Old and new vacua of 5D maximal supergravity

We look for critical points with U(2) residual symmetry in 5-dimensional maximally supersymmetric gauged supergravity, by varying the embedding tensor, rather than directly minimizing the scalar potential. We recover all previously known vacua and we find four new vacua, with different gauge groups and cosmological constants. We provide the first example of a maximal supergravity model in $D \geq 4$ having critical points with both positive and vanishing cosmological constant. For each vacuum we also compute the full mass spectrum. All results are analytic.Comment: 29 pages, 1 figure. v2 References adde

Lazy-CSeq-SP: Boosting Sequentialization-Based Verification of Multi-threaded C Programs via Symbolic Pruning of Redundant Schedules

Abstract. Sequentialization has been shown to be an effective symbolic verification technique for concurrent C programs using POSIX threads. Lazy-CSeq, a tool that applies a lazy sequentialization scheme, has won the Concurrency division of the last two editions of the Competition on Software Verification. The tool encodes all thread schedules up to a given bound into a single non-deterministic sequential C program and then invokes a C model checker. This paper presents a novel optimized imple-mentation of lazy sequentialization, which integrates symbolic pruning of redundant schedules into the encoding. Experimental evaluation shows that our tool outperforms Lazy-CSeq significantly on many benchmarks

Symbolic Partial-Order Execution for Testing Multi-Threaded Programs

We describe a technique for systematic testing of multi-threaded programs. We combine Quasi-Optimal Partial-Order Reduction, a state-of-the-art technique that tackles path explosion due to interleaving non-determinism, with symbolic execution to handle data non-determinism. Our technique iteratively and exhaustively finds all executions of the program. It represents program executions using partial orders and finds the next execution using an underlying unfolding semantics. We avoid the exploration of redundant program traces using cutoff events. We implemented our technique as an extension of KLEE and evaluated it on a set of large multi-threaded C programs. Our experiments found several previously undiscovered bugs and undefined behaviors in memcached and GNU sort, showing that the new method is capable of finding bugs in industrial-size benchmarks.Comment: Extended version of a paper presented at CAV'2

Noncanonical DNA Cleavage by BamHI Endonuclease in Laterally Confined DNA Monolayers Is a Step Function of DNA Density and Sequence

Cleavage of DNA at noncanonical recognition sequences by restriction endonucleases (star activity) in bulk solution can be promoted by global experimental parameters, including enzyme or substrate concentration, temperature, pH, or buffer composition. To study the effect of nanoscale confinement on the noncanonical behaviour of BamHI, which cleaves a single unique sequence of 6 bp, we used AFM nanografting to generate laterally confined DNA monolayers (LCDM) at different densities, either in the form of small patches, several microns in width, or complete monolayers of thiol-modified DNA on a gold surface. We focused on two 44-bp DNAs, each containing a noncanonical BamHI site differing by 2 bp from the cognate recognition sequence. Topographic AFM imaging was used to monitor end-point reactions by measuring the decrease in the LCDM height with respect to the surrounding reference surface. At low DNA densities, BamHI efficiently cleaves only its cognate sequence while at intermediate DNA densities, noncanonical sequence cleavage occurs, and can be controlled in a stepwise (on/off) fashion by varying the DNA density and restriction site sequence. This study shows that endonuclease action on noncanonical sites in confined nanoarchitectures can be modulated by varying local physical parameters, independent of global chemical parameters

Extracting Safe Thread Schedules from Incomplete Model Checking Results

Model checkers frequently fail to completely verify a concurrent program, even if partial-order reduction is applied. The verification engineer is left in doubt whether the program is safe and the effort toward verifying the program is wasted. We present a technique that uses the results of such incomplete verification attempts to construct a (fair) scheduler that allows the safe execution of the partially verified concurrent program. This scheduler restricts the execution to schedules that have been proven safe (and prevents executions that were found to be erroneous). We evaluate the performance of our technique and show how it can be improved using partial-order reduction. While constraining the scheduler results in a considerable performance penalty in general, we show that in some cases our approach—somewhat surprisingly—even leads to faster executions

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale

Evidence against global attention filters selective for absolute bar-orientation in human vision

The finding that an item of type A pops out from an array of distractors of type B typically is taken to support the inference that human vision contains a neural mechanism that is activated by items of type A but not by items of type B. Such a mechanism might be expected to yield a neural image in which items of type A produce high activation and items of type B low (or zero) activation. Access to such a neural image might further be expected to enable accurate estimation of the centroid of an ensemble of items of type A intermixed with to-be-ignored items of type B. Here, it is shown that as the number of items in stimulus displays is increased, performance in estimating the centroids of horizontal (vertical) items amid vertical (horizontal) distractors degrades much more quickly and dramatically than does performance in estimating the centroids of white (black) items among black (white) distractors. Together with previous findings, these results suggest that, although human vision does possess bottom-up neural mechanisms sensitive to abrupt local changes in bar-orientation, and although human vision does possess and utilize top-down global attention filters capable of selecting multiple items of one brightness or of one color from among others, it cannot use a top-down global attention filter capable of selecting multiple bars of a given absolute orientation and filtering bars of the opposite orientation in a centroid task