A Model Checker for Operator Precedence Languages

The problem of extending model checking from finite state machines to procedural programs has fostered much research toward the definition of temporal logics for reasoning on context-free structures. The most notable of such results are temporal logics on Nested Words, such as CaRet and NWTL. Recently, Precedence Oriented Temporal Logic (POTL) has been introduced to specify and prove properties of programs coded trough an Operator Precedence Language (OPL). POTL is complete w.r.t. the FO restriction of the MSO logic previously defined as a logic fully equivalent to OPL. POTL increases NWTL's expressive power in a perfectly parallel way as OPLs are more powerful that nested words.In this article, we produce a model checker, named POMC, for OPL programs to prove properties expressed in POTL. To the best of our knowledge, POMC is the first implemented and openly available model checker for proving tree-structured properties of recursive procedural programs. We also report on the experimental evaluation we performed on POMC on a nontrivial benchmark

Anharmonicity and self-similarity of the free energy landscape of protein G

The near-native free energy landscape of protein G is investigated through 0.4 microseconds-long atomistic molecular dynamics simulations in explicit solvent. A theoretical and computational framework is used to assess the time-dependence of salient thermodynamical features. While the quasi-harmonic character of the free energy is found to degrade in a few ns, the slow modes display a very mild dependence on the trajectory duration. This property originates from a striking self-similarity of the free energy landscape embodied by the consistency of the principal directions of the local minima, where the system dwells for several ns, and of the virtual jumps connecting them.Comment: revtex, 6 pages, 5 figure

Essential role of STAT5a in DCIS formation and invasion following estrogen treatment

Ductal carcinoma in situ (DCIS) is one of the earliest stages of breast cancer (BCa). The mechanisms by which DCIS lesions progress to an invasive state while others remain indolent are yet to be fully characterized and both diagnosis and treatment of this pre-invasive disease could benefit from better understanding the pathways involved. While a decreased expression of Caveolin-1 (Cav-1) in the tumor microenvironment of patients with DCIS breast cancer was linked to progression to invasive breast cancer (IBC), the downstream effector(s) contributing to this process remain elusive. The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions. In addition, STAT5a overexpression in a human DCIS cell line (MCF10DCIS.com) promoted their invasion, a process accelerated by estrogen treatment and associated with increased levels of the matrix metalloproteinase-9 (MMP-9) precursor. In sum, our results demonstrate a novel regulatory axis (Cav-1♦STAT5a♦MMP-9) in DCIS that is fully activated by the presence of estrogen. Our studies suggest to further study phosphorylated STAT5a (Y694) as a potential biomarker to guide and predict outcome of DCIS patient population

Isolation and characterization of oxidizedoligogalacturonides: meccanism of dampening of damps

Oligogalacturonides (OGs) released upon partial degradation of homogalacturonan, are a well-known class of Damage-Associated Molecular Patterns (DAMPs). Besides inducing immunity, OGs negatively affect plant growth by antagonizing auxin responses. Because the recognition of DAMPs poses the intrinsic risk of activating an exaggerated response that may impair plant survival, dampening mechanisms of DAMPs should exist. Transgenic Arabidopsis plants (OGM plants) expressing a chimeric protein called "OGmachine" accumulate oligogalacturonides (OGs) in their tissues and exhibit enhanced resistance to a variety of pathogens; however the growth of these plants is severely impaired. The prolonged release of OGs triggers defense responses that in the long term are deleterious for the plant. We used the OGM plants as a tool to investigate a possible regulatory mechanism by searching for elicitor-inactive OGs that may derive from elicitor-active OGs through an enzymatic modification. By analyzing the OGs produced in the transgenic plants, modified OGs were isolated. The nature of the modification was investigated by electrospray ionization mass spectrometry and resulted to be the oxidation to galactaric acid of the residue at the reducing end of OGs (oxOGs). OxOGs were tested for their ability to induce defense responses and antagonize auxin responses. In all experiments, they were inactive as compared to the corresponding typical OGs. We succeeded to isolate and characterize one of the enzymes that causes the inactivation of OGs: it is a FAD binding oxidase, that we named OGOX1, capable of producing elicitor-inactive oxidized OGs and H2O2

Pregnancy complications in acquired thrombotic thrombocytopenic purpura : a case-control study

BackgroundPregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP.MethodsWe conducted a nested case\ubfcontrol study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias.ResultsFifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to-severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage.ConclusionsADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP

ALADYN: a web server for aligning proteins by matching their large-scale motion

The ALADYN web server aligns pairs of protein structures by comparing their internal dynamics and detecting regions that sustain similar large-scale movements. The latter often accompany functional conformational changes in proteins and enzymes. The ALADYN dynamics-based alignment can therefore highlight functionally-oriented correspondences that could be more elusive to sequence- or structure-based comparisons. The ALADYN server takes the structure files of the two proteins as input. The optimal relative positioning of the molecules is found by maximizing the similarity of the pattern of structural fluctuations which are calculated via an elastic network model. The resulting alignment is presented via an interactive graphical Java applet and is accompanied by a number of quantitative indicators and downloadable data files. The ALADYN web server is freely accessible at the http://aladyn.escience-lab.org address

The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase

We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop