ABC transporters: one, two or four extracytoplasmic substrate-binding sites?

Two families of ATP-binding cassette (ABC) transporters in which one or two extracytoplasmic substrate-binding domains are fused to either the N- or C-terminus of the translocator protein have been detected. This suggests that two, or even four, substrate-binding sites may function in the ABC transporter complex. This domain organization in ABC transporters, widely represented among microorganisms, raises new possibilities for how the substrate-binding protein(s) (SBPs) might interact with the translocator. One appealing hypothesis is that multiple substrate-binding sites in proximity to the entry site of the translocation pore enhance the transport capacity. We also discuss the implications of multiple substrate-binding sites in close proximity to the translocator in terms of broadened substrate specificity and possible cooperative interactions between SBPs and the translocator

WOMM: A weak operational memory model

10.1007/978-3-642-16558-0_43Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)6415 LNCSPART 1519-53

Long-acting β2-adrenoceptor agonists enhance glucocorticoid receptor (GR)-mediated transcription by gene-specific mechanisms rather than generic effects via GR

In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β2-adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2× glucocorticoid response element (2×GRE)-driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)-dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser203, Ser211, Ser226) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2×GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.FWN – Publicaties zonder aanstelling Universiteit Leide

Characterisation of nitride thin films by EBSD

Thin films incorporating GaN, InGaN and AlGaN are presently arousing considerable excitement because of their suitability for UV and visible light-emitting diodes and laser diodes. However, because of the lattice mismatch between presently used substrates and epitaxial nitride thin films, the films are of variable quality. In this paper we describe our preliminary studies of nitride thin films using electron backscattered diffraction (EBSD). We show that the EBSD technique may be used to reveal the relative orientation of an epitaxial thin film with respect to its substrate (a 90° rotation between a GaN epitaxial thin film and its sapphire substrate is observed) and to determine its tilt (a GaN thin film was found to be tilted by 13±1° towards [10 0]GaN), where the tilt is due to the inclination of the sapphire substrate(cut off-axis by 10° from (0001)sapphire towards (10 0)sapphire). We compare EBSD patterns obtained from As-doped GaN films grown by plasma-assisted molecular beam epitaxy (PA-MBE) with low and high As 4 flux, respectively. Higher As 4 flux results in sharper, better defined patterns, this observation is consistent with the improved surface morphology observed in AFM studies. Finally, we show that more detail can be discerned in EBSD patterns from GaN thin films when samples are cooled

Generative Operational Semantics for Relaxed Memory Models ⋆

Abstract. The specification of the Java Memory Model (JMM) is phrased in terms of acceptors of execution sequences rather than the standard generative view of operational semantics. This creates a mismatch with language-based techniques, such as simulation arguments and proofs of type safety. We describe a semantics for the JMM using standard programming language techniques that captures its full expressivity. For data-race-free programs, our model coincides with the JMM. For lockless programs, our model is more expressive than the JMM. The stratification properties required to avoid causality cycles are derived, rather than mandated in the style of the JMM. The JMM is arguably non-canonical in its treatment of the interaction of data races and locks as it fails to validate roach-motel reorderings and various peephole optimizations. Our model differs from the JMM in these cases. We develop a theory of simulation and use it to validate the legality of the above optimizations in any program context.

Software Transactional Memory on Relaxed Memory Models

Pseudo-code descriptions of STMs assume sequentially consistent program execution and atomicity of high-level STM operations like read, write, and commit. These assumptions are often violated in realistic settings, as STM implementations run on relaxed memory models, with the atomicity of operations as provided by the hardware. This paper presents the first approach to verify STMs under relaxed memory models with atomicity of 32 bit loads and stores, and read-modify-write operations. We present RML, a new high-level language for expressing concurrent algorithms with a hardware-level atomicity of instructions, and whose semantics is parametrized by various relaxed memory models. We then present our tool, FOIL, which takes as input the RML description of an STM algorithm and the description of a memory model, and automatically determines the locations of fences, which if inserted, ensure the correctness of the STM algorithm under the given memory model. We use FOIL to verify DSTM, TL2, and McRT STM under the memory models of sequential consistency, total store order, partial store order, and relaxed memory order

Static Analysis of Run-Time Errors in Embedded Critical Parallel C Programs

Abstract. We present a static analysis by Abstract Interpretation to check for run-time errors in parallel C programs. Following our work on Astrée, we focus on embedded critical programs without recursion nor dynamic memory allocation, but extend the analysis to a static set of threads. Our method iterates a slightly modified non-parallel analysis over each thread in turn, until thread interferences stabilize. We prove the soundness of the method with respect to a sequential consistent semantics and a reasonable weakly consistent memory semantics. We then show how to take into account mutual exclusion and thread priorities through partitioning over the scheduler state. We present preliminary experimental results analyzing a real program with our prototype, Thésée, and demonstrate the scalability of our approach