Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain

Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology

Apolipoprotein E Pathology in Vascular Dementia

Vascular dementia (VaD) is the second most common form of dementia and is currently defined as a cerebral vessel vascular disease leading to ischemic episodes. Apolipoprotein E (apoE) gene polymorphism has been proposed as a risk factor for VaD, however, to date there are few documented post-mortem studies on apoE pathology in the VaD brain. To investigate a potential role for the apoE protein, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing an antibody that specifically detects the amino-terminal fragment of apoE. Application of this antibody, termed N-terminal, apoE cleavage fragment (nApoECF) revealed consistent labeling within neurofibrillary tangles (NFTs), blood vessels, and reactive astrocytes. Labeling occurred in VaD cases that had confirmed APOE genotypes of 3/3, 3/4, and 4/4, with respect to NFTs, staining of the nApoECF co-localized with PHF-1 and was predominantly localized to large, stellate neurons in layer II of the entorhinal cortex. Quantitative analysis indicated that approximately 38.4% of all identified NFTs contained the amino-terminal fragment of apoE. Collectively, these data support a role for the proteolytic cleavage of apoE in the VaD and support previous reports that APOE polymorphism is significantly associated with susceptibility in this disease

Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain

Down syndrome (DS) is one of the most common genetic causes of intellectual disability and is characterized by a number of behavioral as well as cognitive symptoms. Many of the neuropathological features of early-onset Alzheimer’s disease (AD) including senile plaques and neurofibrillary tangles (NFTs) are also present in people with DS as a result of triplication of the amyloid precursor gene on chromosome 21. Evidence suggests that harboring one or both apolipoprotein E4 (APOE4) alleles may increase the risk for AD due to the proteolytic cleavage of apoE4 and a subsequent loss of function. To investigate a role for the apoE proteolysis in vivo, we compared three autopsy groups; 7 DS with AD neuropathology cases over 40 years, 5 young DS cases without AD pathology under 40 years (YDS) and 5 age-matched control cases over 40 years by immunohistochemistry utilizing an antibody that detects the amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE fragment antibody (nApoECF) revealed labeling of pyramidal neurons in the frontal cortex of YDS cases, whereas in the DS-AD group, labeling with nApoECF was prominent within NFTs. NFT labeling with nApoECF was significantly greater in the hippocampus versus the frontal cortex in the same DS-AD cases, suggesting a regional distribution of truncated apoE. Colocalization immunofluorescence experiments indicated that 52.5% and 53.2% of AT8- and PHF-1-positive NFTs, respectively, also contained nApoECF. Collectively, these data support a role for the proteolytic cleavage of apoE in DS and suggest that apoE fragmentation is closely associated with NFTs

Immunolocalization of an Amino-Terminal Fragment of Apolipoprotein E in the Pick\u27s Disease Brain

Although the risk factor for apolipoprotein E (apoE) polymorphism in Alzheimer\u27s disease (AD) has been well described, the role that apoE plays in other neurodegenerative diseases, including Pick\u27s disease, is not well established. To examine a possible role of apoE in Pick\u27s disease, an immunohistochemical analysis was performed utilizing a novel site-directed antibody that is specific for an amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE cleavage fragment (nApoECF) antibody, consistently labeled Pick bodies within area CA1 of the hippocampus in 4 of the 5 cases examined. Co-localization of the nApoECF antibody with PHF-1, a general marker for Pick bodies, as well as with an antibody to caspase-cleaved tau (TauC3) was evident within the hippocampus. While staining of the nApoECF antibody was robust in area CA1, little co-localization with PHF-1 in Pick bodies within the dentate gyrus was observed. A quantitative analysis indicated that approximately 86% of the Pick bodies identified in area CA1 labeled with the nApoECF antibody. The presence of truncated apoE within Pick bodies suggests a broader role of apoE beyond AD and raises the question as to whether this protein contributes to pathogenesis associated with Pick\u27s disease

An Expanded Stratigraphic Record of the Devonian-Carboniferous Boundary Hangenberg Biogeochemical Event from Southeast Iowa (U.S.A.)

The Devonian-Carboniferous boundary in the type area of the Mississippian subsystem (tri-state area of Iowa, Illinois, and Missouri) has been historically difficult to identify. Many of the localities contain similar lithologies and stratigraphic successions, but chronostratigraphic correlation of seemingly identical lithologies can vary greatly in this interval and frequently this has led to miscorrelation. In particular, the similar lithofacies that comprise the McCraney Formation and Louisiana Formation have been a source of stratigraphic confusion for over 100 years. To investigate the Devonian-Carboniferous boundary interval in the Mississippian type area we selected two localities in southeastern Iowa, the H-28 core from Lee County outside of Keokuk, Iowa, and the Starr’s Cave outcrop located near Burlington, Iowa. In total, 62 conodont samples and 299 carbonate carbon isotope samples were processed for this study and recorded the Hangenberg positive carbon isotope excursion and 25 conodont species, including a diverse assemblage of siphonodellids. The Hangenberg excursion is recorded in over 20 m of strata in southeast Iowa, making this one of the thickest stratigraphic records of this important biogeochemical event yet recovered, and helps to define more clearly the position of the base of the Carboniferous System in the region. These results show that the “McCraney” Fm. at the Starr’s Cave outcrop and the coeval carbonate unit in the H-28 core are both the Louisiana Formation, and calls into question the use of the name McCraney throughout the State of Iowa

Veteran teachers' identity: what does the research literature tell us?

This paper provides an overview of research on veteran teachers and teacher identity. It analyses issues at the personal, situated and professional levels that have been shown to impact on veteran teachers' identities. The search included empirical studies published in peer-reviewed journals between 2005 and 2016. In total, 19 papers were analysed. Findings revealed that many studies focused on veteran teachers' resilience. Issues concerning veteran teachers' identities are key to understanding why they remain in the profession and are able to sustain their motivation and commitment over time. Many veteran teachers portrayed in the literature built on their confidence regarding their professional competence and relied on internal and external issues to maintain their motivation and commitment to teaching. The role of emotions in the transformation of veteran teachers' identities and the permeable boundaries of the personal, situated and professional scenarios influencing veteran teachers' identities are highlighted in the paper.Financial Support by CIEC (Research Centre on Child Studies, IE, UMinho; FCT R&D unit 317, Portugal) by the Strategic Project UID/CED/00317/2013, with financial support of National Funds through the FCT (Foundation for Science and Technology) and co-financed by European Regional Development Funds (FEDER) through the COMPETE 2020 - Competitiveness and Internationalization Operational Program (POCI) with the reference POCI-01-0145-FEDER-00756

Reviewing Solutions of Scale for Canine Rabies Elimination in India

Canine rabies elimination can be achieved through mass vaccination of the dog population, as advocated by the WHO, OIE and FAO under the 'United Against Rabies' initiative. Many countries in which canine rabies is endemic are exploring methods to access dogs for vaccination, campaign structures and approaches to resource mobilization. Reviewing aspects that fostered success in rabies elimination campaigns elsewhere, as well as examples of largescale resource mobilization, such as that seen in the global initiative to eliminate poliomyelitis, may help to guide the planning of sustainable, scalable methods for mass dog vaccination. Elimination of rabies from the majority of Latin America took over 30 years, with years of operational trial and error before a particular approach gained the broad support of decision makers, governments and funders to enable widespread implementation. The endeavour to eliminate polio now enters its final stages; however, there are many transferrable lessons to adopt from the past 32 years of global scale-up. Additionally, there is a need to support operational research, which explores the practicalities of mass dog vaccination roll-out and what are likely to be feasible solutions at scale. This article reviews the processes that supported the scale-up of these interventions, discusses pragmatic considerations of campaign duration and work-force size and finally provides an examples hypothetical resource requirements for implementing mass dog vaccination at scale in Indian cities, with a view to supporting the planning of pilot campaigns from which expanded efforts can grow

Framing research on school principals' identities

This paper provides a basis for a tentative framework for guiding future research into principals’ identity construction and development. It is situated in the context of persisting emphases placed by government policies on the need for technocratic competencies in principals as a means of demonstrating success defined largely as compliance with demands for the improvement in student test scores. Often this emphasis is at the expense of forwarding a broader view of the need, alongside these, for clear educational values, beliefs and practices that are associated with these. The framework is informed by the theoretical work of Wenger and Bourdieu as well as recent empirical research on the part played by professional identity and emotions in school leadership. In the paper, we highlight different lines of inquiry and the issues they raise for researchers. We argue that the constructions of school leadership identities are located in time, space and place, and emotions reflect complex leadership identities situated within social hierarchies which are part of wider structures and social relations of power and control

First Constraints on Compact Dark Matter from Fast Radio Burst Microstructure

Despite existing constraints, it remains possible that up to $35\%$ of all dark matter is comprised of compact objects, such as the black holes in the 10-100\,M$_\odot$ range whose existence has been confirmed by LIGO. The strong gravitational lensing of transients such as FRBs and GRBs has been suggested as a more sensitive probe for compact dark matter than intensity fluctuations observed in microlensing experiments. Recently ASKAP has reported burst substructure down to $15\mu$s timescales in FRBs in the redshift range $0.3-0.5$. We investigate here the implications of this for the detectability of compact dark matter by FRBs. We find that a sample size of $\sim130$ FRBs would be required to constrain compact dark matter to less than the existing 35$\%$ limit with 95$\%$ confidence, if it were distributed along $\gtrsim 1\,$Gpc-long FRB sightlines through the cosmic web. Conversely, existing constraints on the fraction of compact dark matter permit as many as 1 in $\approx 40$ of all $z \lesssim 0.4$ FRBs to exhibit micro-lensed burst structure. Approximately $170$ FRBs intercepting halos within $\sim 50\,$kpc would be required to exclude the fraction of compact dark matter in each intercepted halo to a similar level. Furthermore, we consider the cumulative effects of lensing of the FRB signal by a macroscopic dark matter distribution. We conclude that lensing from a uniform distribution of compact objects is likely not observable, but suggest that FRBs may set meaningful limits on power-law distributions of dark matter.Comment: 3 Figures, 1 tabl