511 research outputs found

    Introducing Human APOE into Aβ Transgenic Mouse Models

    Get PDF
    Apolipoprotein E (apoE) and apoE/amyloid-β (Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE−/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology, apoE−/− mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβ pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβ pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve

    A customisable pipeline for continuously harvesting socially-minded Twitter users

    Full text link
    On social media platforms and Twitter in particular, specific classes of users such as influencers have been given satisfactory operational definitions in terms of network and content metrics. Others, for instance online activists, are not less important but their characterisation still requires experimenting. We make the hypothesis that such interesting users can be found within temporally and spatially localised contexts, i.e., small but topical fragments of the network containing interactions about social events or campaigns with a significant footprint on Twitter. To explore this hypothesis, we have designed a continuous user profile discovery pipeline that produces an ever-growing dataset of user profiles by harvesting and analysing contexts from the Twitter stream. The profiles dataset includes key network and content-based users metrics, enabling experimentation with user-defined score functions that characterise specific classes of online users. The paper describes the design and implementation of the pipeline and its empirical evaluation on a case study consisting of healthcare-related campaigns in the UK, showing how it supports the operational definitions of online activism, by comparing three experimental ranking functions. The code is publicly available.Comment: Procs. ICWE 2019, June 2019, Kore

    AACP Special Taskforce White Paper on Diversifying Our Investment in Human Capital

    Get PDF
    The 2015-2017 American Association of Colleges of Pharmacy (AACP) Special Taskforce on Diversifying our Investment in Human Capital was appointed for a two-year term, due to the rigors and complexities of its charges. This report serves as a white paper for academic pharmacy on diversifying our investment in human capital. The Taskforce developed and recommended a representation statement that was adapted and adopted by the AACP House of Delegates at the 2016 AACP Annual Meeting. In addition, the Taskforce developed a diversity statement for the Association that was adopted by the AACP Board of Directors in 2017. The Taskforce also provides recommendations to AACP and to academic pharmacy in this white paper

    High resolution observations of Cassiopeia A at meter wavelengths

    Get PDF
    Very long baseline interferometric (VLBI) observations of the supernova remnant Cassiopeia A, at 74 MHz with a 12,000-wavelength baseline and at 111 MHz with a 18,500-wavelength baseline, are reported. The fringe amplitudes are strongly varying on a time scale of about 15 to 30 minutes. The location of the extra source must lie outside the supernova remnant shell possibly associated with a concentration of emission north of the shell, or lying outside the gap in the northeastern side of the shell. The flux and spectral index deduced for the compact source depend on the assumed size, with a range of 100 Jy to 500 Jy at 74 MHz. If the source is associated with the supernova explosion, it must have been traveling at least 5000 km s/2

    Separate F-Type Plasmids Have Shaped the Evolution of the H30 Subclone of Escherichia coli Sequence Type 131.

    Get PDF
    The extraintestinal pathogenic Escherichia coli (ExPEC) H30 subclone of sequence type 131 (ST131-H30) has emerged abruptly as a dominant lineage of ExPEC responsible for human disease. The ST131-H30 lineage has been well described phylogenetically, yet its plasmid complement is not fully understood. Here, single-molecule, real-time sequencing was used to generate the complete plasmid sequences of ST131-H30 isolates and those belonging to other ST131 clades. Comparative analyses revealed separate F-type plasmids that have shaped the evolution of the main fluoroquinolone-resistant ST131-H30 clades. Specifically, an F1:A2:B20 plasmid is strongly associated with the H30R/C1 clade, whereas an F2:A1:B− plasmid is associated with the H30Rx/C2 clade. A series of plasmid gene losses, gains, and rearrangements involving IS26 likely led to the current plasmid complements within each ST131-H30 sublineage, which contain several overlapping gene clusters with putative functions in virulence and fitness, suggesting plasmid-mediated convergent evolution. Evidence suggests that the H30Rx/C2-associated F2:A1:B− plasmid type was present in strains ancestral to the acquisition of fluoroquinolone resistance and prior to the introduction of a multidrug resistance-encoding gene cassette harboring blaCTX-M-15. In vitro experiments indicated a host strain-independent low frequency of plasmid transfer, differential levels of plasmid stability even between closely related ST131-H30 strains, and possible epistasis for carriage of these plasmids within the H30R/Rx lineages. IMPORTANCE A clonal lineage of Escherichia coli known as ST131 has emerged as a dominating strain type causing extraintestinal infections in humans. The evolutionary history of ST131 E. coli is now well understood. However, the role of plasmids in ST131’s evolutionary history is poorly defined. This study utilized real-time, single-molecule sequencing to compare plasmids from various current and historical lineages of ST131. From this work, it was determined that a series of plasmid gains, losses, and recombinational events has led to the currently circulating plasmids of ST131 strains. These plasmids appear to have evolved to acquire similar gene clusters on multiple occasions, suggesting possible plasmid-mediated convergent evolution leading to evolutionary success. These plasmids also appear to be better suited to exist in specific strains of ST131 due to coadaptive mutations. Overall, a series of events has enabled the evolution of ST131 plasmids, possibly contributing to the lineage’s success

    SPECIAL ARTICLES Fostering and Managing Diversity in Schools of Pharmacy

    Get PDF
    Organizational benefits of diversity in the workplace have been well documented. In health professions, however, diversity-related research traditionally has focused on the effect of diversity on health care disparities. Few tools exist describing the benefits of diversity from an organizational standpoint to guide pharmacy administrators and faculty members in nurturing and developing a culture of diversity. Given the scarcity of pharmacy specific data, experience from other academic areas and national/ international diversity reports were incorporated into this manuscript to supplement the available pharmacy evidence base. This review summarizes the benefits of diversity from an academic organizational standpoint, discusses the issues administrators and faculty members must consider when developing programs, and provides guidance on best practices in fostering and managing diversity

    Quantum Electronics

    Get PDF
    Contains reports on three research projects.U. S. Air Force Office of Scientific Research (Contract F44620-71-C-0051)Joint Services Electronics Program (Contract DAAB07-71-C-0300)University of California, Livermore (Subcontract No. 7877409)U. S. Army Research Office - Durham (Contract DAHC04-72-C-0044

    A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity

    Get PDF
    Mutations in LRRK2 are one of the primary genetic causes of Parkinson's disease (PD). LRRK2 contains a kinase and a GTPase domain, and familial PD mutations affect both enzymatic activities. However, the signaling mechanisms regulating LRRK2 and the pathogenic effects of familial mutations remain unknown. Identifying the signaling proteins that regulate LRRK2 function and toxicity remains a critical goal for the development of effective therapeutic strategies. In this study, we apply systems biology tools to human PD brain and blood transcriptomes to reverse-engineer a LRRK2-centered gene regulatory network. This network identifies several putative master regulators of LRRK2 function. In particular, the signaling gene RGS2, which encodes for a GTPase-activating protein (GAP), is a key regulatory hub connecting the familial PD-associated genes DJ-1 and PINK1 with LRRK2 in the network. RGS2 expression levels are reduced in the striata of LRRK2 and sporadic PD patients. We identify RGS2 as a novel interacting partner of LRRK2 in vivo. RGS2 regulates both the GTPase and kinase activities of LRRK2. We show in mammalian neurons that RGS2 regulates LRRK2 function in the control of neuronal process length. RGS2 is also protective against neuronal toxicity of the most prevalent mutation in LRRK2, G2019S. We find that RGS2 regulates LRRK2 function and neuronal toxicity through its effects on kinase activity and independently of GTPase activity, which reveals a novel mode of action for GAP proteins. This work identifies RGS2 as a promising target for interfering with neurodegeneration due to LRRK2 mutations in PD patient
    corecore