PDL on Steroids: on Expressive Extensions of PDL with Intersection and Converse

International audienceWe introduce CPDL+, a family of expressive logics rooted in Propositional Dynamic Logic (PDL). In terms of expressive power, CPDL+ strictly contains PDL extended with intersection and converse (a.k.a. ICPDL) as well as Conjunctive Queries (CQ), Conjunctive Regular Path Queries (CRPQ), or some known extensions thereof (Regular Queries and CQPDL). We investigate the expressive power, characterization of bisimulation, satisfiability, and model checking for CPDL+.We argue that natural subclasses of CPDL+ can be defined in terms of the tree-width of the underlying graphs of the formulas. We show that the class of CPDL+ formulas of tree-width 2 is equivalent to ICPDL, and that it also coincides with CPDL+ formulas of tree-width 1. However, beyond tree-width 2, incrementing the tree-width strictly increases the expressive power. We characterize the expressive power for every class of fixed tree-width formulas in terms of a bisimulation game with pebbles. Based on this characterization, we show that CPDL+ has a tree-like model property. We prove that the satisfiability problem is decidable in 2ExpTime on fixed tree-width formulas, coinciding with the complexity of ICPDL. We also exhibit classes for which satisfiability is reduced to ExpTime. Finally, we establish that the model checking problem for fixed tree-width formulas is in \ptime, contrary to the full class CPDL+

“Stem Cell Pathway” gene expression in human foetallimbus and cadaveric human limbal epithelium

Stem cells play a vital role in the turn over of permanently self-renewing tissues (e.g. corneal epithelium, epidermis, bone marrow). Stratified cornea epithelia serve, as ideal tissue models for studying ‘stemness’, as the site of cells in the different stages of differentiation are anatomically easily identifiable. Studies targeting limbal stem cell maintenance, in-vitro gene expression during storageand differentiation will benefit future therapeutic applications (e.g. cornealtransplantation). Knowledge of stem cell behaviour will help explain thepathophysiology of corneal related ocular surface disorders (e.g. idiopathiclimbal stem cell deficiency, pterygium and limbal dermoids), establish newtreatment modalities (e.g. allogenic cellular transplants) and help promote invivoexpansion of residual stem cell populations in deficiency states. The majorobstacle in the progress of research on limbal stem cells is the lack ofknowledge of phenotypic markers of limbal epithelial stem cells.This project first studied the limbal expression of phenotypic markers that werediscovered in other human adult and embryonic stem cell populations usingmicroarray differential expression studies. Gene expression profiles of therelatively primitive human foetal limbus were compared with that of the centralcornea. Microarray was also performed to identify the differential geneexpression profile of cultured primary human limbal epithelial cells, whencompared to the limbal epithelial cell population isolated after 5 serial cultures.33 genes were upregulated in the human foetal limbus and primary culturedhuman limbal epithelium, when compared respectively to the central foetalcornea (first experiment) and the limbal epithelial cell population after the 5thtrypsin passaged culture (second experiment). Four foetal limbal and primarylimbal epithelial upregulated genes (CK15, CK14, Cdh3, and Wnt4) wereconfirmed to be upregulated by semi quantitative RT-PCR andimmunohistochemical experiments on the human foetal cornea, adult humancadaveric cornea and cultured human limbal epithelial cells. The microarraydefined phenotypic profile of both the foetal limbus and cultured adult limbalepithelial cells will help identify these cells in in-vitro and in-vivo states. Theexpression of these 4 selected markers in the limbal dermoid and pterygiumsuggests that limbal epithelial cells containing a stem cell population areinvolved in the pathogenesis of these two disorders

Natural history of primary paediatric optic nerve sheath meningioma: case series and review

PURPOSE: To study the natural history, clinical and radiological characteristics of primary paediatric optic nerve sheath meningioma (PPONSM). METHODS: Retrospective study of eight paediatric patients who were treated between 1994 and 2016 at the University Hospital Zurich, Switzerland and the Royal Adelaide Hospital, Australia. Clinical records and imaging studies were reviewed. RESULTS: The mean age at presentation was 11 years (range: 6-17 years). There were six female patients and two male patients. 2/8 patients had associated neurofibromatosis type 2.Patients were followed up for 71-297 months (mean 156±70 months). 6/8 patients were observed through the course of their disease and 2/8 patients were treated with radiotherapy. 2/8 patients who were observed had minimal change in vision and did not experience tumour growth after long-term follow-up. CONCLUSIONS: This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone

Pathological Interactions Between Mutant Thyroid Hormone Receptors and Corepressors and Their Modulation by a Thyroid Hormone Analogue with Therapeutic Potential

International audienceBACKGROUND:Thyroid hormone receptors (TRs) are tightly regulated by the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors. Three conserved corepressor/NR signature box motifs (CoRNR1-3) forming the nuclear receptor interaction domain have been identified in these corepressors. Whereas TRs regulate multiple normal physiological and developmental pathways, mutations in TRs can result in endocrine diseases and be associated with cancers due to impairment of corepressor release. Three mutants that are located in helix H11 of TRs are of special interest: TRα-M388I, a mutant associated with the development of renal clear cell carcinomas (RCCCs), and TRβ-Δ430 and TRβ-Δ432, two deletion mutants causing resistance to thyroid hormone syndrome.METHODS:Several cell-based and biophysical methods were used to measure the affinity between wild-type and mutant TRα and TRβ and all the CoRNR motifs from corepressors to quantify the effects of different thyroid hormone analogues on these interactions. This study was coupled with the measurement of interactions between wild-type and mutant TRs in the context of a heterodimer with RXR to a NCoR fragment in the presence of the same ligands. Structural insights into the binding mode of corepressors to TRs were assessed in parallel by nuclear magnetic resonance spectroscopy.RESULTS:The study shows that TRs interact more avidly with the silencing mediator of retinoic acid and thyroid hormone receptors than with NCoR peptides, and that TRα binds most avidly to S-CoRNR3, whereas TRβ binds preferentially to S-CoRNR2. In the studied TR mutants, a transfer of the CoRNR-specificity toward CoRNR1 was observed, coupled with a significant increase in the binding strength. In contrast to 3,5,3'-triiodothyronine (T3), the agonist TRIAC and the antagonist NH-3 were very efficient at dissociating the abnormally strong interactions between mutant TRβs and corepressors. A strong impairment of T3-binding for TRβ mutants was shown compared to TRIAC and NH-3 and could explain the different efficiencies of the different ligands in releasing corepressors from the studied TRβ mutants. Consequently, TRIAC was found to be more effective than T3 in facilitating coactivator recruitment and decreasing the dominant activity of TRβ-Δ430.CONCLUSION:This study helps to clarify the specific interaction surfaces involved in the pathologic phenotype of TR mutants and demonstrates that TRIAC is a potential therapeutic agent for patients suffering from resistance to thyroid hormone syndromes