Relativism, Coherence, and the Problems of Philosophy *

The eventual topic of this paper is the perhaps grandiose question of whether we have any reason to think that philosophical problems can be solved. Philosophy has been around for quite some time, and its record is cause for pessimism: it is not, exactly, that there are no established results, but that what results there are, are negative (such-and-such is false, or won't work), or conditional (as Ernest Nagel used to say, "If we had ham, and if we had eggs, then we'd have ham and eggs"). 1 I hope in what follows first of all to explain the record. My explanation will naturally suggest a way of turning over a new leaf, and I will wrap up the paper by laying out that proposal and critically assessing its prospects. However, the approach to my topic will have to be roundabout. Along the way, I will detour to consider how the problems of philosophy can be * I'm grateful t

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Convergence in the ovipositor system of platygastroid wasps (Hymenoptera)

It is widely accepted that there are two ovipositor system types in Platygastroidea. The Scelio-type ovipositor system features telescoping conjunctiva between metasomal tergites 6 and 7 and operates via internal changes in hydrostatic pressure alone, whereas muscles are involved in ovipositor extension and retraction in the Ceratobaeus-type. We here provide analyses of ovipositor systems in two platygastrine genera that cannot be classified as either Scelio- or Ceratobaeus-type, but exhibit telescoping conjunctivae and extend the ovipositor system without musculature. These represent unique derivations that are clearly identifiable by the location of the telescoping conjunctiva. In Gastrotrypes Brues, the telescoping conjunctiva occurs between T5 and T6, and in Platygaster tubulosa Brues it occurs between each segment from T3 to T6. If there are convergent derivations of a Scelio-type ovipositor system within Scelionidae (sensu Masner 1976), their identification will require examination of new characters, one of which we provide here, the presence and form of a ring of acanthae on the conjunctiva between T6 and T7

Analysis of Sulfur Dioxide Emissions in the Lewis-Clark Valley

Sulfurous odor in the Lewiston-Clarkston (LC) area is a nuisance and possible adverse health factor from a kraft pulp paper mill located along the Clearwater River in the city of Lewiston. One chemical that is emitted from paper mills is sulfur dioxide (SO2), one of many that are a byproduct of the mill\u27s production. The goal of this study was to monitor the emissions of SO2 in the LC Valley and the spatial, temporal and diurnal patterns. SO2 can cause increased irritation from respiratory diseases as well as create damaging acid rain that kills plant life and damages structures. In this study there is a small correlation between increase in elevation and increase in SO2 , as well as a slow increase of SO2 over a year\u27s time. A diurnal cycle of emissions during the morning decreasing after noon is observed. All levels were below attainment

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization

Regulation of IL-17A production is distinct from IL-17F in a primary human cell co-culture model of T cell-mediated B cell activation.

Improper regulation of B cell responses leads to excessive production of antibodies and contributes to the development of autoimmune disease. T helper 17 (Th17) cells also drive the development of autoimmune disease, but the role of B cells in shaping Th17 cell-mediated immune responses, as well as the reciprocal regulation of B cell responses by IL-17 family cytokines, remains unclear. The aim of this study was to characterize the regulation of IL-17A and IL-17F in a model of T cell-dependent B cell activation. Stimulation of primary human B cell and peripheral blood mononuclear cell (BT) co-cultures with α-IgM and a non-mitogenic concentration of superantigens for three days promoted a Th17 cell response as evidenced by increased expression of Th17-related gene transcripts, including Il17f, Il21, Il22, and Il23r, in CD4 T cells, as well as the secretion of IL-17A and IL-17F protein. We tested the ability of 144 pharmacologic modulators representing 91 different targets or pathways to regulate IL-17A and IL-17F production in these stimulated BT co-cultures. IL-17A production was found to be preferentially sensitive to inhibition of the PI3K/mTOR pathway, while prostaglandin EP receptor agonists, including PGE2, increased IL-17A concentrations. In contrast, the production of IL-17F was inhibited by PGE2, but selectively increased by TLR2 and TLR5 agonists. These results indicate that IL-17A regulation is distinct from IL-17F in stimulated BT co-cultures and that this co-culture approach can be used to identify pathway mechanisms and novel agents that selectively inhibit production of IL-17A or IL-17F

Volatile and Semivolatile Organic Compounds in Wildfire Smoke During NOAA/NASA FIREX-AQ Campaign

Wildfires emit particulate matter and carcinogenic compounds, such as benzene, making it important to understand the potential health impacts on the surrounding communities. The National Oceanic and Atmospheric Administration (NOAA) and National Aeronautics and Space Administration (NASA) campaign, Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ), was conducted in summer of 2019 to study wildfire composition and smoke evolution in the U.S. Air sampling was performed by Lewis-Clark State Air Chemistry Research Group as part of FIREX-AQ at various ground locations as well as larger fires. Two major wildfires studied were the Nethker Fire (~2,300 acres burned) in McCall, ID and the Williams Flats Fire (~44,450 acres burned) in Spokane, WA. Air samples were collected through thermal desorption tubes both actively (pumped air) and passively (diffusion) and then analyzed through thermal desorption gas chromatography mass spectrometry (TD/GC/MS). Benzene found in wildfire smoke was 14-134 times higher compared to background concentrations of nearby sites, depending on fire sampling conditions. Smoldering fire samples also contained higher levels of toluene, ethylbenzene, xylenes, phenol, and pinenes. These pollutants can have long and short term health effects

Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4

In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms