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\"Plato's Theaetetus and Sophist are two of his most important dialogues, and are widely read and discussed by philosophers for what they reveal about his epistemology and particularly his accounts of belief and knowledge. Although they form part of a single Platonic project, these dialogues are not usually presented as a pair, as they are in this new and lively translation. Offering a high standard of accuracy and readability, the translation reveals the continuity between these dialogues and others in the Platonic corpus, especially the Republic. Christopher Rowe's supporting introduction and notes help the reader to follow the arguments as they develop, explaining their structure, context and interpretation. This new edition challenges current scholarly approaches to Plato's work and will pave the way for fresh interpretations both of Theaetetus and Sophist and of Plato's writings in general\"-- Provided by publisher.

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.

Resurveys of historical collecting localities have revealed range shifts, primarily leading edge expansions, which have been attributed to global warming. However, there have been few spatially replicated community-scale resurveys testing whether species' responses are spatially consistent. Here we repeated early twentieth century surveys of small mammals along elevational gradients in northern, central and southern regions of montane California. Of the 34 species we analysed, 25 shifted their ranges upslope or downslope in at least one region. However, two-thirds of ranges in the three regions remained stable at one or both elevational limits and none of the 22 species found in all three regions shifted both their upper and lower limits in the same direction in all regions. When shifts occurred, high-elevation species typically contracted their lower limits upslope, whereas low-elevation species had heterogeneous responses. For high-elevation species, site-specific change in temperature better predicted the direction of shifts than change in precipitation, whereas the direction of shifts by low-elevation species was unpredictable by temperature or precipitation. While our results support previous findings of primarily upslope shifts in montane species, they also highlight the degree to which the responses of individual species vary across geographically replicated landscapes.

Use of selective in-vivo tau imaging will enable improved understanding of tau aggregation in the brain, facilitating research into causes, diagnosis, and treatment of major tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. Neuropathological studies of Alzheimer's disease show a strong association between tau deposits, decreased cognitive function, and neurodegenerative changes. Selective tau imaging will allow the in-vivo exploration of such associations and measure the global and regional changes in tau deposits over time. Such imaging studies will comprise non-invasive assessment of the spatial and temporal pattern of tau deposition over time, providing insight into the role tau plays in ageing and helping to establish the relation between cognition, genotype, neurodegeneration, and other biomarkers. Once validated, selective tau imaging might be useful as a diagnostic, prognostic, and progression biomarker, and a surrogate marker for the monitoring of efficacy and patient recruitment for anti-tau therapeutic trials.

Australia has the highest historically recorded rate of mammalian extinction in the world, with 34 terrestrial species declared extinct since European colonization in 1788. Among Australian mammals, rodents have been the most severely affected by these recent extinctions; however, given a sparse historical record, the scale and timing of their decline remain unresolved. Using museum specimens up to 184 y old, we generate genomic-scale data from across the entire assemblage of Australian hydromyine rodents (i.e., eight extinct species and their 42 living relatives). We reconstruct a phylogenomic tree for these species spanning ∼5.2 million years, revealing a cumulative total of 10 million years (>10%) of unique evolutionary history lost to extinction within the past ∼150 y. We find no evidence for reduced genetic diversity in extinct species just prior to or during decline, indicating that their extinction was extremely rapid. This suggests that populations of extinct Australian rodents were large prior to European colonization, and that genetic diversity does not necessarily protect species from catastrophic extinction. In addition, comparative analyses suggest that body size and biome interact to predict extinction and decline, with larger species more likely to go extinct. Finally, we taxonomically resurrect a species from extinction, Gould’s mouse (Pseudomys gouldii Waterhouse, 1839), which survives as an island population in Shark Bay, Western Australia (currently classified as Pseudomys fieldi Waite, 1896). With unprecedented sampling across a radiation of extinct and living species, we unlock a previously inaccessible historical perspective on extinction in Australia. Our results highlight the capacity of collections-based research to inform conservation and management of persisting species.

There is no consensus for a blood-based test for the early diagnosis of Alzheimer’s disease (AD). Expression profiling of small non-coding RNA’s, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum ( N =49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N =60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein ɛ4 (APOE ɛ4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.

A number of microRNAs (miRNAs, miRs) have been shown to play a role in skeletal muscle atrophy, but their role is not completely understood. Here we show that miR-29b promotes skeletal muscle atrophy in response to different atrophic stimuli in cells and in mouse models. miR-29b promotes atrophy of myotubes differentiated from C2C12 or primary myoblasts, and conversely, its inhibition attenuates atrophy induced by dexamethasone (Dex), TNF-α and H 2 O 2 treatment. Targeting of IGF-1 and PI3K(p85α) by miR-29b is required for induction of muscle atrophy. In vivo , miR-29b overexpression is sufficient to promote muscle atrophy while inhibition of miR-29b attenuates atrophy induced by denervation and immobilization. These data suggest that miR-29b contributes to multiple types of muscle atrophy via targeting of IGF-1 and PI3K(p85α), and that suppression of miR-29b may represent a therapeutic approach for muscle atrophy induced by different stimuli. Skeletal muscle atrophy can occur in response to stimuli such as inactivity, fasting, and ageing. Here the authors show that expression of microRNA-29b promotes muscle atrophy by targeting IGF-1 and PI3K, and that its inhibition attenuates atrophy induced by denervation and immobilization in mice.

Why some clades are more species-rich than others is a central question in macroevolution. Most hypotheses explaining exceptionally diverse clades involve the emergence of an ecological opportunity caused by a major biogeographic transition or evolution of a key innovation. The radiation of muroid rodents is an ideal model for testing theories of diversification rates in relation to biogeography and ecological opportunity because the group is exceptionally speciesrich (comprising nearly one-third of all mammal species), it is ecologically diverse, and it has colonized every major landmass except New Zealand and Antarctica, thus providing multiple replicate radiations. We present an extension of the conventional ecological opportunity model to include a geographic incumbency effect, develop the largest muroid phylogeny to date, and use this phylogeny to test the new model. The nearly 300-species phylogeny based on four nuclear genes is robustly resolved throughout. Consistent with the fossil record, we identified Eurasia as the most likely origin of the group and reconstructed five to seven colonizations of Africa, five of North America, four of Southeast Asia, two of South America, two of Sahul, one of Madagascar, and eight to ten recolonizations of Eurasia. We accounted for incomplete taxon sampling by using multiple statistical methods and identified three corroborated regions of the tree with significant shifts in diversification rates. In several cases, higher rates were associated with the first colonization of a continental area, but most colonizations were not followed by bursts of speciation. We found strong evidence for diversification consistent with the ecological opportunity model (initial burst followed by density-dependent slowdown) in the first colonization of South America and partial support for this model in the first colonization of Sahul. Primary colonizers appear to inhibit the ultimate diversity of secondary colonizers, a pattern of incumbency that is consistent with ecological opportunity, but they did not inhibit initial diversification rates of secondary colonizers. These results indicate that ecological opportunity may be a general but weak process in muroids and one that requires specific circumstances to lead to an adaptive radiation. The total land area, length of time between colonizations, and rank of colonizations did not influence the diversification rates of primary colonizers. Models currently employed to test ecological opportunity do a poor job of explaining muroid diversity. In addition, the various rate-shift metrics identified different clades, suggesting that caution should be used when only one is applied, and we discuss which methods are most appropriate to address different questions of diversification.

Fatty acid transport from blood vessels to skeletal muscle, across endothelial cells, is regulated by the branched chain amino acid metabolite 3-hydroxy-isobutyrate. This finding provides a mechanistic explanation for the link between high levels of branched chain amino acids and diabetes. Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear 1 , 2 , 3 . Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species 4 , a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a ), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.