On an alleged truth/falsity asymmetry in context shifting experiments

Keith DeRose has argued that context shifting experiments should be designed in a specific way in order to accommodate what he calls a ‘truth/falsity asymmetry’. I explain and critique DeRose's reasons for proposing this modification to contextualist methodology, drawing on recent experimental studies of DeRose's bank cases as well as experimental findings about the verification of affirmative and negative statements. While DeRose's arguments for his particular modification to contextualist methodology fail, the lesson of his proposal is that there is good reason to pay close attention to several subtle aspects of the design of context shifting experiments.

J. L. Austin and literal meaning

Alice Crary has recently developed a radical reading of J. L. Austin's philosophy of language. The central contention of Crary's reading is that Austin gives convincing reasons to reject the idea that sentences have context-invariant literal meaning. While I am in sympathy with Crary about the continuing importance of Austin's work, and I think Crary's reading is deep and interesting, I do not think literal sentence meaning is one of Austin's targets, and the arguments that Crary attributes to Austin or finds Austinian in spirit do not provide convincing reasons to reject literal sentence meaning. In this paper, I challenge Crary's reading of Austin and defend the idea of literal sentence meaning.

Experimenting on contextualism

In this article we refine the design of context shifting experiments, which play a central role in contextualist debates, and we subject a large number of scenarios involving different types of expressions of interest to contextualists, including ‘know’ and color adjectives like ‘green’, to experimental investigation. Our experiment (i) reveals an effect of changing contexts on the evaluation of uses of the sentences that we examine, thereby overturning the absence of results reported in previous experimental studies (so-called null results), (ii) uncovers evidence for a ‘truth bias' in favor of positive over negative sentences, and (iii) reveals previously unnoticed distinctions between the strength of the contextual effects displayed by scenarios involving knowledge ascriptions and scenarios concerning color and other miscellaneous scenarios.

The multisensory attentional consequences of tool use: a functional magnetic resonance imaging study

Background: Tool use in humans requires that multisensory information is integrated across different locations, from objects seen to be distant from the hand, but felt indirectly at the hand via the tool. We tested the hypothesis that using a simple tool to perceive vibrotactile stimuli results in the enhanced processing of visual stimuli presented at the distal, functional part of the tool. Such a finding would be consistent with a shift of spatial attention to the location where the tool is used. Methodology/Principal Findings: We tested this hypothesis by scanning healthy human participants' brains using functional magnetic resonance imaging, while they used a simple tool to discriminate between target vibrations, accompanied by congruent or incongruent visual distractors, on the same or opposite side to the tool. The attentional hypothesis was supported: BOLD response in occipital cortex, particularly in the right hemisphere lingual gyrus, varied significantly as a function of tool position, increasing contralaterally, and decreasing ipsilaterally to the tool. Furthermore, these modulations occurred despite the fact that participants were repeatedly instructed to ignore the visual stimuli, to respond only to the vibrotactile stimuli, and to maintain visual fixation centrally. In addition, the magnitude of multisensory (visual-vibrotactile) interactions in participants' behavioural responses significantly predicted the BOLD response in occipital cortical areas that were also modulated as a function of both visual stimulus position and tool position. Conclusions/Significance: These results show that using a simple tool to locate and to perceive vibrotactile stimuli is accompanied by a shift of spatial attention to the location where the functional part of the tool is used, resulting in enhanced processing of visual stimuli at that location, and decreased processing at other locations. This was most clearly observed in the right hemisphere lingual gyrus. Such modulations of visual processing may reflect the functional importance of visuospatial information during human tool use

Proteinase-activated receptors, targets for kallikrein signaling

Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs). Although thrombin is a recognized physiological activator of PAR(1) and PAR(4), the endogenous enzymes responsible for activating PAR(2) in settings other than the gastrointestinal system, where trypsin can activate PAR(2), are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR(1), PAR(2), and PAR(4); 2) PAR-dependent calcium signaling responses in cells expressing PAR(1), PAR(2), and PAR(4) and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR(4)-dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR(1), PAR(2), and PAR(4) and to disarm/inhibit PAR(1). Although hK5 and -6 were also able to activate PAR(2), they failed to cause PAR(4)-dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR(2)-mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR(1), PAR(2), and PAR(4).

Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells

Pseudomonas aeruginosa, a major lung pathogen in cystic fibrosis (CF) patients, secretes an elastolytic metalloproteinase (EPa) contributing to bacterial pathogenicity. Proteinase-activated receptor 2 (PAR2), implicated in the pulmonary innate defense, is activated by the cleavage of its extracellular N-terminal domain, unmasking a new N-terminal sequence starting with SLIGKV, which binds intramolecularly and activates PAR2. We show that EPa cleaves the N-terminal domain of PAR2 from the cell surface without triggering receptor endocytosis as trypsin does. As evaluated by measurements of cytosolic calcium as well as prostaglandin E(2) and interleukin-8 production, this cleavage does not activate PAR2, but rather disarms the receptor for subsequent activation by trypsin, but not by the synthetic receptor-activating peptide, SLIGKV-NH(2). Proteolysis by EPa of synthetic peptides representing the N-terminal cleavage/activation sequences of either human or rat PAR2 indicates that cleavages resulting from EPa activity would not produce receptor-activating tethered ligands, but would disarm PAR2 in regard to any further activating proteolysis by activating proteinases. Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF.

Foreword: International Space Science Institute (ISSI) workshop on the Earth’s cryosphere and sea level change

Rising sea level is perhaps the most severe consequence of climate warming, as much of the world’s population and infrastructure is located near current sea level (Lemke et al. 2007). A major rise of a metre or more would cause serious problems. Such possibilities have been suggested by Hansen and Sato (2011) who pointed out that sea level was several metres higher than now during the Holsteinian and Eemian interglacials (about 250,000 and 120,000 years ago, respectively), even though the global temperature was then only slightly higher than it is nowadays. It is consequently of the utmost importance to determine whether such a sea level rise could occur and, if so, how fast it might happen. Sea level undergoes considerable changes due to natural processes such as the wind, ocean currents and tidal motions. On longer time scales, the sea level is influenced by steric effects (sea water expansion caused by temperature and salinity changes of the ocean) and by eustatic effects caused by changes in ocean mass. Changes in the Earth’s cryosphere, such as the retreat or expansion of glaciers and land ice areas, have been the dominant cause of sea level change during the Earth’s recent history. During the glacial cycles of the last million years, the sea level varied by a large amount, of the order of 100 m. If the Earth’s cryosphere were to disappear completely, the sea level would rise by some 65 m. The scientific papers in the present volume address the different aspects of the Earth’s cryosphere and how the different changes in the cryosphere affect sea level change. It represents the outcome of the first workshop held within the new ISSI Earth Science Programme. The workshop took place from 22 to 26 March, 2010, in Bern, Switzerland, with the objective of providing an in-depth insight into the future of mountain glaciers and the large land ice areas of Antarctica and Greenland, which are exposed to natural and anthropogenic climate influences, and their effects on sea level change. The participants of the workshop are experts in different fields including meteorology, climatology, oceanography, glaciology and geodesy; they use advanced space-based observational studies and state-of-the-art numerical modelling.

Geo-Engineering to Confine Climate Change: Is it at all Feasible?

Paul Crutzen (2006) has suggested a research initiative to consider whether it would be feasible to artificially enhance the albedo of the planet Earth to counteract greenhouse warming. The enhancement of albedo would be achieved by intentionally injecting sulfur into the stratosphere. The rational for proposing the experiment is the observed cooling of the atmosphere following the recent major volcanic eruptions by El Chichon in 1984 and Mount Pinatubo in 1991 (Hansen et al., 1992). Although I am principally not against a research initiative to study such a potential experiment, I do have important reservations concerning its general feasibility. And its potential feasibility, I believe, must be the key motivation for embarking on such a study. Here I will bring up three major issues, which must be more thoroughly understood before any geo-engineering of climate could be considered, if at all. The three issues are (i) the lack of accuracy in climate prediction, (ii) the huge difference in timescale between the effect of greenhouse gases and the effect of aerosols and (iii) serious environmental problems which may be caused by high carbon dioxide concentration irrespective of the warming of the climate.

Pollen-based biome reconstructions for Latin America at 0, 6000 and 18000 radiocarbon years

The biomisation method is used to reconstruct Latin American vegetation at 6000±500 and 18 000±1000 radiocarbon years before present (14C yr BP) from pollen data. Tests using modern pollen data from 381 samples derived from 287 locations broadly reproduce potential natural vegetation. The strong temperature gradient associated with the Andes is recorded by a transition from high altitude cool grass/shrubland and cool mixed forest to mid-altitude cool temperate rain forest, to tropical dry, seasonal and rain forest at low altitudes. Reconstructed biomes from a number of sites do not match the potential vegetation due to local factors such as human impact, methodological artefacts and mechanisms of pollen representivity of the parent vegetation.

Linguistic experiments and ordinary language philosophy

J.L. Austin is regarded as having an especially acute ear for fine distinctions of meaning overlooked by other philosophers. Austin employs an informal experimental approach to gathering evidence in support of these fine distinctions in meaning, an approach that has become a standard technique for investigating meaning in both philosophy and linguistics. In this paper, we subject Austin's methods to formal experimental investigation. His methods produce mixed results: We find support for his most famous distinction, drawn on the basis of his `donkey stories', that `mistake' and `accident' apply to different cases, but not for some of his other attempts to distinguish the meaning of philosophically significant terms (such as `intentionally' and `deliberately'). We critically examine the methodology of informal experiments employed in ordinary language philosophy and much of contemporary philosophy of language and linguistics, and discuss the role that experimenter bias can play in influencing judgments about informal and formal linguistic experiments.

A slugfest of intuitions: contextualism and experimental design

This paper considers ways that experimental design can affect judgments about informally presented context shifting experiments. Reasons are given to think that judgments about informal context shifting experiments are affected by an exclusive reliance on binary truth value judgments and by experimenter bias. Exclusive reliance on binary truth value judgments may produce experimental artifacts by obscuring important differences of degree between the phenomena being investigated. Experimenter bias is an effect generated when, for example, experimenters disclose (even unconsciously) their own beliefs about the outcome of an experiment. Eliminating experimenter bias from context shifting experiments makes it far less obvious what the “intuitive” responses to those experiments are. After it is shown how those different kinds of bias can affect judgments about informal context shifting experiments, those experiments are revised to control for those forms of bias. The upshot of these investigations is that participants in the contextualist debate who employ informal experiments should pay just as much attention to the design of their experiments as those who employ more formal experimental techniques if they want to avoid obscuring the phenomena they aim to uncover

Dietary factors impact on the association between CTSS variants and obesity related traits

BACKGROUND/AIMS: Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology--this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors--increased by high protein, glycemic index and energy diets. METHODS: Four tag SNPs (rs7511673, rs11576175, rs10888390 and rs1136774) were selected to capture all common variation in the CTSS region. Association between these four SNPs and several adiposity measurements (BMI, waist circumference, waist for given BMI and being a weight gainer-experiencing the greatest degree of unexplained annual weight gain during follow-up or not) given, where applicable, both as baseline values and gain during the study period (6-8 years) were tested in 11,091 European individuals (linear or logistic regression models). We also examined the interaction between the CTSS variants and dietary factors--energy density, protein content (in grams or in % of total energy intake) and glycemic index--on these four adiposity phenotypes. RESULTS: We found several associations between CTSS polymorphisms and anthropometric traits including baseline BMI (rs11576175 (SNP N°2), p = 0.02, β = -0.2446), and waist change over time (rs7511673 (SNP N°1), p = 0.01, β = -0.0433 and rs10888390 (SNP N°3), p = 0.04, β = -0.0342). In interaction with the percentage of proteins contained in the diet, rs11576175 (SNP N°2) was also associated with the risk of being a weight gainer (p(interaction) = 0.01, OR = 1.0526)--the risk of being a weight gainer increased with the percentage of proteins contained in the diet. CONCLUSION: CTSS variants seem to be nominally associated to obesity related traits and this association may be modified by dietary protein intake.

Influence of dietary protein intake and glycemic index on the association between TCF7L2 HapA and weight gain

BACKGROUND: Genetic polymorphisms of transcription factor 7-like 2 (TCF7L2) have been associated with type 2 diabetes and BMI. OBJECTIVE: The objective was to investigate whether TCF7L2 HapA is associated with weight development and whether such an association is modulated by protein intake or by the glycemic index (GI). DESIGN: The investigation was based on prospective data from 5 cohort studies nested within the European Prospective Investigation into Cancer and Nutrition. Weight change was followed up for a mean (±SD) of 6.8 ± 2.5 y. TCF7L2 rs7903146 and rs10885406 were successfully genotyped in 11,069 individuals and used to derive HapA. Multiple logistic and linear regression analysis was applied to test for the main effect of HapA and its interaction with dietary protein or GI. Analyses from the cohorts were combined by random-effects meta-analysis. RESULTS: HapA was associated neither with baseline BMI (0.03 ± 0.07 BMI units per allele; P = 0.6) nor with annual weight change (8.8 ± 11.7 g/y per allele; P = 0.5). However, a previously shown positive association between intake of protein, particularly of animal origin, and subsequent weight change in this population proved to be attenuated by TCF7L2 HapA (P-interaction = 0.01). We showed that weight gain becomes independent of protein intake with an increasing number of HapA alleles. Substitution of protein with either fat or carbohydrates showed the same effects. No interaction with GI was observed. CONCLUSION: TCF7L2 HapA attenuates the positive association between animal protein intake and long-term body weight change in middle-aged Europeans but does not interact with the GI of the diet.

Association between FTO variant and change in body weight and its interaction with dietary factors: the DiOGenes study

Although FTO is an established obesity-susceptibility locus, it remains unknown whether it influences weight change in adult life and whether diet attenuates this association. Therefore, we investigated the association of FTO-rs9939609 with changes in weight and waist circumference (WC) during 6.8 years follow-up in a large-scale prospective study and examined whether these associations were modified by dietary energy percentage from fat, protein, carbohydrate, or glycemic index (GI). This study comprised data from five countries of European Prospective Investigation into Cancer and Nutrition (EPIC) and was designed as a case-cohort study for weight gain. Analyses included 11,091 individuals, of whom 5,584 were cases (age (SD), 47.6 (7.5) years), defined as those with the greatest unexplained annual weight gain during follow-up and 5,507 were noncases (48.0 (7.3) years), who were compared in our case-noncase (CNC) analyses. Furthermore, 6,566 individuals (47.9 (7.3) years) selected from the total sample (all noncases and 1,059 cases) formed the random subcohort (RSC), used for continuous trait analyses. Interactions were tested by including interaction terms in the models. In the RSC-analyses, FTO-rs9939609 was associated with BMI (β (SE), 0.17 (0.08) kg·m(-2)/allele; P = 0.034) and WC (0.47 (0.21) cm/allele; P = 0.026) at baseline, but not with weight change (5.55 (12.5) g·year(-1)/allele; P = 0.66) during follow up. In the CNC-analysis, FTO-rs9939609 was associated with increased risk of being a weight-gainer (OR: 1.1; P = 0.045). We observed no interaction between FTO-rs9939609 and dietary fat, protein and carbohydrate, and GI on BMI and WC at baseline or on change in weight and WC. FTO-rs9939609 is associated with BMI and WC at baseline, but association with weight gain is weak and only observed for extreme gain. Dietary factors did not influence the associations.

Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. AIM: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. METHODS AND FINDINGS: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). CONCLUSIONS: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.