Advanced Modalizing De Dicto and De Re

Lewis’ (1968, 1986) analysis of modality faces a problem in that it appears to confer unintended truth values to certain modal claims about the pluriverse: e.g. ‘It is possible that there are many worlds’ is false when we expect truth. This is the problem of advanced modalizing. Divers (1999, 2002) presents a principled solution to this problem by treating modal modifiers as semantically redundant in some such cases. However, this semantic move does not deal adequately with advanced de re modal claims. Here, we motivate and detail a comprehensive semantics (a la Lewis 1968) for advanced modalizing de dicto and de re. The generalized semantic feature of the initial solution is not redundancy but absence from counterpart-theoretic translations of world-constrictions

Three Conceptions of Modal Realism

The thesis is divided into three sections. The first of these is a critique of the conceptions of modal realism due to Lewis; the second, a critique of that due to McGinn. The third section comprises the development and initial evaluation of a third conception of moral realism which I term secondary modal realism. In Section One of the thesis [Ch.1- Ch.5] I argue against the acceptability of the objectual modal realism of David Lewis and I argue (tentatively) for one theory of the meaning of possible world statements which is consistent with this denial of the existence of possible worlds. Chapters 1- 4 concern the former argument, Ch.5 concerns the latter. In Ch.1, I argue that there is no genuine semantic utility afforded by the adoption of realism about possible worlds. The case is (i) that the genuine semantical utility which does accrue via the ontological commitment to possible worlds can be had without that ontological commitmment and (ii) that other claims to semanti utility which are associated with possible world semantics do not reflect legitimate semantic-explanatory interests. The main part of the discussion of objectual realism - constituted by Chapters 2, 3 & 4 - takes a different turn. Since Lewis is fond of comparing his modal realism to realism about the entities of mathematics, I attempt to show that, on both epistemological and metaphysical grounds, the comparison is quite unfavourable for objectual modal realism. In Ch.2, I defend the objectual modal realist's right to an a priori epistemology of modality in face of Benaceraffs dilemma, but, it is argued in Ch.3, even granted a priority, there is still a serious epistemological difficulty since the internal epistemology of modal realism which is proposed by Lewis is seriously flawed. In Ch.4, it is argued that there is at least one important metaphysical consideration which militates against an ontological commitment to worlds but which does not appear to have the same impact re. mathematical ontology, viz: that the mooted possible worlds are identification- transcendent. Having made the case for anti-realism about possible worlds I am concerned in Ch.5 with the outline of a theory of the meaning of possible world statements which is consistent with this ontological position. I argue for the unacceptability of a theory, outlined by Forbes, which depends upon the claim that possible world statements do not mean what they appear to mean. I then counterpose the options of an error theory and a metaphor theory of world-talk arguing that while both of these are prima facie tenable, the latter is preferable. In Section Two of the thesis [Ch.6 - Ch.9] I deal with the non-objectual modal realism of McGinn. Having set out the salient theses of McGinn's conception of modal realism [Ch.6], the critique of this conception follows. Ch. 6: the variety and resources of anti-realisms about modality are seriously underestimated by McGinn. In particular the option of anti-realism based on the strategy of proposing a sceptical solution as a response to a sceptical paradox is ignored. Ch.7: McGinn proposes that the only defensible form of modal realism consists in endorsing the thesis of supervenience (without reduction) of the modal on the actual. However, the discussion of supervenience fails to acknowledge many of the difficulties associated with the application of supervenience and related theses in the modal case. Furthermore, there is every reason to believe that acceptance of modal/actual supervenience involves no commitment to modal realism. Ch.8: consideration of the issues that flow from the discussion of the thesis of supervenience should point towards a central question of modal epistemology i.e. whether modal knowledge is attainable by conceptual means alone. However, McGinn's discussion of supervenience leads him away from this central question and as a result he mislocates the problematic nature of modal epistemology in the claim that we cannot represent modal facts as causally explaining our knowledge of them. Ch.9:The modal realism that McGinn offers is wholly unacceptable since it provides neither a clear conception of the truth-conditions of modal statements nor any account of how we detect modalities. The realism he offers is redolent of sceptical paradox and seems ripe for an anti-realist treatment in the form of a sceptical solution. Hence, the upshot of the first two sections is that the existing conceptions of modal realism, i.e. those of Lewis and of McGinn respectively, are indefensible. In Section Three of the thesis [Ch.10 - Ch. 12] the aim is to characterize and evaluate a third conception of modal realism - secondary modal realism. This project is inspired by (i) McDowell's secondary quality conception of moral reality and (ii) the observation of crucial similarities between the failings of more traditional conceptions of moral realism and those conceptions of modal realisms dealt with above. In Ch.10, I argue that anthropocentricity as opposed to perceptibility is the feature of paradigmatic secondary properties which is an appropriately generalizable feature of secondary realism and that a proper conception of the standard of correctness for secondary property judgments facilitates the extrapolation of that standard to the cases of moral and modal judgement. (Abstract shortened by ProQuest.)

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial.

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30 mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mm Hg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08-1.73) and log UACR estimated slope (β) 0.33) and negatively associated with eGFR (β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g

Interrogation of ecotoxic elements distribution in slag and precipitated calcite through a machine larning-based approach aided by mass spectrometry

CO2 mineralization in slag has been widely investigated as a potential solution for offsetting steelmaking industry emissions. However, it can be associated with ecotoxic elements release (e.g., V and Cr). The presence of such elements in heterogenous slag at the micro-scale remains difficult for analysis since microstructural features can be missed during microscopy data inspection, thereby presenting a challenge in understanding how ecotoxic elements exist in slag. Here, an unsupervised machine learning-based technique is used to analyze slag's microstructural features. Energy Dispersive Spectroscopy (EDS) data are analyzed through Hierarchical Density-Based Spatial Clustering of Applications with Noise (HDBSCAN) method. Results show that passive CO2 mineralization has occurred in situ in the studied samples, on the surface, and within their pores. Additionally, V and Cr regions with equivalent diameters < 42 µm can exist within slag, potentially making such elements prone to mobilization due to slag pulverization. Interrogation of the samples with Laser Ablation Inductively Coupled Plasma Mass Spectroscopy (LA-ICP-MS) confirms the distribution of the elements obtained from the clustering algorithm and further demonstrates that up to 84 and 9 ppm of V and Cr are incorporated in the precipitated calcite, respectively. This implies that ecotoxic elements may be immobilized through calcite precipitation

APOL1 Kidney-Risk Variants Induce Mitochondrial Fission

IntroductionAPOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1-nephropathy.MethodsA global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.ResultsAPOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.ConclusionResults suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1-nephropathy

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 × 10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin