Montague's Paradox without Necessitation

Some such as Dean (2014) suggest that Montague's paradox requires the necessitation rule, and that the use of the rule in such a context is contentious. But here, I show that the paradox arises independently of the necessitation rule. A derivation of the paradox is given in modal system T without deploying necessitation; a necessitation-free derivation is also formulated in a significantly weaker system

Quantification of Interactions between Influenza Hemagglutinin and Host Cell Phosphoinositides by Super-Resolution Microscopy

The influenza viral membrane protein hemagglutinin (HA) forms dense nanoscale clusters on host cell plasma membranes (PM), but the mechanisms that direct HA clustering are not well understood. Previous studies have observed HA associated with actin rich regions of the PM, but there are no known direct interactions between HA and actin. Phosphatidylinositol 4,5-biphosphate (PIP2) is a signaling lipid in the PM which can regulate the actin cytoskeleton, and actin comets initiated by PIP2 are known to be exploited by HA to reach the PM of infected cells. PIP2 is also used by other viruses, such as HIV and Ebola, to form clusters of viral proteins on the PM. Using diffraction-limited and super-resolution FPALM methods, we observed that HA and PH domain, a protein marker for PIP2, are closely spatially related at the PM. Clusters of PIP2 are also significantly altered in both density and area in the presence of high levels of HA, while HA clusters are significantly altered in the presence of high levels of PIP2, suggestive of an interaction between the two. Although HA mutates rapidly, there are 3 cysteines and 1-2 basic residues in the cytoplasmic tail domain (CTD) which remain highly conserved among HA subtypes. These cysteines are known to undergo palmitoylation in the Golgi, a post-translational modification where hydrophobic palmitic acids are attached. Using HA mutants and super-resolution FPALM, we examined the role of both palmitoylation and charge on the clustering properties of HA and spatial association with PIP2. Mutation of the cysteines or basic residues causes significant reductions to cluster densities (relative to cell average), while mutation of the charges appears to modulate association with PIP2. The greatest changes were observed when both the cysteines and net charge of the HA CTD were changed, causing a maximal 22% ± 6% reduction in the radial distribution functions (RDF) of clusters and a maximal 30% ± 15% increase in associated PH domain RDF amplitude. Cluster properties, density, perimeter, and circularity were also significantly affected. Even though clusters were not eliminated through CTD mutations, these findings suggest that the CTD of HA does play a role in the clustering of HA and spatial association with PIP2

Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo

Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined1,2. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects3,4,5,6,7,8,9,10,11. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration12, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue

Modeling Presenilin-Dependent Familial Alzheimer's Disease: Emphasis on Presenilin Substrate-Mediated Signaling and Synaptic Function

Mutations in PSEN genes, which encode presenilin proteins, cause familial early-onset Alzheimer's disease (AD). Transgenic mouse models based on coexpression of familial AD-associated presenilin and amyloid precursor protein variants successfully mimic characteristic pathological features of AD, including plaque formation, synaptic dysfunction, and loss of memory. Presenilins function as the catalytic subunit of γ-secretase, the enzyme that catalyzes intramembraneous proteolysis of amyloid precursor protein to release β-amyloid peptides. Familial AD-associated mutations in presenilins alter the site of γ-secretase cleavage in a manner that increases the generation of longer and highly fibrillogenic β-amyloid peptides. In addition to amyloid precursor protein, γ-secretase catalyzes intramembrane proteolysis of many other substrates known to be important for synaptic function. This paper focuses on how various animal models have enabled us to elucidate the physiological importance of diverse γ-secretase substrates, including amyloid precursor protein and discusses their roles in the context of cellular signaling and synaptic function

Optimal design under uncertainty of a passive defense structure against snow avalanches: from a general Bayesian framework to a simple analytical model

For snow avalanches, passive defense structures are generally designed by considering high return period events. In this paper, taking inspiration from other natural hazards, an alternative method based on the maximization of the economic benefit of the defense structure is proposed. A general Bayesian framework is described first. Special attention is given to the problem of taking the poor local information into account in the decision-making process. Therefore, simplifying assumptions are made. The avalanche hazard is represented by a Peak Over Threshold (POT) model. The influence of the dam is quantified in terms of runout distance reduction with a simple relation derived from small-scale experiments using granular media. The costs corresponding to dam construction and the damage to the element at risk are roughly evaluated for each dam height-hazard value pair, with damage evaluation corresponding to the maximal expected loss. Both the classical and the Bayesian risk functions can then be computed analytically. The results are illustrated with a case study from the French avalanche database. A sensitivity analysis is performed and modelling assumptions are discussed in addition to possible further developments

Metasemantics: on the limits of semantic theory

METASEMANTICS is a wake-up call for semantic theory: It reveals that some semantic questions have no adequate answer. (This is meant to be the epistemic point that certain semantic questions cannot be settled--not a metaphysical point about whether there is a fact-of-the-matter.) METASEMANTICS thus checks our default optimism that any well-formed semantic question can be settled (at least in principle). Chapter One argues that relative to certain assumptions, a question like What does 'Pollux' denote? has no adequate answer. If an answer is to be non-circular, then any answer ultimately depends on an uninterpreted term--meaning that this term occurs absent an answer to what it denotes. This, I argue, makes the answer uninformative in certain crucial respects. The lesson here essentially vindicates Quine's thesis of ontological relativity (though not his behaviorism or semantic nihilism). Chapter Two and Three build on this pessimism in considering ontic-idioms, such as 'exist', 'actual', etc. If Chapter One entails there is no saying what an ontic-idiom's extension is, these chapters show there is no saying what their intension is. Any attempt, I claim, will be equivocal. As corollaries, I show that a univocal statement of Realism about x is impossible--as well as a criterion of ontological commitment. Chapter Four considers truth-conditional semantics, generally speaking. After elaborating Davidson's claim about the folly of defining truth, I counter-balance his pessimism by showing that an informative analysis of 'true' is still possible (though only for certain translational purposes). Finally, Chapter Five evaluates a pessimistic argument concerning mental content. I argue that under externalism, a priori knowledge of content is impossible, at least for knowing whether a concept is about H2O versus XYZ. But this limit on the a priori should be unsurprising; I argue, moreover, that for other purposes we indeed know a priori what we think

Segmentation of Loops from Coronal EUV Images

We present a procedure which extracts bright loop features from solar EUV images. In terms of image intensities, these features are elongated ridge-like intensity maxima. To discriminate the maxima, we need information about the spatial derivatives of the image intensity. Commonly, the derivative estimates are strongly affected by image noise. We therefore use a regularized estimation of the derivative which is then used to interpolate a discrete vector field of ridge points ``ridgels'' which are positioned on the ridge center and have the intrinsic orientation of the local ridge direction. A scheme is proposed to connect ridgels to smooth, spline-represented curves which fit the observed loops. Finally, a half-automated user interface allows one to merge or split, eliminate or select loop fits obtained form the above procedure. In this paper we apply our tool to one of the first EUV images observed by the SECCHI instrument onboard the recently launched STEREO spacecraft. We compare the extracted loops with projected field lines computed from almost-simultaneously-taken magnetograms measured by the SOHO/MDI Doppler imager. The field lines were calculated using a linear force-free field model. This comparison allows one to verify faint and spurious loop connections produced by our segmentation tool and it also helps to prove the quality of the magnetic-field model where well-identified loop structures comply with field-line projections. We also discuss further potential applications of our tool such as loop oscillations and stereoscopy.Comment: 13 pages, 9 figures, Solar Physics, online firs

Benthic foraminiferal responses to anthropogenic manipulation on a wild oyster reef

Benthic foraminifera are known to respond quickly to environmental changes. Biological indices are used in marine subtidal areas (Barras et al., 2014) to monitor impacted marine environments (Mojtahid et al., 2006, 2008). Such indices could be useful in transitional marine environments such as estuaries and mudflats where no accurate indices are available. To develop such to ols and to improve our knowledge on b enthic foraminifera in intertidal environments, we followed the spatial and temporal distribution of b enthic foraminifera in Bourgneuf Bay, a coastal bay with a large mudflat situated south of the Loire estuary on French west coast. At this location, wild oyster reefs are present. Partial release of organic and inorganic nutrients through oyster excretion enriches the nutrients flow leading to microphytobenthos bloom around the reef. To show this relation and to understand the relation between the different biological compartments,we analysed the foraminiferal composition of the sediment around the reef before and after ananthrop ogenic manipulation. In July 2014, the oysters of the reef were removed in order to assess their impact on microphytob enthos and meiofauna. In this study, we showed a strong impact of this anthrop ogenic manipulation on benthic foraminiferal densities and species composition. These results confirmed the strong and quick responses of benthic foraminifera from intertidal areas to environmental changes and showed that intertidal benthic foraminifera can be used as an index to monitor transitional marine environments

Consideration of pyloric stenosis as a cause of feeding dysfunction in children with cyanotic heart disease

Feeding difficulty has been reported at a higher incidence in infants with cyanotic heart disease and single ventricle physiology necessitating specialized feeding strategies. However, structural causes of feed intolerance in this subset of patients should not be ignored. This case series highlights three recent cases of pyloric stenosis in infants with left-sided obstructive lesions at our institution. In all three cases, the initial presumed diagnosis was feeding intolerance related to heart disease, and there was significant clinical improvement following identification and correction of pyloric stenosis