Singly generated quasivarieties and residuated structures

A quasivariety K of algebras has the joint embedding property (JEP) iff it is generated by a single algebra A. It is structurally complete iff the free countably generated algebra in K can serve as A. A consequence of this demand, called "passive structural completeness" (PSC), is that the nontrivial members of K all satisfy the same existential positive sentences. We prove that if K is PSC then it still has the JEP, and if it has the JEP and its nontrivial members lack trivial subalgebras, then its relatively simple members all belong to the universal class generated by one of them. Under these conditions, if K is relatively semisimple then it is generated by one K-simple algebra. It is a minimal quasivariety if, moreover, it is PSC but fails to unify some finite set of equations. We also prove that a quasivariety of finite type, with a finite nontrivial member, is PSC iff its nontrivial members have a common retract. The theory is then applied to the variety of De Morgan monoids, where we isolate the sub(quasi)varieties that are PSC and those that have the JEP, while throwing fresh light on those that are structurally complete. The results illuminate the extension lattices of intuitionistic and relevance logics

Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases

On Algorithms Related to Expressibility of Functions of Diagonalizable Algebras

Access full text: https://doi.org/10.1007/978-3-030-61334-1_13It is well known the connection of diagonalizable algebras with propositional provability logics. The notion of expressibility of functions and related algorithmic problems is very well studied in the case of boolean functions. We propose and analyse algorithms for detecting functional expressibility of functions of a 4-valued diagonalizable algebra and examine other problems connected to iterative algebras based on diagonalizable algebras

Persistent millennial-scale climate variability in Southern Europe during Marine Isotope Stage 6

Exploring the mode and tempo of millennial-scale climate variability under evolving boundary conditions can provide insights into tipping points in different parts of the Earth system, and can facilitate a more detailed understanding of climate teleconnections and phase relationships between different Earth system components. Here we use fossil diatom and stable carbon and oxygen isotope analysis of lake sediment deposits (core I-284) from the Ioannina basin, NW Greece, to explore in further detail millennial-scale climate instability in southern Europe during Marine Isotope Stage 6 (MIS 6; ca. 185‒130 ka). This interval correlates with the Vlasian Stage in Greece and the Late Saalian Substage in northern Europe, which were both characterised by extensive glaciations. The new dataset resolves at least 18 discrete warmer/wetter intervals, many of which were associated with strong Asian Monsoon events and North Atlantic interstadials. A number of cooler/drier intervals are also identified in the I-284 record, which are typically associated with weaker Asian Monsoon events and North Atlantic stadials, consistent with a variable Atlantic Meridional Overturning Circulation. Unlike the subdued changes in tree populations that are observed at Ioannina during mid-to-late MIS 6, the diatom record contains frequent high-amplitude oscillations in species assemblages, pointing to its sensitivity at a time when the lake system must have been close to environmental thresholds. Millennial-scale variability in diatom species assemblages continues into late MIS 6 at Ioannina, contributing important evidence for an emerging picture of frequent and persistent climate instability even at times of high global ice volume

Cardiovascular effects of sub-daily levels of ambient fine particles: a systematic review

<p>Abstract</p> <p>Background</p> <p>While the effects of daily fine particulate exposure (PM) have been well reviewed, the epidemiological and physiological evidence of cardiovascular effects associated to sub-daily exposures has not. We performed a theoretical model-driven systematic non-meta-analytical literature review to document the association between PM sub-daily exposures (≤6 hours) and arrhythmia, ischemia and myocardial infarction (MI) as well as the likely mechanisms by which sub-daily PM exposures might induce these acute cardiovascular effects. This review was motivated by the assessment of the risk of exposure to elevated sub-daily levels of PM during fireworks displays.</p> <p>Methods</p> <p>Medline and Elsevier's EMBase were consulted for the years 1996-2008. Search keywords covered potential cardiovascular effects, the pollutant of interest and the short duration of the exposure. Only epidemiological and experimental studies of adult humans (age > 18 yrs) published in English were reviewed. Information on design, population and PM exposure characteristics, and presence of an association with selected cardiovascular effects or physiological assessments was extracted from retrieved articles.</p> <p>Results</p> <p>Of 231 articles identified, 49 were reviewed. Of these, 17 addressed the relationship between sub-daily exposures to PM and cardiovascular effects: five assessed ST-segment depression indicating ischemia, eight assessed arrhythmia or fibrillation and five considered MI. Epidemiologic studies suggest that exposure to sub-daily levels of PM is associated with MI and ischemic events in the elderly. Epidemiological studies of sub-daily exposures suggest a plausible biological mechanism involving the autonomic nervous system while experimental studies suggest that vasomotor dysfunction may also relate to the occurrence of MI and ischemic events.</p> <p>Conclusions</p> <p>Future studies should clarify associations between cardiovascular effects of sub-daily PM exposure with PM size fraction and concurrent gaseous pollutant exposures. Experimental studies appear more promising for elucidating the physiological mechanisms, time courses and causes than epidemiological studies which employ central pollution monitors for measuring effects and for assessing their time course. Although further studies are needed to strengthen the evidence, given that exposure to sub-daily high levels of PM (for a few hours) is frequent and given the suggestive evidence that sub-daily PM exposures are associated with the occurrence of cardiovascular effects, we recommend that persons with cardiovascular diseases avoid such situations.</p

Development of a Chromosomally Integrated Metabolite-Inducible Leu3p-α-IPM “Off-On” Gene Switch

Background: Present technology uses mostly chimeric proteins as regulators and hormones or antibiotics as signals to induce spatial and temporal gene expression. Methodology/Principal Findings: Here, we show that a chromosomally integrated yeast ‘Leu3p-a-IRM ’ system constitutes a ligand-inducible regulatory ‘‘off-on’ ’ genetic switch with an extensively dynamic action area. We find that Leu3p acts as an active transcriptional repressor in the absence and as an activator in the presence of a-isopropylmalate (a-IRM) in primary fibroblasts isolated from double transgenic mouse embryos bearing ubiquitously expressing Leu3p and a Leu3p regulated GFP reporter. In the absence of the branched amino acid biosynthetic pathway in animals, metabolically stable a-IPM presents an EC 50 equal to 0.8837 mM and fast ‘‘OFF-ON’ ’ kinetics (t 50ON = 43 min, t 50OFF = 2.18 h), it enters the cells via passive diffusion, while it is non-toxic to mammalian cells and to fertilized mouse eggs cultured ex vivo. Conclusions/Significance: Our results demonstrate that the ‘Leu3p-a-IRM ’ constitutes a simpler and safer system for inducible gene expression in biomedical applications

Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study

Abstract Background Immune monitoring by flow cytometry is a fast and highly informative way of studying the effects of novel therapeutics aimed at reducing transplant rejection or treating autoimmune diseases. The ONE Study consortium has recently initiated a series of clinical trials aimed at using different cell therapies to promote tolerance to renal allografts. To compare the effectiveness of different cell therapies, the consortium developed a robust immune monitoring strategy, including procedures for whole blood (WB) leukocyte subset profiling by flow cytometry. Methods Six leukocyte profiling panels computing 7- to 9-surface marker antigens for monitoring the major leukocyte subsets as well as characteristics of T cell, B cell, and dendritic cell (DC) subsets were designed. The precision and variability of these panels were estimated. The assay was standardized within eight international laboratories using Flow-Set Pro beads for mean fluorescence intensity target definition and the flow cytometer setup procedure. Standardization was demonstrated by performing inter-site comparisons. Results Optimized methods for sample collection, storage, preparation, and analysis were established, including protocols for gating target subsets. WB specimen age testing demonstrated that staining must be performed within 4 hours of sample collection to keep variability low, meaning less than or equal to 10% for the majority of defined leukocyte subsets. Inter-site comparisons between all participating centers testing shipped normal WB revealed good precision, with a variability of 0.05% to 30% between sites. Intra-assay analyses revealed a variability of 0.05% to 20% for the majority of subpopulations. This was dependent on the frequency of the particular subset, with smaller subsets showing higher variability. The intra-assay variability performance defined limits of quantitation (LoQ) for subsets, which will be the basis for assessing statistically significant differences achieved by the different cell therapies. Conclusions Local performance and central analysis of the ONE Study flow cytometry panel yields acceptable variability in a standardized assay at multiple international sites. These panels and procedures with WB allow unmanipulated analysis of changes in absolute cell numbers of leukocyte subsets in single- or multicenter clinical trials. Accordingly, we propose the ONE Study panel may be adopted as a standardized method for monitoring patients in clinical trials enrolling transplant patients, particularly trials of novel tolerance promoting therapies, to facilitate fair and meaningful comparisons between trials. </jats:sec