Asynchronous Games over Tree Architectures

We consider the task of controlling in a distributed way a Zielonka asynchronous automaton. Every process of a controller has access to its causal past to determine the next set of actions it proposes to play. An action can be played only if every process controlling this action proposes to play it. We consider reachability objectives: every process should reach its set of final states. We show that this control problem is decidable for tree architectures, where every process can communicate with its parent, its children, and with the environment. The complexity of our algorithm is l-fold exponential with l being the height of the tree representing the architecture. We show that this is unavoidable by showing that even for three processes the problem is EXPTIME-complete, and that it is non-elementary in general

DNA polymerase B deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts

Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12 - p11 and encodes a key DNA base excision repair protein. Pol β may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol β in breast cancer. We investigated pol β gene copy number changes in two cohorts (n=128 & n=1952), pol β mRNA expression in two cohorts (n=249 & n=1952) and pol β protein expression in two cohorts (n=1406 & n=252). Artificial neural network analysis for pol β interacting genes was performed in 249 tumours. For mechanistic insights, pol β gene copy number changes, mRNA and protein levels were investigated together in 1 28 tumours and validated in 1952 tumours. Low pol β mRNA expression as well as low pol β protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal - like phenotypes and poor survival (ps<0.001). In oestrogen receptor (ER) positive sub - group that received tamoxifen, low pol β protein remains associated with aggressive phenotype and poor survival (ps<0.001). Artificial neural network analysis revealed ER as a top pol β interacting gene. Mechanistically, there was strong positive correlation between pol β gene copy number changes and pol β mRNA expression (p<0.0000001) and between pol β mRNA and pol β protein expression (p<0.0000001). This is the first study to provide evidence that pol β deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients

Clinical profile of anemia among 6–60-month children living in South Karnataka – A cross sectional study

Introduction: Anemia is a worldwide public health problem and has a variable impact on the physical development of child. This study aims to assess the epidemiological characteristics and clinical profile of anemia among 6–60 month children living in South Karnataka. Methods: This was a cross-sectional, community-based study conducted in Bengaluru, from 2012 to 2014. Participants were weighed and measured, and their blood was taken. Demographic, morbidity, and feeding data were obtained from mothers. All the collected data were tabulated and stastically analyzed. Results: Prevalence of anemia in children is 77.8%. Seventy-five children (90%) with anemia belonged to lower socioeconomic status. The chief presenting symptoms in the present study were easy fatigability (34%), loss of appetite (36%), pallor (26), and irritability (24%). The chief clinical signs in anemic children were pallor of mucosa (76%), pallor of skin, palms, and soles (64%), tachycardia (23%), cheilitis (13%), and hemic murmur (9%). Conclusions: Most of the children suffering from anemia were from lower socioeconomic status. Diarrhea was the chief associated symptom in more than half of the cases studied. Hence, the proper periodic deworming measure is advised. Furthermore, timely giving of weaning food, reducing infection by proper immunization, and good personal hygiene will help to prevent anemia

Propositional Dynamic Logic with Converse and Repeat for Message-Passing Systems

The model checking problem for propositional dynamic logic (PDL) over message sequence charts (MSCs) and communicating finite state machines (CFMs) asks, given a channel bound $B$, a PDL formula $\varphi$ and a CFM $\mathcal{C}$, whether every existentially $B$-bounded MSC $M$ accepted by $\mathcal{C}$ satisfies $\varphi$. Recently, it was shown that this problem is PSPACE-complete. In the present work, we consider CRPDL over MSCs which is PDL equipped with the operators converse and repeat. The former enables one to walk back and forth within an MSC using a single path expression whereas the latter allows to express that a path expression can be repeated infinitely often. To solve the model checking problem for this logic, we define message sequence chart automata (MSCAs) which are multi-way alternating parity automata walking on MSCs. By exploiting a new concept called concatenation states, we are able to inductively construct, for every CRPDL formula $\varphi$, an MSCA precisely accepting the set of models of $\varphi$. As a result, we obtain that the model checking problem for CRPDL and CFMs is still in PSPACE

Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer

Background: ATR-Chk1 signalling network is critical for genomic stability. ATR-Chk1 may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. Patients and methods: We investigated ATR and phosphorylated CHK1Ser345 protein (pChk1) expression in 1712 breast cancers (Nottingham Tenovus series). ATR and Chk1 mRNA were evaluated in 1950 breast cancers (METABRIC cohort). Pre-clinically, biological consequences of ATR gene knockdown or ATR inhibition by small molecule inhibitor (VE-821) were investigated in MCF-7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). Results: High ATR and high cytoplasmic pChk1 expression was significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analysis, high ATR and high cytoplasmic pChk1 protein expression was associated with shorter breast cancer specific survival (BCSS). In multivariate analysis, high ATR remains an independent predictor of adverse outcome. At the mRNA level, high Chk1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple-negative phenotype and molecular classes associated with aggressive behaviour and shorter survival.. Pre-clinically, Chk1 phosphorylation at serine 345 following replication stress (induced by gemcitabine or hydroxyurea treatment) was impaired in ATR knockdown and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but had no effect on non-tumorigenic breast epithelial cells (MCF10A). Conclusions: We provides evidence that ATR and Chk1 are promising biomarkers and rational drug target for personalized therapy in breast cancer

Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy

BRCA1, a key factor in homologous recombination repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n=1602 sporadic and n=50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n=1952 and n=249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p<0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps<0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy

Extending Compositional Message Sequence Graphs

We extend the formal developments for message sequence charts (MSCs) to support scenarios with lost and found messages. We define a notion of extended compositional message sequence charts (ECMSCs) which subsumes the notion of compositional message sequence charts in expressive power but additionally allows to define lost and found messages explicitly. As usual, ECMSCs might be combined by means of choice and repetition towards (extended) compositional message sequence graphs. We show that - despite extended expressive power - model checking of monadic second-order logic (MSO) for this framework remains to be decidable. The key technique to achieve our results is to use an extended notion for linearizations

Distributed Synthesis in Continuous Time

We introduce a formalism modelling communication of distributed agents strictly in continuous-time. Within this framework, we study the problem of synthesising local strategies for individual agents such that a specified set of goal states is reached, or reached with at least a given probability. The flow of time is modelled explicitly based on continuous-time randomness, with two natural implications: First, the non-determinism stemming from interleaving disappears. Second, when we restrict to a subclass of non-urgent models, the quantitative value problem for two players can be solved in EXPTIME. Indeed, the explicit continuous time enables players to communicate their states by delaying synchronisation (which is unrestricted for non-urgent models). In general, the problems are undecidable already for two players in the quantitative case and three players in the qualitative case. The qualitative undecidability is shown by a reduction to decentralized POMDPs for which we provide the strongest (and rather surprising) undecidability result so far

Preparation and pharmacokinetic studies of mucoadhesive oral multiple unit systems of metronidazole

The objective of the present study was to investigate the applicability of matrix type chitosan treated alginate multiple unit systems (MUS) for sustained release of metronidazole prepared by ionotropic gelation method. Spherical MUS with 0.64 ± 0.95 to 0.75 ± 0.38 mm length and 0.63 ± 0.34 to 0.74 ± 0.28 mm breadth and 71.60 ± 0.42 to 82.15 ± 0.35 % entrapment efficiency were produced. The fluoroscopic study reveals that the MUS was retained in gastrointestinal tract (GIT) for more than 5 h and found to be distributed throughout the GIT. The in vivo evaluation in healthy human volunteers of the MUS and that of Flagyl® IR tablets each containing 400 mg drug revealed that the MUS showed improved pharmacokinetic parameters to Flagyl® producing a significantly different (p < 0.05) AUC. This study demonstrates that the MUS could be a good alternative to immediate release tablets to deliver metronidazole and expected to be less irritant to gastric and intestinal mucosa.Colegio de Farmacéuticos de la Provincia de Buenos Aire

FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

\ua9 2021 by the authors. Licensee MDPI, Basel, Switzerland.FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemother-apy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy