109 research outputs found
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
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. 185â130 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 (â€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 âOff-Onâ 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 âLeu3p-a-IRM â system constitutes a ligand-inducible regulatory ââoff-onâ â 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 ââOFF-ONâ â 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 âLeu3p-a-IRM â constitutes a simpler and safer system for inducible gene expression in biomedical applications
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