onset. Healthy adults were repeatedly stimulated with an affective image, allowed to sleep and awoken seconds to minutes later, during waking (WK), N1 or N2 sleep stages. ‘Image Residue’ was objectively defined as the formal semantic similarity between oral reports describing the last image visualized before closing the eyes (‘ground image’), and oral reports of subsequent visual imagery (‘hypnagogic imagery). Similarly, ‘Affect Residue’ measured the proximity of affective valences between ‘ground image’ and ‘hypnagogic imagery’. We then compared these grounded measures of two distinct aspects of the ‘day residue’, calculated within participants, to randomly generated values calculated across participants. The results show that Image Residue persisted throughout the transition to sleep, increasing during N1 in proportion to the time spent in this stage. In contrast, the Affect Residue was gradually neutralized as sleep progressed, decreasing in proportion to the time spent in N1 and reaching a minimum during N2. EEG power in the theta band (4.5-6.5 Hz) was inversely correlated with the Image Residue during N1. The results show that the visual and affective aspects of the ‘day residue’ in hypnagogic imagery diverge at sleep onset, possibly decoupling visual contents from strong negative emotions, in association with increased theta rhythm.Neuroimag

The Brain's Router: A Cortical Network Model of Serial Processing in the Primate Brain

The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality of operations (100–500 ms per step). A limit on parallel processing is demonstrated in experimental setups such as the psychological refractory period (PRP) and the attentional blink (AB) in which the processing of an element either significantly delays (PRP) or impedes conscious access (AB) of a second, rapidly presented element. Here we present a spiking-neuron implementation of a cognitive architecture where a large number of local parallel processors assemble together to produce goal-driven behavior. The precise mapping of incoming sensory stimuli onto motor representations relies on a “router” network capable of flexibly interconnecting processors and rapidly changing its configuration from one task to another. Simulations show that, when presented with dual-task stimuli, the network exhibits parallel processing at peripheral sensory levels, a memory buffer capable of keeping the result of sensory processing on hold, and a slow serial performance at the router stage, resulting in a performance bottleneck. The network captures the detailed dynamics of human behavior during dual-task-performance, including both mean RTs and RT distributions, and establishes concrete predictions on neuronal dynamics during dual-task experiments in humans and non-human primates

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Tell-Tale Heart: heart rate fluctuations index objective and subjective events during a game of chess

During a decision making process, the body changes. These somatic changes have been related to specific cognitive events and also have been postulated to assist decision making indexing possible outcomes of different options. We used chess to analyze heart rate (HR) modulations on specific cognitive events. In a chess game, players have a limited time-budget to make about 40 moves (decisions) that can be objectively evaluated and retrospectively assigned to specific subjectively perceived events, such as setting a goal and the process to reach a known goal. We show that HR signals events: it predicts the conception of a plan, the concrete analysis of variations or the likelihood to blunder by fluctuations before to the move, and it reflects reactions, such as a blunder made by the opponent, by fluctuations subsequent to the move. Our data demonstrate that even if HR constitutes a relatively broad marker integrating a myriad of physiological variables, its dynamic is rich enough to reveal relevant episodes of inner thought

How language flows when movements don't: An automated analysis of spontaneous discourse in Parkinson's disease

To assess the impact of Parkinson's disease (PD) on spontaneous discourse, we conducted computerized analyses of brief monologues produced by 51 patients and 50 controls. We explored differences in semantic fields (via latent semantic analysis), grammatical choices (using part-of-speech tagging), and word-level repetitions (with graph embedding tools). Although overall output was quantitatively similar between groups, patients relied less heavily on action-related concepts and used more subordinate structures. Also, a classification tool operating on grammatical patterns identified monologues as pertaining to patients or controls with 75% accuracy. Finally, while the incidence of dysfluent word repetitions was similar between groups, it allowed inferring the patients’ level of motor impairment with 77% accuracy. Our results highlight the relevance of studying naturalistic discourse features to tap the integrity of neural (and, particularly, motor) networks, beyond the possibilities of standard token-level instruments.Fil: García, Adolfo Martín. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt.; ArgentinaFil: Carrillo, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Orozco Arroyave, Juan Rafael. Universidad de Antioquia; Colombia. Universitat Erlangen-Nuremberg; AlemaniaFil: Trujillo, Natalia. Universidad de Antioquia; ColombiaFil: Vargas Bonilla, Jesús F.. Universidad de Antioquia; ColombiaFil: Fittipaldi, María Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt.; ArgentinaFil: Gonzalez Adolfi, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt.; ArgentinaFil: Nöth, Elmar. Universitat Erlangen-Nuremberg; AlemaniaFil: Sigman, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Torcuato Di Tella; ArgentinaFil: Fernandez Slezak, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Ibáñez Barassi, Agustín Mariano. Universidad Adolfo Ibanez; Chile. Universidad Autonoma del Caribe; Colombia. Macquarie University; Australia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt.; ArgentinaFil: Cecchi, Guillermo Alberto. Ibm Research. Thomas J. Watson Research Center; Estados Unido

A Window into the Intoxicated Mind? : speech as an Index of Psychoactive Drug Effects

Abused drugs can profoundly alter mental states in ways that may motivate drug use. These effects are usually assessed with self-report, an approach that is vulnerable to biases. Analyzing speech during intoxication may present a more direct, objective measure, offering a unique ‘window’ into the mind. Here, we employed computational analyses of speech semantic and topological structure after ±3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) and methamphetamine in 13 ecstasy users. In 4 sessions, participants completed a 10-min speech task after MDMA (0.75 and 1.5 mg/kg), methamphetamine (20 mg), or placebo. Latent Semantic Analyses identified the semantic proximity between speech content and concepts relevant to drug effects. Graph-based analyses identified topological speech characteristics. Group-level drug effects on semantic distances and topology were assessed. Machine-learning analyses (with leave-one-out cross-validation) assessed whether speech characteristics could predict drug condition in the individual subject. Speech after MDMA (1.5 mg/kg) had greater semantic proximity than placebo to the concepts friend, support, intimacy, and rapport. Speech on MDMA (0.75 mg/kg) had greater proximity to empathy than placebo. Conversely, speech on methamphetamine was further from compassion than placebo. Classifiers discriminated between MDMA (1.5 mg/kg) and placebo with 88% accuracy, and MDMA (1.5 mg/kg) and methamphetamine with 84% accuracy. For the two MDMA doses, the classifier performed at chance. These data suggest that automated semantic speech analyses can capture subtle alterations in mental state, accurately discriminating between drugs. The findings also illustrate the potential for automated speech-based approaches to characterize clinically relevant alterations to mental state, including those occurring in psychiatric illness.Fil: Bedi, Gillinder. Columbia University; Estados UnidosFil: Cecchi, Guillermo Alberto. Ibm Research. Thomas J. Watson Research Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez Slezak, Diego. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Carrillo, Facundo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sigman, Mariano. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Wit, Harriet. Columbia University; Estados Unido

Euclid. I. Overview of the Euclid mission

The current standard model of cosmology successfully describes a variety ofmeasurements, but the nature of its main ingredients, dark matter and darkenergy, remains unknown. Euclid is a medium-class mission in the Cosmic Vision2015-2025 programme of the European Space Agency (ESA) that will providehigh-resolution optical imaging, as well as near-infrared imaging andspectroscopy, over about 14,000 deg^2 of extragalactic sky. In addition toaccurate weak lensing and clustering measurements that probe structureformation over half of the age of the Universe, its primary probes forcosmology, these exquisite data will enable a wide range of science. This paperprovides a high-level overview of the mission, summarising the surveycharacteristics, the various data-processing steps, and data products. We alsohighlight the main science objectives and expected performance