Toward an Energy Efficient Language and Compiler for (Partially) Reversible Algorithms

We introduce a new programming language for expressing reversibility, Energy-Efficient Language (Eel), geared toward algorithm design and implementation. Eel is the first language to take advantage of a partially reversible computation model, where programs can be composed of both reversible and irreversible operations. In this model, irreversible operations cost energy for every bit of information created or destroyed. To handle programs of varying degrees of reversibility, Eel supports a log stack to automatically trade energy costs for space costs, and introduces many powerful control logic operators including protected conditional, general conditional, protected loops, and general loops. In this paper, we present the design and compiler for the three language levels of Eel along with an interpreter to simulate and annotate incurred energy costs of a program.Comment: 17 pages, 0 additional figures, pre-print to be published in The 8th Conference on Reversible Computing (RC2016

Optimization of CABRI power transients with the SPARTE code and the URANIE uncertainty platform

International audienceIn a Pressurized Water Reactor (PWR), the rod ejection is a design basis accident for uncontrolled evolution of the nuclear reaction.In case of failure of a rod mechanism, the rod ejection is caused by the pressure differential between the primary loop (155 bar) and the confinement-s enclosure (atmospheric pressure).It leads to a local power transient and a fast fuel temperature increase.The power transient is limited by the reactivity feedbacks before the automatic reactor shutdown.The CABRI experimental pulsed reactor is funded by the French Nuclear Safety and Radioprotection Institute (IRSN) and is operated by CEA at the Cadarache research center.It is designed to study fuel rods behavior under Reactivity Initiated Accident (RIA) conditions.The tested fuel rod is placed at the center of the CABRI core, inside a pressurized water loop reproducing PWR conditions.CABRI is a pool type reactor, made of 1487 UO$_2$ fuel rods and controlled by 6 Hafnium control rods.A specific device allows the fast depressurization of $^3$He contained in 4 transient rods to reproduce control rods ejection conditions.Based on a BEPU approach, we developed a tool, named SPARTE, for CABRI power transients calculation.This tool is based on point kinetics, simplified thermal-hydraulics and thermal-mechanics.It computes the global behavior of the core by the calculation of a mean fuel rod. It includes models of reactivity insertion specific to the CABRI transient rods system, variable kinetics parameters and variable Doppler coefficient.This code is validated on the basis of 66 CABRI start-up power transients realized during the first quarter of 2017. One goal of the SPARTE code is to be used for the prediction of future CABRI power transients.This paper focuses on methods for optimizing a specific CABRI power transient (FWHM $\simeq$ 30 ms, Deposited energy $\simeq$ 130 $MJ$) using the target characteristics of the pulse. The selection of a method may help the experimentalists and the operation team to minimize the number of white- power transients to perform before the final test with the fuel sample. The optimization can lead to different results, that can be ranked according to their projected uncertainties. Different optimization methods are tested and compared in this paper. The Subplex method based on reiterations of the Nelder-Mead algorithm (simplex method) was selected for its high precision. Indeed, the CABRI power transients are not completely reproducible and present some uncertainties linked to the test parameters. This article focuses on the uncertainties propagation in order to identify and select the parameters that minimize the output uncertainties. The results are very satisfactory and lead to several optimized scenarios that will be tested during the next qualification test campaign

Maximum Power Efficiency and Criticality in Random Boolean Networks

Random Boolean networks are models of disordered causal systems that can occur in cells and the biosphere. These are open thermodynamic systems exhibiting a flow of energy that is dissipated at a finite rate. Life does work to acquire more energy, then uses the available energy it has gained to perform more work. It is plausible that natural selection has optimized many biological systems for power efficiency: useful power generated per unit fuel. In this letter we begin to investigate these questions for random Boolean networks using Landauer's erasure principle, which defines a minimum entropy cost for bit erasure. We show that critical Boolean networks maximize available power efficiency, which requires that the system have a finite displacement from equilibrium. Our initial results may extend to more realistic models for cells and ecosystems.Comment: 4 pages RevTeX, 1 figure in .eps format. Comments welcome, v2: minor clarifications added, conclusions unchanged. v3: paper rewritten to clarify it; conclusions unchange

Sparse Rational Univariate Representation

International audienceWe present explicit worst case degree and height bounds for the rational univariate representation of the isolated roots of polynomial systems based on mixed volume. We base our estimations on height bounds of resultants and we consider the case of 0-dimensional, positive dimensional, and parametric polynomial systems

A cost-effective method to quantify biological surface sediment reworking

We propose a simple and inexpensive method to determine the rate and pattern of surface sediment reworking by benthic organisms. Unlike many existing methods commonly used in bioturbation studies, which usually require sediment sampling, our approach is fully non-destructive and is well suited for investigating non-cohesive fine sediments in streams and rivers. Optical tracer (e.g., luminophores or coloured sand) disappearance or appearance is assessed through time based on optical quantification of surfaces occupied by tracers. Data are used to calculate surface sediment reworking (SSR) coefficients depicting bioturbation intensities. Using this method, we evaluated reworking activity of stream organisms (three benthic invertebrates and a fish) in laboratory microcosms mimicking pool habitats or directly in the field within arenas set in depositional zones. Our method was sensitive enough to measure SSR as low as 0.2 cm2.d-1, such as triggered by intermediate density (774 m-2) of Gammarus fossarum (Amphipoda) in microcosms. In contrast, complex invertebrate community in the field and a fish (Barbatula barabatula) in laboratory microcosms were found to yield to excessively high SSR (>60 cm2.d-1). Lastly, we suggest that images acquired during experiments can be used for qualitative evaluation of species-specific effects on sediment distribution

An Engineered Viral Protease Exhibiting Substrate Specificity for a Polyglutamine Stretch Prevents Polyglutamine-Induced Neuronal Cell Death

BACKGROUND: Polyglutamine (polyQ)-induced protein aggregation is the hallmark of a group of neurodegenerative diseases, including Huntington's disease. We hypothesized that a protease that could cleave polyQ stretches would intervene in the initial events leading to pathogenesis in these diseases. To prove this concept, we aimed to generate a protease possessing substrate specificity for polyQ stretches. METHODOLOGY/PRINCIPAL FINDINGS: Hepatitis A virus (HAV) 3C protease (3CP) was subjected to engineering using a yeast-based method known as the Genetic Assay for Site-specific Proteolysis (GASP). Analysis of the substrate specificity revealed that 3CP can cleave substrates containing glutamine at positions P5, P4, P3, P1, P2', or P3', but not substrates containing glutamine at the P2 or P1' positions. To accommodate glutamine at P2 and P1', key residues comprising the active sites of the S2 or S1' pockets were separately randomized and screened. The resulting sets of variants were combined by shuffling and further subjected to two rounds of randomization and screening using a substrate containing glutamines from positions P5 through P3'. One of the selected variants (Var26) reduced the expression level and aggregation of a huntingtin exon1-GFP fusion protein containing a pathogenic polyQ stretch (HttEx1(97Q)-GFP) in the neuroblastoma cell line SH-SY5Y. Var26 also prevented cell death and caspase 3 activation induced by HttEx1(97Q)-GFP. These protective effects of Var26 were proteolytic activity-dependent. CONCLUSIONS/SIGNIFICANCE: These data provide a proof-of-concept that proteolytic cleavage of polyQ stretches could be an effective modality for the treatment of polyQ diseases

Selection and characterisation of a phage-displayed human antibody (Fab) reactive to the lung resistance-related major vault protein

The major vault protein is the main component on multimeric vault particles, that are likely to play an essential role in normal cell physiology and to be associated with multidrug resistance of tumour cells. In order to unravel the function of vaults and their putative contribution to multidrug resistance, specific antibodies are invaluable tools. Until now, only conventional major vault protein-reactive murine monoclonal antibodies have been generated, that are most suitable for immunohistochemical analyses. The phage display method allows for selection of human antibody fragments with potential use in clinical applications. Furthermore, cDNA sequences encoding selected antibody fragments are readily identified, facilitating various molecular targeting approaches. In order to obtain such human Fab fragments recognising major vault protein we used a large non-immunized human Fab fragment phage library. Phages displaying major vault protein-reactive Fabs were obtained through several rounds of selection on major vault protein-coated immunotubes and subsequent amplification in TG1 E coli bacteria. Eventually, one major vault protein-reactive clone was selected and further examined. The anti-major vault protein Fab was found suitable for immunohistochemical and Western blot analysis of tumour cell lines and human tissues. BIAcore analysis showed that the binding affinity of the major vault protein-reactive clone almost equalled that of the murine anti-major vault protein Mabs. The cDNA sequence of this human Fab may be exploited to generate an intrabody for major vault protein-knock out studies. Thus, this human Fab fragment should provide a valuable tool in elucidating the contribution(s) of major vault protein/vaults to normal physiology and cellular drug resistance mechanisms

Bifunctional Anti-Huntingtin Proteasome-Directed Intrabodies Mediate Efficient Degradation of Mutant Huntingtin Exon 1 Protein Fragments

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide (CAG)n repeat expansion in the coding sequence of the huntingtin gene, and an expanded polyglutamine (>37Q) tract in the protein. This results in misfolding and accumulation of huntingtin protein (htt), formation of neuronal intranuclear and cytoplasmic inclusions, and neuronal dysfunction/degeneration. Single-chain Fv antibodies (scFvs), expressed as intrabodies that bind htt and prevent aggregation, show promise as immunotherapeutics for HD. Intrastriatal delivery of anti-N-terminal htt scFv-C4 using an adeno-associated virus vector (AAV2/1) significantly reduces the size and number of aggregates in HDR6/1 transgenic mice; however, this protective effect diminishes with age and time after injection. We therefore explored enhancing intrabody efficacy via fusions to heterologous functional domains. Proteins containing a PEST motif are often targeted for proteasomal degradation and generally have a short half life. In ST14A cells, fusion of the C-terminal PEST region of mouse ornithine decarboxylase (mODC) to scFv-C4 reduces htt exon 1 protein fragments with 72 glutamine repeats (httex1-72Q) by ∼80–90% when compared to scFv-C4 alone. Proteasomal targeting was verified by either scrambling the mODC-PEST motif, or via proteasomal inhibition with epoxomicin. For these constructs, the proteasomal degradation of the scFv intrabody proteins themselves was reduced<25% by the addition of the mODC-PEST motif, with or without antigens. The remaining intrabody levels were amply sufficient to target N-terminal httex1-72Q protein fragment turnover. Critically, scFv-C4-PEST prevents aggregation and toxicity of httex1-72Q fragments at significantly lower doses than scFv-C4. Fusion of the mODC-PEST motif to intrabodies is a valuable general approach to specifically target toxic antigens to the proteasome for degradation

Conformational Targeting of Fibrillar Polyglutamine Proteins in Live Cells Escalates Aggregation and Cytotoxicity

Misfolding- and aggregation-prone proteins underlying Parkinson's, Huntington's and Machado-Joseph diseases, namely alpha-synuclein, huntingtin, and ataxin-3 respectively, adopt numerous intracellular conformations during pathogenesis, including globular intermediates and insoluble amyloid-like fibrils. Such conformational diversity has complicated research into amyloid-associated intracellular dysfunction and neurodegeneration. To this end, recombinant single-chain Fv antibodies (scFvs) are compelling molecular tools that can be selected against specific protein conformations, and expressed inside cells as intrabodies, for investigative and therapeutic purposes.Using atomic force microscopy (AFM) and live-cell fluorescence microscopy, we report that a human scFv selected against the fibrillar form of alpha-synuclein targets isomorphic conformations of misfolded polyglutamine proteins. When expressed in the cytoplasm of striatal cells, this conformation-specific intrabody co-localizes with intracellular aggregates of misfolded ataxin-3 and a pathological fragment of huntingtin, and enhances the aggregation propensity of both disease-linked polyglutamine proteins. Using this intrabody as a tool for modulating the kinetics of amyloidogenesis, we show that escalating aggregate formation of a pathologic huntingtin fragment is not cytoprotective in striatal cells, but rather heightens oxidative stress and cell death as detected by flow cytometry. Instead, cellular protection is achieved by suppressing aggregation using a previously described intrabody that binds to the amyloidogenic N-terminus of huntingtin. Analogous cytotoxic results are observed following conformational targeting of normal or polyglutamine-expanded human ataxin-3, which partially aggregate through non-polyglutamine domains.These findings validate that the rate of aggregation modulates polyglutamine-mediated intracellular dysfunction, and caution that molecules designed to specifically hasten aggregation may be detrimental as therapies for polyglutamine disorders. Moreover, our findings introduce a novel antibody-based tool that, as a consequence of its general specificity for fibrillar conformations and its ability to function intracellularly, offers broad research potential for a variety of human amyloid diseases