Abstract
Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear ...magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by
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N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the
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N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand
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N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies.
Chronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical ...presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugby players with dementia were assessed for neurodegenerative pathologies using established and preliminary consensus protocols. Thereafter, next of kin interviews were conducted to obtain detailed accounts of the patient’s clinical presentation and course of disease to inform a final, integrated clinicopathological diagnosis. Neuropathologic change consistent with CTE (CTE-NC) was confirmed in five of seven former soccer and three of four former rugby players’ brains, invariably in combination with mixed, often multiple neurodegenerative pathologies. However, in just three cases was the integrated dementia diagnosis consistent with CTE, the remainder having alternate diagnoses, with the most frequent integrated diagnosis Alzheimer’s disease (AD) (four cases; one as mixed AD and vascular dementia). This consecutive autopsy series identifies neuropathologic change consistent with preliminary diagnostic criteria for CTE (CTE-NC) in a high proportion of former soccer and rugby players dying with dementia. However, in the majority, CTE-NC appears as a co-morbidity rather than the primary, dementia causing pathology. As such, we suggest that while CTE-NC might be common in former athletes with dementia, in many cases its clinical significance remains uncertain.
Explaining how animals respond to an increasingly urbanised world is a major challenge for evolutionary biologists. Urban environments often present animals with novel problems that differ from those ...encountered in their evolutionary past. To navigate these rapidly changing habitats successfully, animals may need to adjust their behaviour flexibly over relatively short timescales. These behavioural changes, in turn, may be facilitated by an ability to acquire, store, and process information from the environment. The question of how cognitive abilities allow animals to avoid threats and exploit resources (or constrain their ability to do so) is attracting increasing research interest, with a growing number of studies investigating cognitive and behavioural differences between urban-dwelling animals and their non-urban counterparts. In this review we consider why such differences might arise, focusing on the informational challenges faced by animals living in urban environments, and how different cognitive abilities can assist in overcoming these challenges. We focus largely on birds, as avian taxa have been the subject of most research to date, but discuss work in other species where relevant. We also address the potential consequences of cognitive variation at the individual and species level. For instance, do urban environments select for, or influence the development of, particular cognitive abilities? Are individuals or species with particular cognitive phenotypes more likely to become established in urban habitats? How do other factors, such as social behaviour and individual personality, interact with cognition to influence behaviour in urban environments? The aim of this review is to synthesise current knowledge and identify key avenues for future research, in order to improve our understanding of the ecological and evolutionary consequences of urbanisation.
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been ...linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
Geometrically structured polymer nanocolloids, including Janus nanocolloids, have been widely investigated for their unique properties, which are derived from their anisotropy. Controlled surface ...decoration with inorganic nanoparticles could induce another level of functionality into structured nanocolloids that could enable applications in fields ranging from rewriteable electronics to biphasic catalysis. Here, we demonstrate flash nanoprecipitation (FNP) as a one-step, scalable process platform for manufacturing hybrid polymer–inorganic nanocolloids in which one phase is selectively decorated with a metal nanocatalyst by tuning the molecular interactions between the feed ingredients during the process. For instance, by modifying the polymer end-group functionality, we document the ability to tune the location of the metal nanocatalyst, including placement at the nanocolloid circumference. Moreover, the addition of molecular additives is shown to transform the Janus nanocolloid structure from spherical to dumbbell or snowman while maintaining the ability to control the nanocatalyst location. In considering the flexibility and continuous nature of the FNP process, it offers an industrial-scale platform for the manufacturing of nanomaterials that are anticipated to impact many technologies.
To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would ...differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms.
To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.
This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis.
Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study.
The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes.
A total of 60 participants were randomized to infliximab (n = 29 48%; mean SD age, 45.0 11.7 years; 20 of 28 female 71%) or to placebo (n = 31 52%; mean SD age, 46.8 10.2 years; 26 of 30 female 87%) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04).
Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo.
ClinicalTrials.gov identifier: NCT02363738.
Humans have a profound effect on the planet's ecosystems, and unprecedented rates of human population growth and urbanization have brought wild animals into increasing contact with people. For many ...species, appropriate responses toward humans are likely to be critical to survival and reproductive success. Although numerous studies have investigated the impacts of human activity on biodiversity and species distributions, relatively few have examined the effects of humans on the behavioral responses of animals during human-wildlife encounters, and the cognitive processes underpinning those responses. Furthermore, while humans often present a significant threat to animals, the presence or behavior of people may be also associated with benefits, such as food rewards. In scenarios where humans vary in their behavior, wild animals would be expected to benefit from the ability to discriminate between dangerous, neutral and rewarding people. Additionally, individual differences in cognitive and behavioral phenotypes and past experiences with humans may affect animals' ability to exploit human-dominated environments and respond appropriately to human cues. In this review, we examine the cues that wild animals use to modulate their behavioral responses toward humans, such as human facial features and gaze direction. We discuss when wild animals are expected to attend to certain cues, how information is used, and the cognitive mechanisms involved. We consider how the cognitive abilities of wild animals are likely to be under selection by humans and therefore influence population and community composition. We conclude by highlighting the need for long-term studies on free-living, wild animals to fully understand the causes and ecological consequences of variation in responses to human cues. The effects of humans on wildlife behavior are likely to be substantial, and a detailed understanding of these effects is key to implementing effective conservation strategies and managing human-wildlife conflict.
Colloids with internally structured geometries have shown great promise in applications ranging from biosensors to optics to drug delivery, where the internal particle structure is paramount to ...performance. The growing demand for such nanomaterials necessitates the development of a scalable processing platform for their production. Flash nanoprecipitation (FNP), a rapid and inherently scalable colloid precipitation technology, is used to prepare internally structured colloids from blends of block copolymers and homopolymers. As revealed by a combination of experiments and simulations, colloids prepared from different molecular weight diblock copolymers adopt either an ordered lamellar morphology consisting of concentric shells or a disordered lamellar morphology when chain dynamics are sufficiently slow to prevent defect annealing during solvent exchange. Blends of homopolymer and block copolymer in the feed stream generate more complex internally structured colloids, such as those with hierarchically structured Janus and patchy morphologies, due to additional phase separation and kinetic trapping effects. The ability of the FNP process to generate such a wide range of morphologies using a simple and scalable setup provides a pathway to manufacturing internally structured colloids on an industrial scale.
Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as ...patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology.
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