Logical Inference Techniques for Loop Parallelization

This paper presents a fully automatic approach to loop parallelization that integrates the use of static and run-time analysis and thus overcomes many known difficulties such as nonlinear and indirect array indexing and complex control flow. Our hybrid analysis framework validates the parallelization transformation by verifying the independence of the loop’s memory references. To this end it represents array references using the USR (uniform set representation) language and expresses the independence condition as an equation, S = ∅, where S is a set expression representing array indexes. Using a language instead of an array-abstraction representation for S results in a smaller number of conservative approximations but exhibits a potentially-high runtime cost. To alleviate this cost we introduce a language translation F from the USR set-expression language to an equally rich language of predicates (F(S) ⇒ S = ∅). Loop parallelization is then validated using a novel logic inference algorithm that factorizes the obtained complex predicates (F(S)) into a sequence of sufficient-independence conditions that are evaluated first statically and, when needed, dynamically, in increasing order of their estimated complexities. We evaluate our automated solution on 26 benchmarks from PERFECT-CLUB and SPEC suites and show that our approach is effective in parallelizing large, complex loops and obtains much better full program speedups than the Intel and IBM Fortran compilers

Symplectic cohomology and q-intersection numbers

Given a symplectic cohomology class of degree 1, we define the notion of an equivariant Lagrangian submanifold. The Floer cohomology of equivariant Lagrangian submanifolds has a natural endomorphism, which induces a grading by generalized eigenspaces. Taking Euler characteristics with respect to the induced grading yields a deformation of the intersection number. Dehn twists act naturally on equivariant Lagrangians. Cotangent bundles and Lefschetz fibrations give fully computable examples. A key step in computations is to impose the "dilation" condition stipulating that the BV operator applied to the symplectic cohomology class gives the identity. Equivariant Lagrangians mirror equivariant objects of the derived category of coherent sheaves.Comment: 32 pages, 9 figures, expanded introduction, added details of example 7.5, added discussion of sign

Verification of loop parallelisations

Writing correct parallel programs becomes more and more difficult as the complexity and heterogeneity of processors increase. This issue is addressed by parallelising compilers. Various compiler directives can be used to tell these compilers where to parallelise. This paper addresses the correctness of such compiler directives for loop parallelisation. Specifically, we propose a technique based on separation logic to verify whether a loop can be parallelised. Our approach requires each loop iteration to be specified with the locations that are read and written in this iteration. If the specifications are correct, they can be used to draw conclusions about loop (in)dependences. Moreover, they also reveal where synchronisation is needed in the parallelised program. The loop iteration specifications can be verified using permission-based separation logic and seamlessly integrate with functional behaviour specifications. We formally prove the correctness of our approach and we discuss automated tool support for our technique. Additionally, we also discuss how the loop iteration contracts can be compiled into specifications for the code coming out of the parallelising compiler

Contact orderability up to conjugation

We study in this paper the remnants of the contact partial order on the orbits of the adjoint action of contactomorphism groups on their Lie algebras. Our main interest is a class of non-compact contact manifolds, called convex at infinity.Comment: 28 pages, 1 figur

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation.

SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type 4 (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with the cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic L374 variant. Our data suggest that SLC45A2 maintains melanosome neutralization that is initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common allelic variant imparts reduced activity due to protein instability

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies

Acessível em: www.ncbi.nlm.nih.gov/pmc/articles/PMC4423738/Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition

Near-Membrane Dynamics and Capture of TRPM8 Channels within Transient Confinement Domains

The cold and menthol receptor, TRPM8, is a non-selective cation channel expressed in a subset of peripheral neurons that is responsible for neuronal detection of environmental cold stimuli. It was previously shown that members of the transient receptor potential (TRP) family of ion channels are translocated toward the plasma membrane (PM) in response to agonist stimulation. Because the spatial and temporal dynamics of cold receptor cell-surface residence may determine neuronal activity, we hypothesized that the movement of TRPM8 to and from the PM might be a regulated process. Single particle tracking (SPT) is a useful tool for probing the organization and dynamics of protein constituents in the plasma membrane.We used SPT to study the receptor dynamics and describe membrane/near-membrane behavior of particles containing TRPM8-EGFP in transfected HEK-293T and F-11 cells. Cells were imaged using total internal reflection fluorescence (TIRF) microscopy and the 2D and 3D trajectories of TRPM8 molecules were calculated by analyzing mean-square particle displacement against time. Four characteristic types of motion were observed: stationary mode, simple Brownian diffusion, directed motion, and confined diffusion. In the absence of cold or menthol to activate the channel, most TRPM8 particles move in network covering the PM, periodically lingering for 2–8 s in confined microdomains of about 800 nm radius. Removing cholesterol with methyl-beta-cyclodextrin (MβCD) stabilizes TRPM8 motion in the PM and is correlated with larger TRPM8 current amplitude that results from an increase in the number of available channels without a change in open probability.These results reveal a novel mechanism for regulating TRPM8 channel activity, and suggest that PM dynamics may play an important role in controlling electrical activity in cold-sensitive neurons

Properties of metabolic graphs: biological organization or representation artifacts?

<p>Abstract</p> <p>Background</p> <p>Standard graphs, where each edge links two nodes, have been extensively used to represent the connectivity of metabolic networks. It is based on this representation that properties of metabolic networks, such as hierarchical and small-world structures, have been elucidated and null models have been proposed to derive biological organization hypotheses. However, these graphs provide a simplistic model of a metabolic network's connectivity map, since metabolic reactions often involve more than two reactants. In other words, this map is better represented as a hypergraph. Consequently, a question that naturally arises in this context is whether these properties truly reflect biological organization or are merely an artifact of the representation.</p> <p>Results</p> <p>In this paper, we address this question by reanalyzing topological properties of the metabolic network of <it>Escherichia coli </it>under a hypergraph representation, as well as standard graph abstractions. We find that when clustering is properly defined for hypergraphs and subsequently used to analyze metabolic networks, the scaling of clustering, and thus the hierarchical structure hypothesis in metabolic networks, become unsupported. Moreover, we find that incorporating the distribution of reaction sizes into the null model further weakens the support for the scaling patterns.</p> <p>Conclusions</p> <p>These results combined suggest that the reported scaling of the clustering coefficients in the metabolic graphs and its specific power coefficient may be an artifact of the graph representation, and may not be supported when biochemical reactions are atomically treated as hyperedges. This study highlights the implications of the way a biological system is represented and the null model employed on the elucidated properties, along with their support, of the system.</p

Systematic reconstruction of TRANSPATH data into Cell System Markup Language

<p>Abstract</p> <p>Background</p> <p>Many biological repositories store information based on experimental study of the biological processes within a cell, such as protein-protein interactions, metabolic pathways, signal transduction pathways, or regulations of transcription factors and miRNA. Unfortunately, it is difficult to directly use such information when generating simulation-based models. Thus, modeling rules for encoding biological knowledge into system-dynamics-oriented standardized formats would be very useful for fully understanding cellular dynamics at the system level.</p> <p>Results</p> <p>We selected the TRANSPATH database, a manually curated high-quality pathway database, which provides a plentiful source of cellular events in humans, mice, and rats, collected from over 31,500 publications. In this work, we have developed 16 modeling rules based on hybrid functional Petri net with extension (HFPNe), which is suitable for graphical representing and simulating biological processes. In the modeling rules, each Petri net element is incorporated with Cell System Ontology to enable semantic interoperability of models. As a formal ontology for biological pathway modeling with dynamics, CSO also defines biological terminology and corresponding icons. By combining HFPNe with the CSO features, it is possible to make TRANSPATH data to simulation-based and semantically valid models. The results are encoded into a biological pathway format, Cell System Markup Language (CSML), which eases the exchange and integration of biological data and models.</p> <p>Conclusion</p> <p>By using the 16 modeling rules, 97% of the reactions in TRANSPATH are converted into simulation-based models represented in CSML. This reconstruction demonstrates that it is possible to use our rules to generate quantitative models from static pathway descriptions.</p