Learning automata with side-effects

Automata learning has been successfully applied in the verification of hardware and software. The size of the automaton model learned is a bottleneck for scalability, and hence optimizations that enable learning of compact representations are important. This paper exploits monads, both as a mathematical structure and a programming construct, to design and prove correct a wide class of such optimizations. Monads enable the development of a new learning algorithm and correctness proofs, building upon a general framework for automata learning based on category theory. The new algorithm is parametric on a monad, which provides a rich algebraic structure to capture non-determinism and other side-effects. We show that this allows us to uniformly capture existing algorithms, develop new ones, and add optimizations

Canonical Automata via Distributive Law Homomorphisms

The classical powerset construction is a standard method converting a non-deterministic automaton into a deterministic one recognising the same language. Recently, the powerset construction has been lifted to a more general framework that converts an automaton with side-effects, given by a monad, into a deterministic automaton accepting the same language. The resulting automaton has additional algebraic properties, both in the state space and transition structure, inherited from the monad. In this paper, we study the reverse construction and present a framework in which a deterministic automaton with additional algebraic structure over a given monad can be converted into an equivalent succinct automaton with side-effects. Apart from recovering examples from the literature, such as the canonical residual finite-state automaton and the átomaton, we discover a new canonical automaton for a regular language by relating the free vector space monad over the two element field to the neighbourhood monad. Finally, we show that every regular language satisfying a suitable property parametric in two monads admits a size-minimal succinct acceptor

Relation between cytokines and routine laboratory data in children with septic shock and purpura

Objective To establish the relation between routine laboratory data (lactate, fibrinogen, CRP) and cytokines (TNF,IL-1 and-6) and to estimate their prognostic value in pediatric patients with severe infectious purpura on admission. Design Prospective study. Setting Pediatric intensive care unit (PICU). Patients 17 children aged 5–172 months (median 46) were hospitalized in our PICU in 1989–90 with severe infectious purpura.Neisseria meningitidis was isolated in 15 children andHaemophilus influenzae in two. The patients were divided into 3 groups: non-shock, shock and severe shock leading to death. Shock was defined by standard criteria. Measurements Arterial blood was sampled for lactate, CRP, fibrinogen, TNF, and IL-1 and-6 on admission. The PRISM (pediatric risk of morality)-score was recorded. Methods Statistical analysis was performed with the Student'st-test using the logarithmic values of the cytokine concentration, and Spearman correlation analysis. Results According to the shock criteria, 9 patients were in shock of whom 4 did not survive. Significant differences existed between the 3 groups concerning lactate, TNF, and IL-6. Fibrinogen, CRP, IL-1, and PRISM-score discriminated only between survivors and non-survivors. A highly significant correlation existed between cytokines, the PRISM-score and lactate (TNF:r=0.69, IL-1:r=0.56, IL-6:r=0.65, PRISM:r=0.65). A significant inverse correlation existed between cytokines and CRP (TNF:r=−0.55, IL-1:r=−0.64, and IL-6:r=−0.56), and IL-6 and fibrinogen (r=−0.65). Conclusion These results show a significant correlation between cytokines and lactate, and lactate, TNF and IL-6 are closely associated with the severity of septic shock with purpura in children

Axillary Dissection and Nodal Irradiation Can Be Avoided for Most Node-positive Z0011-eligible Breast Cancers : a Prospective Validation Study of 793 Patients

OBJECTIVE: To determine rates of axillary dissection (ALND) and nodal recurrence in patients eligible for ACOSOG Z0011. BACKGROUND: Z0011 demonstrated that patients with cT1-2N0 breast cancers and 1 to 2 involved sentinel lymph nodes (SLNs) having breast-conserving therapy had no difference in locoregional recurrence or survival after SLN biopsy alone or ALND. The generalizability of the results and importance of nodal radiotherapy (RT) is unclear. METHODS: Patients eligible for Z0011 had SLN biopsy alone. Prospectively defined indications for ALND were metastases in 653 SLNs or gross extracapsular extension. Axillary imaging was not routine. SLN and ALND groups and radiation fields were compared with chi-square and t tests. Cumulative incidence of recurrences was estimated with competing risk analysis. RESULTS: From August 2010 to December 2016, 793 patients met Z0011 eligibility criteria and had SLN metastases. Among them, 130 (16%) had ALND; ALND did not vary based on age, estrogen receptor, progesterone receptor, or HER2 status. Five-year event-free survival after SLN alone was 93% with no isolated axillary recurrences. Cumulative 5-year rates of breast\u200a+\u200anodal and nodal\u200a+\u200adistant recurrence were each 0.7%. In 484 SLN-only patients with known RT fields (103 prone, 280 supine tangent, 101 breast\u200a+\u200anodes) and follow-up 6512 months, the 5-year cumulative nodal recurrence rate was 1% and did not differ significantly by RT fields. CONCLUSIONS: We confirm that even without preoperative axillary imaging or routine use of nodal RT, ALND can be avoided in a large majority of Z0011-eligible patients with excellent regional control. This approach has the potential to spare substantial numbers of women the morbidity of ALND

Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis

Contains fulltext : 97862.pdf (publisher's version ) (Open Access)BACKGROUND/AIM: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS: Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS: Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION: Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect

Species trait shifts in vegetation and soil seed bank during fen degradation

Fens in Central Europe are characterised by waterlogged organic substrate and low productivity. Human-induced changes due to drainage and mowing lead to changes in plant species composition from natural fen communities to fen meadows and later to over-drained, degraded meadows. Moderate drainage leads to increased vegetation productivity, and severe drainage results in frequent soil disturbances and less plant growth. In the present article, we analyse changes in plant trait combinations in the vegetation and the soil seed bank as well as changes in the seed bank types along gradient of drainage intensity. We hypothesize that an increase in productivity enhances traits related to persistence and that frequent disturbance selects for regeneration traits. We use multivariate statistics to analyse data from three disturbance levels: undisturbed fen, slightly drained fen meadow and severely drained degraded meadow. We found that the abundance of plants regenerating from seeds and accumulating persistent seed banks was increasing with degradation level, while plants reproducing vegetatively were gradually eliminated along the same trajectory. Plants with strong resprouting abilities increased during degradation. We also found that shifts in trait combinations were similar in the aboveground vegetation and in soil seed banks. We found that the density of short-term persistent seeds in the soil is highest in fen meadows and the density of long-term persistent seeds is highest in degraded meadows. The increase in abundance of species with strong regeneration traits at the cost of species with persistence-related traits has negative consequences for the restoration prospects of severely degraded sites

Tumor Cell Phenotype Is Sustained by Selective MAPK Oxidation in Mitochondria

Mitochondria are major cellular sources of hydrogen peroxide (H2O2), the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H2O2 concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H2O2 due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs) orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H2O2 yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 µM H2O2 increased cell proliferation in ERK1/2-dependent manner whereas high 50 µM H2O2 arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei), the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs) facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H2O2 level. Like this, high H2O2 or directed mutation of redox-sensitive ERK2 Cys214 impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to increase H2O2 yield should disrupt synchronized MAPK oxidations and the regulation of cell cycle leading cells to remain in a proliferating phenotype