The clinical spectrum of Alzheimer’s disease (AD) extends well beyond the classic amnestic–predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden ...between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite
z
score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (
p
= 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (
p
= 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.
Amino acid functionalized perylene bisimides (PBIs) form self‐assembled structures in solution, the nature of which depends on the local environment. Using a high‐throughput photocatalysis setup, ...five PBIs are studied for the hydrogen evolution reaction (HER) under a range of conditions (pH and hole scavenger concentration) across 350 experiments to explore the relationship between supramolecular structure and photocatalytic activity. Using small angle X‐ray scattering (SAXS), NMR spectroscopy and ultraviolet‐visible (UV‐vis) absorption spectroscopy, it is shown that photocatalytic activity is determined by the nature of the self‐assembled aggregate that is formed, demonstrating the potential of self‐assembly to tune activity. There is a clear correlation between the presence of charged flexible cylindrical aggregates and the occurrence of photocatalytic H2 production, with UV–vis spectroscopy indicating that the most active structure type has a distinctive form of π‐aggregation which is proposed to enable efficient charge separation across multiple PBI units.
Self‐assembly is an exciting but underexplored field in photocatalysis. The design of molecular chromophores is common, but less attention is paid to how these building blocks assemble. Using high‐throughput testing and detailed characterization, it is shown how a single set of starting molecules can give rise to profoundly different levels of photocatalytic activity depending on their supramolecular structure.
The form of political polarization where citizens develop strongly negative attitudes toward out-party members and policies has become increasingly prominent across many democracies. Economic ...hardship and social inequality, as well as intergroup and racial conflict, have been identified as important contributing factors to this phenomenon known as "affective polarization." Research shows that partisan animosities are exacerbated when these interests and identities become aligned with existing party cleavages. In this paper, we use a model of cultural evolution to study how these forces combine to generate and maintain affective political polarization. We show that economic events can drive both affective polarization and the sorting of group identities along party lines, which, in turn, can magnify the effects of underlying inequality between those groups. But, on a more optimistic note, we show that sufficiently high levels of wealth redistribution through the provision of public goods can counteract this feedback and limit the rise of polarization. We test some of our key theoretical predictions using survey data on intergroup polarization, sorting of racial groups, and affective polarization in the United States over the past 50 y.
Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund ...Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions.
TorsinA is an ER-resident AAA + ATPase, whose deletion of glutamate E303 results in the genetic neuromuscular disease primary dystonia. TorsinA is an unusual AAA + ATPase that needs an external ...activator. Also, it likely does not thread a peptide substrate through a narrow central channel, in contrast to its closest structural homologs. Here, we examined the oligomerization of TorsinA to get closer to a molecular understanding of its still enigmatic function. We observe TorsinA to form helical filaments, which we analyzed by cryo-electron microscopy using helical reconstruction. The 4.4 Å structure reveals long hollow tubes with a helical periodicity of 8.5 subunits per turn, and an inner channel of ~ 4 nm diameter. We further show that the protein is able to induce tubulation of membranes in vitro, an observation that may reflect an entirely new characteristic of AAA + ATPases. We discuss the implications of these observations for TorsinA function.
Abstract
We review results from field experiments that simulate drought, an ecologically impactful global change threat that is predicted to increase in magnitude, extent, duration and frequency. Our ...goal is to address, from primarily an ecosystem perspective, the questions ‘What have we learned from drought experiments?’ and ‘Where do we go from here?’.
Drought experiments are among the most numerous climate change manipulations and have been deployed across a wide range of biomes, although most are conducted in short‐statured, water‐limited ecosystems. Collectively, these experiments have enabled ecologists to quantify the negative responses to drought that occur for most aspects of ecosystem structure and function. Multiple meta‐analyses of responses have also enabled comparisons of relative effect sizes of drought across hundreds of sites, particularly for carbon cycle metrics. Overall, drought experiments have provided strong evidence that ecosystem sensitivity to drought increases with aridity, but that plant traits associated with aridity are not necessarily predictive of drought resistance. There is also intriguing evidence that as drought magnitude or duration increases to extreme levels, plant strategies may shift from drought tolerance to drought escape/avoidance.
We highlight three areas where more drought experiments are needed to advance our understanding. First, because drought is intensifying in multiple ways, experiments are needed that address alterations in drought magnitude versus duration, timing and/or frequency (individually and interactively). Second, drivers of drought may be shifting—from precipitation deficits to rising atmospheric demand for water—and disentangling how ecosystems respond to changes in hydrological ‘supply versus demand’ is critical for understanding drought impacts in the future. Finally, more attention should be focussed on post‐drought recovery periods since legacies of drought can affect ecosystem functioning much longer than the drought itself.
We conclude with a call for a fundamental shift in the focus of drought experiments from those designed primarily as ‘response experiments’, quantifying the magnitude of change in ecosystem structure and function, to more ‘mechanistic experiments’—those that explicitly manipulate ecological processes or attributes thought to underpin drought responses.
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Whole-body vibration and muscle fatigue have both been shown to delay the trunk muscle reflex response and increase trunk muscle activation, leading to an increased risk of low back injuries. ...However, the effects of whole-body vibration on previously fatigued trunk muscles have never been tested, despite studies showing that prolonged exposure to whole-body vibration can lead to muscle fatigue. The purpose of this research was to investigate the effects of muscle fatigue on muscle latency, muscle activation and perceived discomfort when exposed to whole-body vibration. The results showed that a fatigued muscle state resulted in increased muscle latency, muscle activation and perceived discomfort, which all escalate the risk of low back injuries. Additionally, the ISO 2631-1 comfort ratings did not increase with fatigue, showing a disconnect between these comfort ratings and the perceived discomfort ratings in a fatigued muscle state.
Practitioner summary: When exposed to whole-body vibration, fatigued back muscles result in delayed muscle contraction, higher overall muscle activation and increased perceived discomfort, all of which are known to increase low back injury risk. ISO 2631-1 comfort ratings are unable to increase with fatigue, showing a disconnect with perceived discomfort ratings.
Abbreviations: EMG: electromyography; EO: external oblique; IO: internal oblique; LE: lumbar erector spinae; LEO: left externaloblique; LIO: left internal oblique; LLE: left lumbar erector spinae; LTE: left thoracic erector spinae; MVC: maximum voluntarycontraction; REO: right external oblique; RIO: right internal oblique; RLE: right lumbar erector spinae; RTE: right thoracicerector spinae; SEAT: Seat Effective Amplitude Transmissibility; TE: thoracic erector spinae; WBV: whole body vibration
Social and political polarization is an important source of conflict in many societies. Understanding its causes has become a priority of scholars across disciplines. We demonstrate that shifts in ...socialization strategies analogous to political polarization can arise as a locally beneficial response to both rising wealth inequality and economic decline. In many contexts, interaction with diverse out-groups confers benefits from innovation and exploration greater than those that arise from interacting exclusively with a homogeneous in-group. However, when the economic environment favors risk aversion, a strategy of seeking lower-risk in-group interactions can be important to maintaining individual solvency. Our model shows that under conditions of economic decline or increasing inequality, some members of the population benefit from adopting a risk-averse, in-group favoring strategy. Moreover, we show that such in-group polarization can spread rapidly to the whole population and persist even when the conditions that produced it have reversed.
Objective Endovascular aneurysm repair (EVAR) is associated with significant direct device costs. Such costs place EVAR at odds with efforts to constrain healthcare expenditures. This study examines ...the procedure-associated costs and operating margins associated with EVAR at a tertiary care academic medical center. Methods All infrarenal EVARs performed from April 2011 to March 2012 were identified (n = 127). Among this cohort, 49 patients met standard commercial instruction for use guidelines, were treated using a single manufacturer device, and billed to Medicare diagnosis-related group (DRG) 238. Of these 49 patients, net technical operating margins (technical revenue minus technical cost) were calculated in conjunction with the hospital finance department. EVAR implant costs were determined for each procedure. DRG 238-associated costs and length of stay were benchmarked against other academic medical centers using University Health System Consortium 2012 data. Results Among the studied EVAR cohort (age 75, 82% male, mean length of stay, 1.7 days), mean technical costs totaled $31,672. Graft implants accounted for 52% of the allocated technical costs. Institutional overhead was 17% ($5495) of total technical costs. Net mean total technical EVAR-associated operating margins were −$4015 per procedure. Our institutional costs and length of stay, when benchmarked against comparable centers, remained in the lowest quartile nationally using University Health System Consortium costs for DRG 238. Stent graft price did not correlate with total EVAR market share. Conclusions EVAR is currently associated with significant negative operating margins among Medicare beneficiaries. Currently, device costs account for over 50% of EVAR-associated technical costs and did not impact EVAR market share, reflecting an unawareness of cost differential among surgeons. These data indicate that EVAR must undergo dramatic care delivery redesign for this practice to remain sustainable.
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