The book is an opinionated survey of philosophical work on paradoxes of truth and of related notions, such as property-instantiation, with occasional forays into related topics such as vagueness, the ...nature of validity, and the Gödel incompleteness theorems. It advocates a particular approach, according to which the paradoxes are to be resolved by the adoption of a non-classical logic: a logic in which excluded middle is restricted. (The logic is quite different from intuitionist logic, which doesn't avoid the paradoxes and also has many unnatural features; and it is much more powerful than the most familiar logic of the paradoxes, the strong Kleene logic, in that it contains a serious conditional.) The book also provides a systematic and detailed look at the main competing approaches. These include Tarski's theory, Kripke's theories, Lukasiewicz's theory, classical gap theories, classical glut theories, supervaluational theories, revision theories, stratified theories, contextual theories, and dialetheic theories. It attempts to compare the virtues of such theories on a range of issues. It also argues against the view that any solution to the paradoxes is inevitably faced with ‘revenge paradoxes’.
Delirium is a profound, acute confusional state that leads to long-term cognitive decline. Increased anticholinergic medications and prior dementia, in which basal forebrain cholinergic degeneration ...is a prominent feature, both predict delirium. Thus, cholinergic hypoactivity is thought to be important in cognitive dysfunction during delirium, and acute systemic inflammation is a major trigger for this dysfunction. Here, we hypothesize that decreased cholinergic function confers increased susceptibility to acute inflammation-induced cognitive deficits. We used the murine-p75-saporin immunotoxin (mu-p75-sap) to induce selective lesions of the basal forebrain cholinergic system in mice, mimicking early dementia-associated cholinergic loss, and superimposed systemic inflammation using low-dose bacterial lipopolysaccharide (LPS). Intracerebroventricular injection of mu-p75-sap produced depletion of cholinergic neurons in the basal forebrain and decreased innervation of the hippocampus, but left performance on hippocampal-dependent reference and working memory tasks relatively intact. However, systemic LPS (100 μg/kg) induced acute and transient working memory deficits in lesioned animals without effect in unlesioned controls. CNS inflammatory responses were similar in normal and lesioned animals and the acetylcholinesterase inhibitor, donepezil (1 mg/kg), protected against the acute cognitive deficits in this cholinergic-dependent task. Thus, cholinergic depletion predisposes to development of acute cognitive deficits upon subsequent systemic inflammatory insult. These data provide a useful model for examining interactions between acute systemic inflammation and chronic cholinergic hypofunction in delirium and have implications for the recent trial of rivastigmine in sepsis-associated delirium.
Type I interferons (IFN‐I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN‐I has been implicated in ...neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN‐I in murine prion disease (ME7) and examined the contribution of the IFN‐I receptor IFNAR1 to disease progression. The data indicate a robust IFNβ response, specifically in microglia, with evidence of IFN‐dependent genes in both microglia and astrocytes. This IFN‐I response was absent in stimulator of interferon genes (STING−/−) mice. Microglia showed increased numbers and activated morphology independent of genotype, but transcriptional signatures indicated an IFNAR1‐dependent neuroinflammatory phenotype. Isolation of microglia and astrocytes demonstrated disease‐associated microglial induction of Tnfα, Tgfb1, and of phagolysosomal system transcripts including those for cathepsins, Cd68, C1qa, C3, and Trem2, which were diminished in IFNAR1 and STING deficient mice. Microglial increases in activated cathepsin D, and CD68 were significantly reduced in IFNAR1−/− mice, particularly in white matter, and increases in COX‐1 expression, and prostaglandin synthesis were significantly mitigated. Disease progressed more slowly in IFNAR1−/− mice, with diminished synaptic and neuronal loss and delayed onset of neurological signs and death but without effect on proteinase K‐resistant PrP levels. Therefore, STING‐dependent IFN‐I influences microglial phenotype and influences neurodegenerative progression despite occurring secondary to initial degenerative changes. These data expand our mechanistic understanding of IFN‐I induction and its impact on microglial function during chronic neurodegeneration.
Main Points
Microglial IFN‐I during chronic neurodegeneration is STING‐dependent.
Microglial phagolysosomal, complement and prostaglandin pathways are suppressed in IFNAR1‐/‐ mice.
Synaptic & neuronal degeneration and motor decline are slowed in IFNAR1‐/‐ mice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
During 2017-2018, the National Seismic Hazard Model for the conterminous United States was updated as follows: (1) an updated seismicity catalog was incorporated, which includes new earthquakes that ...occurred from 2013 to 2017; (2) in the central and eastern United States (CEUS), new ground motion models were updated that incorporate updated median estimates, modified assessments of the associated epistemic uncertainties and aleatory variabilities, and new soil amplification factors; (3) in the western United States (WUS), amplified shaking estimates of long-period ground motions at sites overlying deep sedimentary basins in the Los Angeles, San Francisco, Seattle, and Salt Lake City areas were incorporated; and (4) in the conterminous United States, seismic hazard is calculated for 22 periods (from 0.01 to 10 s) and 8 uniform VS30 maps (ranging from 1500 to 150 m/s). We also include a description of updated computer codes and modeling details. Results show increased ground shaking in many (but not all) locations across the CEUS (up to ∼30%), as well as near the four urban areas overlying deep sedimentary basins in the WUS (up to ∼50%). Due to population growth and these increased hazard estimates, more people live or work in areas of high or moderate seismic hazard than ever before, leading to higher risk of undesirable consequences from forecasted future ground shaking.
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Summary
Objective
To examine the relationship between anti‐Müllerian hormone (AMH) and the severity of the phenotype of patients with polycystic ovary syndrome (PCOS) and whether AMH can act as a ...diagnostic marker for PCOS?
Design
A prospective diagnostic utility study of AMH as a marker of PCOS.
Patients
A consecutive series of women presenting to a tertiary infertility clinic (n = 164) plus a second series of women prepared for assisted conception treatments (n = 89) recruited between June 2012 and May 2013.
Measurements
Polycystic ovary syndrome was diagnosed using the Rotterdam criteria. AMH was measured using the Generation II assay (Beckman Coulter). The diagnostic utility of AMH was established using receiver operator characteristic (ROC) curves. Cut‐off values for the individual features of PCOS are proposed.
Results
There was a significant difference in serum AMH concentration in women with normal ovaries (13·2 pmol/l), polycystic ovary morphology (PCOM) alone (37·8 pmol/l) and PCOS (53·2 pmol/l). Follicle number, increasing cycle length and evidence of hyperandrogenism were all independently associated with serum AMH concentration (P < 0·01). AMH was significantly affected by the different phenotypic presentations of PCOS with those with all components (PCOM, HA and OA) having the highest mean value 72·7 pmol/l (P < 0·01).
Conclusions
Serum AMH has the capacity to act as a diagnostic test for PCOS. Moreover, since its value rises with the more marked phenotypes, different cut‐off values need to be used to differentiate those patients with polycystic ovarian morphology (PCOM), hyperandrogenism (HA) and oligoanovulation (OA).
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Abstract
Grinding stones and ground stone implements are important technological innovations in later human evolution, allowing the exploitation and use of new plant foods, novel tools (e.g., bone ...points and edge ground axes) and ground pigments. Excavations at the site of Madjedbebe recovered Australia’s (if not one of the world’s) largest and longest records of Pleistocene grinding stones, which span the past 65 thousand years (ka). Microscopic and chemical analyses show that the Madjedbebe grinding stone assemblage displays the earliest known evidence for seed grinding and intensive plant use, the earliest known production and use of edge-ground stone hatchets (aka axes), and the earliest intensive use of ground ochre pigments in Sahul (the Pleistocene landmass of Australia and New Guinea). The Madjedbebe grinding stone assemblage reveals economic, technological and symbolic innovations exemplary of the phenotypic plasticity of
Homo sapiens
dispersing out of Africa and into Sahul.
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In orthopteran insects, a complex tibial organ has evolved to detect substrate vibrations and/or airborne sound. Species of New Zealand weta (Anostostomatidae) with tympanal ears on the foreleg tibia ...use this organ to communicate by sound, while in atympanate species (which communicate by substrate drumming) the organ is unstudied. We investigated the complex tibial organ of the atympanate ground weta, Hemiandrus pallitarsis, for vibration detection adaptations. This system contains four sensory components (subgenual organ, intermediate organ, crista acustica homolog, accessory organ) in all legs, together with up to 90 scolopidial sensilla. Microcomputed tomography shows that the subgenual organ spans the hemolymph channel, with attachments suggesting that hemolymph oscillations displace the organ in a hinged-plate fashion. Subgenual sensilla are likely excited by substrate oscillations transmitted within the leg. Instead of the usual suspension within the middle of the tibial cavity, we show that the intermediate organ and crista acustica homolog comprise a cellular mass broadly attached to the anterior tibial wall. They likely detect cuticular vibrations, and not airborne sound. This atympanate complex tibial organ shows elaborate structural changes suggesting detection of vibrational stimuli by parallel input pathways, thus correlating well with the burrowing lifestyle and communication by substrate-transmitted vibration.
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Nearly 75% of all emerging infectious diseases (EIDs) that impact or threaten human health are zoonotic. The majority have spilled from wildlife reservoirs, either directly to humans or via domestic ...animals. The emergence of many can be attributed to predisposing factors such as global travel, trade, agricultural expansion, deforestation/habitat fragmentation, and urbanization; such factors increase the interface and/or the rate of contact between human, domestic animal, and wildlife populations, thereby creating increased opportunities for spillover events to occur. Infectious disease emergence can be regarded as primarily an ecological process. The epidemiological investigation of EIDs associated with wildlife requires a trans-disciplinary approach that includes an understanding of the ecology of the wildlife species, and an understanding of human behaviours that increase risk of exposure. Investigations of the emergence of Nipah virus in Malaysia in 1999 and severe acute respiratory syndrome (SARS) in China in 2003 provide useful case studies. The emergence of Nipah virus was associated with the increased size and density of commercial pig farms and their encroachment into forested areas. The movement of pigs for sale and slaughter in turn led to the rapid spread of infection to southern peninsular Malaysia, where the high-density, largely urban pig populations facilitated transmission to humans. Identifying the factors associated with the emergence of SARS in southern China requires an understanding of the ecology of infection both in the natural reservoir and in secondary market reservoir species. A necessary extension of understanding the ecology of the reservoir is an understanding of the trade, and of the social and cultural context of wildlife consumption. Emerging infectious diseases originating from wildlife populations will continue to threaten public health. Mitigating and managing the risk requires an appreciation of the connectedness between human, livestock and wildlife health, and of the factors and processes that disrupt the balance.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Around 88 large vertebrate taxa disappeared from Sahul sometime during the Pleistocene, with the majority of losses (54 taxa) clearly taking place within the last 400,000 years. The largest was the ...2.8-ton browsing Diprotodon optatum, whereas the ~100- to 130-kg marsupial lion, Thylacoleo carnifex, the world's most specialized mammalian carnivore, and Varanus priscus, the largest lizard known, were formidable predators. Explanations for these extinctions have centered on climatic change or human activities. Here, we review the evidence and arguments for both. Human involvement in the disappearance of some species remains possible but unproven. Mounting evidence points to the loss of most species before the peopling of Sahul (circa 50-45 ka) and a significant role for climate change in the disappearance of the continent's megafauna.
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