Stem cells as a therapeutic tool for the blind: biology and future prospects

Retinal degeneration due to genetic, diabetic and age-related disease is the most common cause of blindness in the developed world. Blindness occurs through the loss of the light-sensing photoreceptors; to restore vision, it would be necessary to introduce alternative photosensitive components into the eye. The recent development of an electronic prosthesis placed beneath the severely diseased retina has shown that subretinal stimulation may restore some visual function in blind patients. This proves that residual retinal circuits can be reawakened after photoreceptor loss and defines a goal for stem-cell-based therapy to replace photoreceptors. Advances in reprogramming adult cells have shown how it may be possible to generate autologous stem cells for transplantation without the need for an embryo donor. The recent success in culturing a whole optic cup in vitro has shown how large numbers of photoreceptors might be generated from embryonic stem cells. Taken together, these threads of discovery provide the basis for optimism for the development of a stem-cell-based strategy for the treatment of retinal blindness

Automated Synthesis of Tableau Calculi

This paper presents a method for synthesising sound and complete tableau calculi. Given a specification of the formal semantics of a logic, the method generates a set of tableau inference rules that can then be used to reason within the logic. The method guarantees that the generated rules form a calculus which is sound and constructively complete. If the logic can be shown to admit finite filtration with respect to a well-defined first-order semantics then adding a general blocking mechanism provides a terminating tableau calculus. The process of generating tableau rules can be completely automated and produces, together with the blocking mechanism, an automated procedure for generating tableau decision procedures. For illustration we show the workability of the approach for a description logic with transitive roles and propositional intuitionistic logic.Comment: 32 page

One Health Approach: An Overview of Q Fever in Livestock, Wildlife and Humans in Asturias (Northwestern Spain)

This study aimed to investigate the seroprevalence of C. burnetii in domestic ruminants, wild ungulates, as well as the current situation of Q fever in humans in a small region in northwestern Spain where a close contact at the wildlife–livestock–human interface exists, and information on C. burnetii infection is scarce. Seroprevalence of C. burnetii was 8.4% in sheep, 18.4% in cattle, and 24.4% in goats. Real-time PCR analysis of environmental samples collected in 25 livestock farms detected Coxiella DNA in dust and/or aerosols collected in 20 of them. Analysis of sera from 327 wild ungulates revealed lower seroprevalence than that found in domestic ruminants, with 8.4% of Iberian red deer, 7.3% chamois, 6.9% fallow deer, 5.5% European wild boar and 3.5% of roe deer harboring antibodies to C. burnetii. Exposure to the pathogen in humans was determined by IFAT analysis of 1312 blood samples collected from patients admitted at healthcare centers with Q fever compatible symptoms, such as fever and/or pneumonia. Results showed that 15.9% of the patients had IFAT titers ≥ 1/128 suggestive of probable acute infection. This study is an example of a One Health approach with medical and veterinary institutions involved in investigating zoonotic diseasesThis work was funded by INIA—Spanish National Institute for Agricultural and Food Research and Technology (RTA2017-00055-C02-02), the European Regional Development Funds (ERDF), and PCTI 2018–2020 (GRUPIN: IDI2018-000237)S

A modal theorem-preserving translation of a class of three-valued logics of incomplete information

International audienceThere are several three-valued logical systems that form a scattered landscape, even if all reasonable connectives in three-valued logics can be derived from a few of them. Most papers on this subject neglect the issue of the relevance of such logics in relation with the intended meaning of the third truth-value. Here, we focus on the case where the third truth-value means unknown, as suggested by Kleene. Under such an understanding, we show that any truth-qualified formula in a large range of three-valued logics can be translated into KD as a modal formula of depth 1, with modalities in front of literals only, while preserving all tautologies and inference rules of the original three-valued logic. This simple information logic is a two-tiered classical propositional logic with simple semantics in terms of epistemic states understood as subsets of classical interpretations. We study in particular the translations of Kleene, Gödel, ᴌukasiewicz and Nelson logics. We show that Priest’s logic of paradox, closely connected to Kleene’s, can also be translated into our modal setting, simply by exchanging the modalities possible and necessary. Our work enables the precise expressive power of three-valued logics to be laid bare for the purpose of uncertainty management

Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages

Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain preexposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in futur

Novel CTCF binding at a site in exon1A of BCL6 is associated with active histone marks and a transcriptionally active locus

BCL6 is a zinc-finger transcriptional repressor, which is highly expressed in germinal centre B-cells and is essential for germinal centre formation and T-dependent antibody responses. Constitutive BCL6 expression is sufficient to produce lymphomas in mice. Deregulated expression of BCL6 due to chromosomal rearrangements, mutations of a negative autoregulatory site in the BCL6 promoter region and aberrant post-translational modifications have been detected in a number of human lymphomas. Tight lineage and temporal regulation of BCL6 is, therefore, required for normal immunity, and abnormal regulation occurs in lymphomas. CCCTC-binding factor (CTCF) is a multi-functional chromatin regulator, which has recently been shown to bind in a methylation-sensitive manner to sites within the BCL6 first intron. We demonstrate a novel CTCF-binding site in BCL6 exon1A within a potential CpG island, which is unmethylated both in cell lines and in primary lymphoma samples. CTCF binding, which was found in BCL6-expressing cell lines, correlated with the presence of histone variant H2A.Z and active histone marks, suggesting that CTCF induces chromatin modification at a transcriptionally active BCL6 locus. CTCF binding to exon1A was required to maintain BCL6 expression in germinal centre cells by avoiding BCL6-negative autoregulation. Silencing of CTCF in BCL6-expressing cells reduced BCL6 mRNA and protein expression, which is sufficient to induce B-cell terminal differentiation toward plasma cells. Moreover, lack of CTCF binding to exon1A shifts the BCL6 local chromatin from an active to a repressive state. This work demonstrates that, in contexts in which BCL6 is expressed, CTCF binding to BCL6 exon1A associates with epigenetic modifications indicative of transcriptionally open chromatin

Logics of knowledge and action: critical analysis and challenges

International audienceWe overview the most prominent logics of knowledge and action that were proposed and studied in the multiagent systems literature. We classify them according to these two dimensions, knowledge and action, and moreover introduce a distinction between individual knowledge and group knowledge, and between a nonstrategic an a strategic interpretation of action operators. For each of the logics in our classification we highlight problematic properties. They indicate weaknesses in the design of these logics and call into question their suitability to represent knowledge and reason about it. This leads to a list of research challenges