Implicit task sequence learning in patients with Parkinson's disease, frontal lesions and amnesia: The critical role of fronto–striatal loops

The purpose of this study was to investigate the role of the fronto–striatal system for implicit task sequence learning. We tested performance of patients with compromised functioning of the fronto–striatal loops, that is, patients with Parkinson's disease and patients with lesions in the ventromedial or dorsolateral prefrontal cortex. We also tested amnesic patients with lesions either to the basal forebrain/orbitofrontal cortex or to thalamic/medio-temporal regions. We used a task sequence learning paradigm involving the presentation of a sequence of categorical binary-choice decision tasks. After several blocks of training, the sequence, hidden in the order of tasks, was replaced by a pseudo-random sequence. Learning (i.e., sensitivity to the ordering) was assessed by measuring whether this change disrupted performance. Although all the patients were able to perform the decision tasks quite easily, those with lesions to the fronto–striatal loops (i.e., patients with Parkinson's disease, with lesions in the ventromedial or dorsolateral prefrontal cortex and those amnesic patients with lesions to the basal forebrain/orbitofrontal cortex) did not show any evidence of implicit task sequence learning. In contrast, those amnesic patients with lesions to thalamic/medio-temporal regions showed intact sequence learning. Together, these results indicate that the integrity of the fronto–striatal system is a prerequisite for implicit task sequence learning.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

A reduced model clarifies the role of feedback loops and time delays in the Drosophila circadian oscillator.

Although several detailed models of molecular processes essential for circadian oscillations have been developed, their complexity makes intuitive understanding of the oscillation mechanism difficult. The goal of the present study was to reduce a previously developed, detailed model to a minimal representation of the transcriptional regulation essential for circadian rhythmicity in Drosophila. The reduced model contains only two differential equations, each with time delays. A negative feedback loop is included, in which PER protein represses per transcription by binding the dCLOCK transcription factor. A positive feedback loop is also included, in which dCLOCK indirectly enhances its own formation. The model simulated circadian oscillations, light entrainment, and a phase-response curve with qualitative similarities to experiment. Time delays were found to be essential for simulation of circadian oscillations with this model. To examine the robustness of the simplified model to fluctuations in molecule numbers, a stochastic variant was constructed. Robust circadian oscillations and entrainment to light pulses were simulated with fewer than 80 molecules of each gene product present on average. Circadian oscillations persisted when the positive feedback loop was removed. Moreover, elimination of positive feedback did not decrease the robustness of oscillations to stochastic fluctuations or to variations in parameter values. Such reduced models can aid understanding of the oscillation mechanisms in Drosophila and in other organisms in which feedback regulation of transcription may play an important role.

Analysis of Pressure Head-Flow Loops of Pulsatile Rotodynamic Blood Pumps

The clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. A commonly used method for restoring pulsatility with rotodynamic blood pumps (RBPs) is to modulate the speed profile, synchronized to the cardiac cycle. This introduces additional parameters that influence the (un)loading of the heart, including the timing (phase shift) between the native cardiac cycle and the pump pulses, and the amplitude of speed modulation. In this study, the impact of these parameters upon the heart-RBP interaction was examined in terms of the pressure head-flow (HQ) diagram. The measurements were conducted using a rotodynamic Deltastream DP2 pump in a validated hybrid mock circulation with baroreflex function. The pump was operated with a sinusoidal speed profile, synchronized to the native cardiac cycle. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. The HQ loops displayed characteristic shapes depending on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS ]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift.

Interlinked dual-time feedback loops can enhance robustness to stochasticity and persistence of memory.

Multiple interlinked positive feedback loops shape the stimulus responses of various biochemical systems, such as the cell cycle or intracellular Ca2+ release. Recent studies with simplified models have identified two advantages of coupling fast and slow feedback loops. This dual-time structure enables a fast response while enhancing resistances of responses and bistability to stimulus noise. We now find that (1) the dual-time structure similarly confers resistance to internal noise due to molecule number fluctuations, and (2) model variants with altered coupling, which better represent some specific biochemical systems, share all the above advantages. We also develop a similar bistable model with coupling of a fast autoactivation loop to a slow loop. This model's topology was suggested by positive feedback proposed to play a role in long-term synaptic potentiation (LTP). The advantages of fast response and noise resistance are also present in this autoactivation model. Empirically, LTP develops resistance to reversal over approximately 1h . The model suggests this resistance may result from increased amounts of synaptic kinases involved in positive feedback.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

New Constraints on Dark Matter Effective Theories from Standard Model Loops

We consider an effective field theory for a gauge singlet Dirac dark matter particle interacting with the standard model fields via effective operators suppressed by the scale Λ≳1  TeV. We perform a systematic analysis of the leading loop contributions to spin-independent Dirac dark matter–nucleon scattering using renormalization group evolution between Λ and the low-energy scale probed by direct detection experiments. We find that electroweak interactions induce operator mixings such that operators that are naively velocity suppressed and spin dependent can actually contribute to spin-independent scattering. This allows us to put novel constraints on Wilson coefficients that were so far poorly bounded by direct detection. Constraints from current searches are already significantly stronger than LHC bounds, and will improve in the near future. Interestingly, the loop contribution we find is isospin violating even if the underlying theory is isospin conserving.

Graphics Processor Unit Based Parallelization of Optimized Baseline Wander Filtering Algorithms for Long-term Electrocardiography

Long-term electrocardiogram (ECG) often suffers from relevant noise. Baseline wander in particular is pronounced in ECG recordings using dry or esophageal electrodes, which are dedicated for prolonged registration. While analog high-pass filters introduce phase distortions, reliable offline filtering of the baseline wander implies a computational burden that has to be put in relation to the increase in signal-to-baseline ratio (SBR). Here we present a graphics processor unit (GPU) based parallelization method to speed up offline baseline wander filter algorithms, namely the wavelet, finite, and infinite impulse response, moving mean, and moving median filter. Individual filter parameters were optimized with respect to the SBR increase based on ECGs from the Physionet database superimposed to auto-regressive modeled, real baseline wander. A Monte-Carlo simulation showed that for low input SBR the moving median filter outperforms any other method but negatively affects ECG wave detection. In contrast, the infinite impulse response filter is preferred in case of high input SBR. However, the parallelized wavelet filter is processed 500 and 4 times faster than these two algorithms on the GPU, respectively, and offers superior baseline wander suppression in low SBR situations. Using a signal segment of 64 mega samples that is filtered as entire unit, wavelet filtering of a 7-day high-resolution ECG is computed within less than 3 seconds. Taking the high filtering speed into account, the GPU wavelet filter is the most efficient method to remove baseline wander present in long-term ECGs, with which computational burden can be strongly reduced.

Current Mode with RMS Voltage and Offset Control Loops for a Single-Phase Aircraft Inverter Suitable for Parallel and 3-Phase Operation Modes

Rms voltage regulation may be an attractive possibility for controlling power inverters. Combined with a Hall Effect sensor for current control, it keeps its parallel operation capability while increasing its noise immunity, which may lead to a reduction of the Total Harmonic Distortion (THD). Besides, as voltage regulation is designed in DC, a simple PI regulator can provide accurate voltage tracking. Nevertheless, this approach does not lack drawbacks. Its narrow voltage bandwidth makes transients last longer and it increases the voltage THD when feeding non-linear loads, such as rectifying stages. On the other hand, the implementation can fall into offset voltage error. Furthermore, the information of the output voltage phase is hidden for the control as well, making the synchronization of a 3-phase setup not trivial. This paper explains the concept, design and implementation of the whole control scheme, in an on board inverter able to run in parallel and within a 3-phase setup. Special attention is paid to solve the problems foreseen at implementation level: a third analog loop accounts for the offset level is added and a digital algorithm guarantees 3-phase voltage synchronization.

High Performance Algorithms and Implementations Using Sparse and Parallelization Techniques on MBS

In this paper we will see how the efficiency of the MBS simulations can be improved in two different ways, by considering both an explicit and implicit semi-recursive formulation. The explicit method is based on a double velocity transformation that involves the solution of a redundant but compatible system of equations. The high computational cost of this operation has been drastically reduced by taking into account the sparsity pattern of the system. Regarding this, the goal of this method is the introduction of MA48, a high performance mathematical library provided by Harwell Subroutine Library. The second method proposed in this paper has the particularity that, depending on the case, between 70 and 85% of the computation time is devoted to the evaluation of forces derivatives with respect to the relative position and velocity vectors. Keeping in mind that evaluating these derivatives can be decomposed into concurrent tasks, the main goal of this paper lies on a successful and straightforward parallel implementation that have led to a substantial improvement with a speedup of 3.2 by keeping all the cores busy in a quad-core processor and distributing the workload between them, achieving on this way a huge time reduction by doing an ideal CPU usage

Effectiveness of abstract interpretation in automatic parallelization: a case study in logic programming

We report on a detailed study of the application and effectiveness of program analysis based on abstract interpretation to automatic program parallelization. We study the case of parallelizing logic programs using the notion of strict independence. We first propose and prove correct a methodology for the application in the parallelization task of the information inferred by abstract interpretation, using a parametric domain. The methodology is generic in the sense of allowing the use of different analysis domains. A number of well-known approximation domains are then studied and the transformation into the parametric domain defined. The transformation directly illustrates the relevance and applicability of each abstract domain for the application. Both local and global analyzers are then built using these domains and embedded in a complete parallelizing compiler. Then, the performance of the domains in this context is assessed through a number of experiments. A comparatively wide range of aspects is studied, from the resources needed by the analyzers in terms of time and memory to the actual benefits obtained from the information inferred. Such benefits are evaluated both in terms of the characteristics of the parallelized code and of the actual speedups obtained from it. The results show that data flow analysis plays an important role in achieving efficient parallelizations, and that the cost of such analysis can be reasonable even for quite sophisticated abstract domains. Furthermore, the results also offer significant insight into the characteristics of the domains, the demands of the application, and the trade-offs involved.

Automatic compile-time parallelization of logic programs for restricted, goal-level, independent and-parallelism.

A framework for the automatic parallelization of (constraint) logic programs is proposed and proved correct. Intuitively, the parallelization process replaces conjunctions of literals with parallel expressions. Such expressions trigger at run-time the exploitation of restricted, goal-level, independent and-parallelism. The parallelization process performs two steps. The first one builds a conditional dependency graph (which can be implified using compile-time analysis information), while the second transforms the resulting graph into linear conditional expressions, the parallel expressions of the &-Prolog language. Several heuristic algorithms for the latter ("annotation") process are proposed and proved correct. Algorithms are also given which determine if there is any loss of parallelism in the linearization process with respect to a proposed notion of maximal parallelism. Finally, a system is presented which implements the proposed approach. The performance of the different annotation algorithms is compared experimentally in this system by studying the time spent in parallelization and the effectiveness of the results in terms of speedups.

Abstract specialization and its application to program parallelization

Program specialization optimizes programs for known valúes of the input. It is often the case that the set of possible input valúes is unknown, or this set is infinite. However, a form of specialization can still be performed in such cases by means of abstract interpretation, specialization then being with respect to abstract valúes (substitutions), rather than concrete ones. This paper reports on the application of abstract múltiple specialization to automatic program parallelization in the &-Prolog compiler. Abstract executability, the main concept underlying abstract specialization, is formalized, the design of the specialization system presented, and a non-trivial example of specialization in automatic parallelization is given.