Knockout of PARG110 confers resistance to cGMP-induced toxicity in mammalian photoreceptors.

Hereditary retinal degeneration (RD) relates to a heterogeneous group of blinding human diseases in which the light sensitive neurons of the retina, the photoreceptors, die. RD is currently untreatable and the underlying cellular mechanisms remain poorly understood. However, the activity of the enzyme poly-ADP-ribose polymerase-1 (PARP1) and excessive generation of poly-ADP-ribose (PAR) polymers in photoreceptor nuclei have been shown to be causally involved in RD. The activity of PARP1 is to a large extent governed by its functional antagonist, poly-ADP-glycohydrolase (PARG), which thus also may have a role in RD. To investigate this, we analyzed PARG expression in the retina of wild-type (wt) mice and in the rd1 mouse model for human RD, and detected increased PARG protein in a subset of degenerating rd1 photoreceptors. Knockout (KO) animals lacking the 110 kDa nuclear PARG isoform were furthermore analyzed, and their retinal morphology and function were indistinguishable from wild-type animals. Organotypic wt retinal explants can be experimentally treated to induce rd1-like photoreceptor death, but PARG110 KO retinal explants were unexpectedly highly resistant to such treatment. The resistance was associated with decreased PAR accumulation and low PARP activity, indicating that PARG110 may positively regulate PARP1, an event that therefore is absent in PARG110 KO tissue. Our study demonstrates a causal involvement of PARG110 in the process of photoreceptor degeneration. Contrasting its anticipated role as a functional antagonist, absence of PARG110 correlated with low PARP activity, suggesting that PARG110 and PARP1 act in a positive feedback loop, which is especially active under pathologic conditions. This in turn highlights both PARG110 and PARP1 as potential targets for neuroprotective treatments for RD

Молитвенная практика в жизни студенческой молодежи Гомельского региона и Малопольского воеводства

Материалы XI Междунар. науч. конф. студентов, аспирантов и молодых ученых, Гомель, 17-18 мая 2018 г

Modal satisfiability via SMT solving

Modal logics extend classical propositional logic, and they are robustly decidable. Whereas most existing decision procedures for modal logics are based on tableau constructions, we propose a framework for obtaining decision procedures by adding instantiation rules to standard SAT and SMT solvers. Soundness, completeness, and termination of the procedures can be proved in a uniform and elementary way for the basic modal logic and some extensions.Fil: Areces, Carlos Eduardo. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Areces, Carlos Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Fontaine, Pascal. Université de Lorraine; Francia.Fil: Fontaine, Pascal. National Institute for Research in Digital Science and Technology; Francia.Fil: Merz, Stephan. Université de Lorraine; Francia.Fil: Merz, Stephan. National Institute for Research in Digital Science and Technology; Francia.Ciencias de la Computació

Decidable fragments of first-order temporal logics

Accepted versio

Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use

Trabajo presentado en el 42nd Annual MidWinter Meeting of the Association of Otorhinolaryngology, celebrado en Baltimore (Estados Unidos) del 9 al 13 de febrero de 2019.[Background]: Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials (Maura et al. 2016, Curr Opin Microbiol 33: 41-46; Tacconelli et al. 2018, Lancet Infect Dis 18: 318-327). Although aminoglycoside antibiotics (AGs) exhibit potent antimicrobial activity, their use has been largely restricted due to serious sideeffects, mainly nephrotoxicity and ototoxicity (Forge and Schacht 2000, Audiol Neurootol 5: 3-22; Huth et al. 2011, Int J Otolaryngol 2011: 937861). It is therefore of great importance to identify AGs of strong antibacterial activity that lack their most harmful side effects.[Methods]: A large number of AGs were tested against a series of multidrug-resistant clinical isolates of the ESKAPE panel; of these, five AGs showing strong antibacterial activity were selected to evaluate their ototoxicity. A stepwise approach was followed, aiming at setting up a protocol that could be used in future high-throughput screenings. In vitro tests were initially conducted by assessing the viability of two established otic cell lines following AG treatment, and subsequently on murine cochlear organotypic cultures, by analysing hair cell survival. In vivo work was then carried out on a guinea pig model, following local round window application of the AGs.[Results]: Commercial gentamicin mixture (GM), the GM congener gentamicin C1a (GM C1a), apramycin (Apra), paromomycin (Paro) and neomycin (Neo) were selected for ototoxicity testing. In vitro analyses confirmed GM and Neo as the most toxic of the tested AGs, and Apra and Paro as those with the lowest toxicity; interestingly, GM C1a appeared to be less toxic than GM. Regarding the in vivo work, a dose-dependent effect of AGs on outer hair cell (OHC) survival and compound action potentials (CAPs) showed that GM C1a and Apra were the least toxic. Strikingly, although no changes were observed in CAP thresholds and OHC survival following treatment with low concentrations of Neo, GM and Paro, the number of inner hair cell (IHC) synaptic ribbons and the CAP amplitudes were reduced. This indication of hidden hearing loss was not observed with GM C1a or Apra at such concentrations.[Conclusion]: These findings have: (a) validated our screening approach, approach that will now be used for high-throughput testing of newly isolated AG congeners, (b) revealed the IHCs as the inner ear’;s most vulnerable element to AG treatment, and (c) identified GM C1a and Apra as promising bases for the development of clinically useful antibiotics

Hilbert's epsilon as an Operator of Indefinite Committed Choice

Paul Bernays and David Hilbert carefully avoided overspecification of Hilbert's epsilon-operator and axiomatized only what was relevant for their proof-theoretic investigations. Semantically, this left the epsilon-operator underspecified. In the meanwhile, there have been several suggestions for semantics of the epsilon as a choice operator. After reviewing the literature on semantics of Hilbert's epsilon operator, we propose a new semantics with the following features: We avoid overspecification (such as right-uniqueness), but admit indefinite choice, committed choice, and classical logics. Moreover, our semantics for the epsilon supports proof search optimally and is natural in the sense that it does not only mirror some cases of referential interpretation of indefinite articles in natural language, but may also contribute to philosophy of language. Finally, we ask the question whether our epsilon within our free-variable framework can serve as a paradigm useful in the specification and computation of semantics of discourses in natural language.Comment: ii + 73 pages. arXiv admin note: substantial text overlap with arXiv:1104.244

Venerische Krankheiten: Redigirt von Prof. Neisser nd Dr. Schäffer in Breslau

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Stemness of the Organ of Corti Relates to the Epigenetic Status of Sox2 Enhancers

In the adult mammalian auditory epithelium, the organ of Corti, loss of sensory hair cells results in permanent hearing loss. The underlying cause for the lack of regenerative response is the depletion of otic progenitors in the cell pool of the sensory epithelium. Here, we show that an increase in the sequence-specific methylation of the otic Sox2 enhancers NOP1 and NOP2 is correlated with a reduced self-renewal potential in vivo and in vitro; additionally, the degree of methylation of NOP1 and NOP2 is correlated with the dedifferentiation potential of postmitotic supporting cells into otic stem cells. Thus, the stemness the organ of Corti is related to the epigenetic status of the otic Sox2 enhancers. These observations validate the continued exploration of treatment strategies for dedifferentiating or reprogramming of differentiated supporting cells into progenitors to regenerate the damaged organ of Corti

Distribution of glucocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase isoforms in the rat inner ear.

11β-hydroxysteroid dehydrogenase (11β-HSD) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone, and two isoforms of the enzyme (11β-HSD1 and 11β-HSD2) have been cloned and characterized. An immunohistochemical study was performed to determine the precise distribution of glucocorticoid receptors (GRs) and the isoforms of 11β-HSD in the rat (postnatal day 1, 4, 10, and adult). Immunoreactivity of GRs was detected in the stria vascularis (SV), the outer hair cells (OHCs), the inner hair cells (IHCs), the spiral ligament (SLig), the spiral limbus (SLib), the spiral ganglion cells (SGCs), Reissner\u27s membrane (RM), the cochlear nerve (CN), the vestibular hair cells (VHCs), the dark cells (DCs), and the vestibular nerve (VN) in the rats. Immunostaining of 11β-HSD1 was observed in almost all the tissues in the cochlea and the vestibule except SLig, SLib, SGCs, CN, VHCs, and VN during all developmental stages, whereas, immunoreactivity of 11β-HSD2 was not detected in any of the inner ear tissues. A polymerase chain reaction (PCR) study was also performed on GRs, 11β-HSD1, and 11β-HSD2 in the OC, SV and vestibule of the postnatal rats, and revealed that mRNAs were detected in all those and tissues in all the developmental days of postnatal days 1, 4, and 10. This data indicates that expression of GRs and 11β-HSD isoforms in the inner ear is tissue and age-specific, and that different local steroid regulation by GRs and the isoforms of 11β-HSD is present in each part of the inner ear