237 research outputs found
Verification of Java Bytecode using Analysis and Transformation of Logic Programs
State of the art analyzers in the Logic Programming (LP) paradigm are
nowadays mature and sophisticated. They allow inferring a wide variety of
global properties including termination, bounds on resource consumption, etc.
The aim of this work is to automatically transfer the power of such analysis
tools for LP to the analysis and verification of Java bytecode (JVML). In order
to achieve our goal, we rely on well-known techniques for meta-programming and
program specialization. More precisely, we propose to partially evaluate a JVML
interpreter implemented in LP together with (an LP representation of) a JVML
program and then analyze the residual program. Interestingly, at least for the
examples we have studied, our approach produces very simple LP representations
of the original JVML programs. This can be seen as a decompilation from JVML to
high-level LP source. By reasoning about such residual programs, we can
automatically prove in the CiaoPP system some non-trivial properties of JVML
programs such as termination, run-time error freeness and infer bounds on its
resource consumption. We are not aware of any other system which is able to
verify such advanced properties of Java bytecode
Cell Migration in the Immune System: the Evolving Inter-Related Roles of Adhesion Molecules and Proteinases
Leukocyte extravasation into perivascular tissue during inflammation and lymphocyte homing
to lymphoid organs involve transient adhesion to the vessel endothelium, followed by transmigration
through the endothelial cell (EC) layer and establishment of residency at the tissue site
for a period of time. In these processes, leukocytes undergo multiple attachments to, and detachments
from, the vessel-lining endothelial cells, prior to transendothelial cell migration. Transmigrating
leukocytes must traverse a subendothelial basement membrane en route to perivascular
tissues and utilize enzymes known as matrix metalloproteinases to make selective clips in the
extracellular matrix components of the basement membrane. This review will focus on the evidence
for a link between adhesion of leukocytes to endothelial cells, the induction of matrix
metalloproteinases mediated by engagement of adhesion receptors on leukocytes, and the ability
to utilize these matrix metalloproteinases to facilitate leukocyte invasion of tissues. Leukocytes
with invasive phenotypes express high levels of MMPs, and expression of MMPs
enhances the migratory and invasive properties of these cells. Furthermore, MMPs may be used
by lymphocytes to proteolytically cleave molecules such as adhesion receptors and membrane
bound cytokines, increasing their efficiency in the immune response. Engagement of leukocyte
adhesion receptors may modulate adhesive (modulation of integrin affinities and expression),
synthetic (proteinase induction and activation), and surface organization (clustering of proteolyric
complexes) behaviors of invasive leukocytes. Elucidation of these pathways will lead to
better understanding of controlling mechanisms in order to develop rational therapeutic
approaches in the areas of inflammation and autoimmunity
Trypanosoma brucei BRCA2 acts in a life cycle-specific genome stability process and dictates BRC repeat number-dependent RAD51 subnuclear dynamics
Trypanosoma brucei survives in mammals through antigenic variation, which is driven by RAD51-directed homologous recombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repository of >1000 silent genes. A key regulator of RAD51 is BRCA2, which in T. brucei contains a dramatic expansion of a motif that mediates interaction with RAD51, termed the BRC repeats. BRCA2 mutants were made in both tsetse fly-derived and mammal-derived T. brucei, and we show that BRCA2 loss has less impact on the health of the former. In addition, we find that genome instability, a hallmark of BRCA2 loss in other organisms, is only seen in mammal-derived T. brucei. By generating cells expressing BRCA2 variants with altered BRC repeat numbers, we show that the BRC repeat expansion is crucial for RAD51 subnuclear dynamics after DNA damage. Finally, we document surprisingly limited co-localization of BRCA2 and RAD51 in the T. brucei nucleus, and we show that BRCA2 mutants display aberrant cell division, revealing a function distinct from BRC-mediated RAD51 interaction. We propose that BRCA2 acts to maintain the huge VSG repository of T. brucei, and this function has necessitated the evolution of extensive RAD51 interaction via the BRC repeats, allowing re-localization of the recombinase to general genome damage when needed
Homeomorphic Embedding for Online Termination of Symbolic Methods
Well-quasi orders in general, and homeomorphic embedding in particular, have gained popularity to ensure the termination of techniques for program analysis, specialisation, transformation, and verification. In this paper we survey and discuss this use of homeomorphic embedding and clarify the advantages of such an approach over one using well-founded orders. We also discuss various extensions of the homeomorphic embedding relation. We conclude with a study of homeomorphic embedding in the context of metaprogramming, presenting some new (positive and negative) results and open problems
Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria
Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria). However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC. Reactive oxygen species (ROS) scavengers completely inhibited MALM. A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. Deficiency of NIX also completely impaired MALM. When MALM was inhibited, Mieap induced vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulfed and degraded the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impaired both MALM and MIV generation, leading to accumulation of unhealthy mitochondria. These results suggest that (1) mitochondrial ROS and NIX are essential factors for MALM, (2) MIV is a novel mechanism for lysosomal degradation of mitochondria, and (3) the p53-Mieap pathway plays a pivotal role in MQC by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively
Maximal operator in variable exponent generalized morrey spaces on quasi-metric measure space
We consider generalized Morrey spaces on quasi-metric measure spaces , in general unbounded, with variable exponent p(x) and a general function defining the Morrey-type norm. No linear structure of the underlying space X is assumed. The admission of unbounded X generates problems known in variable exponent analysis. We prove the boundedness results for maximal operator known earlier only for the case of bounded sets X. The conditions for the boundedness are given in terms of the so called supremal inequalities imposed on the function , which are weaker than Zygmund-type integral inequalities often used for characterization of admissible functions . Our conditions do not suppose any assumption on monotonicity of in r
Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice
Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder
Successful Inhibition of Tumor Development by Specific Class-3 Semaphorins Is Associated with Expression of Appropriate Semaphorin Receptors by Tumor Cells
The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as sema3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full length semaphorins in four different tumorigenic cell lines expressing different combinations of class-3 semaphorin receptors. We show for the first time that sema3A, sema3D, sema3E and sema3G can function as potent anti-tumorigenic agents. All the semaphorins we examined were also able to reduce the concentration of tumor associated blood vessels although the potencies of the anti-angiogenic effects varied depending on the tumor cell type. Surprisingly, there was little correlation between the ability to inhibit tumor angiogenesis and their anti-tumorigenic activity. None of the semaphorins inhibited the adhesion of the tumor cells to plastic or fibronectin nor did they modulate the proliferation of tumor cells cultured in cell culture dishes. However, various semaphorins were able to inhibit the formation of soft agar colonies from tumor cells expressing appropriate semaphorin receptors, although in this case too the inhibitory effect was not always correlated with the anti-tumorigenic effect. In contrast, the anti-tumorigenic effect of each of the semaphorins correlated very well with tumor cell expression of specific signal transducing receptors for particular semaphorins. This correlation was not broken even in cases in which the tumor cells expressed significant concentrations of endogenous semaphorins. Our results suggest that combinations of different class-3 semaphorins may be more effective than single semaphorins in cases in which tumor cells express more than one type of semaphorin receptors
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