Introduction:The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome-wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2-73), a selective sigma-1 receptor (SIGMAR1) agonist, was studied in a 57-week Phase 2a trial (NCT02244541).The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint. Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS-ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS-ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.

We start from the geometrical-logical extension of Aristotle's square in [6,15] and [14], and study them from both syntactic and semantic points of view. Recall that Aristotle's square under its modal form has the following four vertices: A is α, E is ¬α, I is ¬ ¬α and O is ¬ α, where α is a logical formula and is a modality which can be defined axiomatically within a particular logic known as S5 (classical or intuitionistic, depending on whether ¬ is involutive or not) modal logic.[3] has proposed extensions which can be interpreted respectively within paraconsistent and paracomplete logical frameworks.[15] has shown that these extensions are subfigures of a tetraicosahedron whose vertices are actually obtained by closure of {α, α} by the logical operations {¬, ∧, ∨}, under the assumption of classical S5 modal logic. We pursue these researches on the geometrical-logical extensions of Aristotle's square: first we list all modal squares of opposition. We show that if the vertices of that geometrical figure are logical formulae and if the sub-alternation edges are interpreted as logical implication relations, then the underlying logic is none other than classical logic. Then we consider a higher-order extension introduced by [14], and we show that the same tetraicosahedron plays a key role when additional modal operators are introduced. Finally we discuss the relation between the logic underlying these extensions and the resulting geometrical-logical figures.

Protein sequence alignments can be improved when at least one of the proteins to be aligned has a known 3-D structure. In this work, geometrical constraints extracted from the target fold are evaluated in independent units that deal with complementary structural features. This information is used to set up mutation tables specific to the locally observed structural environments. The resulting partial evaluations are then combined linearly into a global function which is optimized by dynamic programming. Eventually, a score based on tertiary interactions can be used as a selection criterion to discriminate among a set of suboptimal alignments. The relevance of the scores given by each unit is tested on a representative set of protein families. Finally, a method for combining the different scores is described and its efficiency is evaluated on a few pairs of weakly homologous proteins.

Based on concrete examples gathered from the Mediterranean region, this article shows why restoration ecology around the Mediterranean Basin must go beyond ecological science to embrace a contrasting local vision which integrates social and political realities. By taking into account the growing gap between the northern and southern/eastern shores of the Mediterranean, we propose the adoption of a double agenda for restoration around the Mediterranean to overcome the fact that restoration objectives are often jeopardized by political decisions initially aimed to promote conservation and lack of available technical means (even when appropriate scientific and political means are secured), and to enhance local actions with lasting impacts on the ecosystems. Our discussion illustrates how current ecological problems have become extremely complex and how the success of restoration projects depends on effective social interactions. Here, the simple juxtaposition of disciplines is no longer sufficient. We suggest going beyond existing ecological and socioeconomic frontiers to fill three main gaps. To fill the "design gap" it is important from the outset to promote a full debate for correct definition of the project's objectives and success indicators. Second, to fill the "implementation gap" ecological restoration science should be linked to information technology and cognition science to develop tools adapted for ecological debate. Third, to fill the "evaluation gap" aesthetic, social, cultural, and economic indicators should be defined during the debate process.