688 research outputs found
Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects
SummaryThe recent Zika virus (ZIKV) outbreak in the Western hemisphere is associated with severe pathology in newborns, including microcephaly and brain damage. The mechanisms underlying these outcomes are under intense investigation. Here, we show that a 2015 ZIKV isolate replicates in multiple cell types, including primary human fetal neural progenitors (hNPs). In immortalized cells, ZIKV is cytopathic and grossly rearranges endoplasmic reticulum membranes similar to other flaviviruses. In hNPs, ZIKV infection has a partial cytopathic phase characterized by cell rounding, pyknosis, and activation of caspase 3. Despite notable cell death, ZIKV did not activate a cytokine response in hNPs. This lack of cell intrinsic immunity to ZIKV is consistent with our observation that virus replication persists in hNPs for at least 28 days. These findings, supported by published fetal neuropathology, establish a proof-of-concept that neural progenitors in the developing human fetus can be direct targets of detrimental ZIKV-induced pathology
Characteristics associated with quality of life among people with drug-resistant epilepsy
Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants, what clinical and psycho-social characteristics are associated with QoL. We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced â„10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case level, with 63% reporting felt stigma. While a maximum QOLIE-31-P score is 100, participantsâ mean score was 66, with a wide range (25â99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy
A Proposal for a Three Detector Short-Baseline Neutrino Oscillation Program in the Fermilab Booster Neutrino Beam
A Short-Baseline Neutrino (SBN) physics program of three LAr-TPC detectors
located along the Booster Neutrino Beam (BNB) at Fermilab is presented. This
new SBN Program will deliver a rich and compelling physics opportunity,
including the ability to resolve a class of experimental anomalies in neutrino
physics and to perform the most sensitive search to date for sterile neutrinos
at the eV mass-scale through both appearance and disappearance oscillation
channels. Using data sets of 6.6e20 protons on target (P.O.T.) in the LAr1-ND
and ICARUS T600 detectors plus 13.2e20 P.O.T. in the MicroBooNE detector, we
estimate that a search for muon neutrino to electron neutrino appearance can be
performed with ~5 sigma sensitivity for the LSND allowed (99% C.L.) parameter
region. In this proposal for the SBN Program, we describe the physics analysis,
the conceptual design of the LAr1-ND detector, the design and refurbishment of
the T600 detector, the necessary infrastructure required to execute the
program, and a possible reconfiguration of the BNB target and horn system to
improve its performance for oscillation searches.Comment: 209 pages, 129 figure
Fibre Distribution and the Process-Property Dilemma
The options for the fibre reinforcement of polymer matrix composites cover a range from short-fibre chopped strand mat, through woven fabric to unidirectional pre-impregnated (prepreg) reinforcements. The modelling of such materials may be simplified by assumptions such as perfect regular packing of fibres and the total absence of fibre waviness. However, these and other features such as the crimp or waviness in woven fabrics make real materials more complex than the simplified models. Clustering of fibres creates fibre-rich and resin-rich volumes (FRV and RRV respectively) in the composites. Prior to impregnation, large RRV will be pore-space that can expedite the flow of resin in liquid composite moulding processes (especially resin transfer moulding (RTM) and resin infusion under flexible tooling (RIFT). In the composite, the clustering of fibres tends to reduce the mechanical properties. The use of image processing and analysis can permit micro-/meso-structural characterisation which may correlate to the respective properties. This chapter considers the quantification of microstructure images in the context of the process-property dilemma for woven carbon-fibre reinforced composites with the aim of increasing understanding of the balance between processability and mechanical performance
Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF
The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at
the Fermilab Long-Baseline Neutrino Facility (LBNF) is described
Effects of shoe sole geometry on toe clearance and walking stability in older adults
Thirty-five percent of people above age 65 fall each year, and half of their falls are associated with tripping: tripping, an apparently âmundaneâ everyday problem, therefore significantly impacts on older people's health and associated medical costs. To avoid tripping and subsequent falling, sufficient toe clearance during the swing phase is crucial. We previously found that a rocker-shaped shoe sole enhances toe clearance in young adults, thereby decreasing their trip-risk. This study investigates whether such sole design also enhances older adultsâ toe clearance, without inadvertently affecting their walking stability.
Toe clearance and its variability are reported together with measures of walking stability for twelve older adults, walking in shoes with rocker angles of 10°, 15°, and 20° degrees. Surface inclinations (flat, incline, decline) were chosen to reflect a potential real-world environment.
Toe clearance increased substantially from the 10° to the 15° degree rocker angle (p = 0.003) without compromising measures of walking stability (p > 0.05). A further increase in rocker angle to 20° degrees resulted in less substantial enhancement of toe clearance and came at the cost of a decrease in gait speed on the decline.
The novelty of this investigation lies in the exploration of the trade-off between reduction of trip- risk through footwear design and adverse effects on walking stability on real-life relevant surfaces. A large amount of slip-resistant footwear is already available; our two studies highlight that footwear may also be designed to reduce trip-risk
Aripiprazole Augmentation in the Treatment of Military-Related PTSD with Major Depression: a retrospective chart review
<p>Abstract</p> <p>Background</p> <p>In this chart review, we attempted to evaluate the benefits of adding aripiprazole in veterans with military-related PTSD and comorbid depression, who had been minimally or partially responsive to their existing medications.</p> <p>Methods</p> <p>A retrospective chart review of patients who received an open-label, flexible-dose, 12- week course of adjunctive aripiprazole was conducted in 27 military veterans meeting DSM-IV criteria for PTSD and comorbid major depression. Concomitant psychiatric medications continued unchanged, except for other antipsychotics which were discontinued prior to initiating aripiprazole. The primary outcome variable was a change from baseline in the PTSD checklist-military version (PCL-M) and the Beck Depression Inventory (BDI-II).</p> <p>Results</p> <p>PTSD severity (Total PCL scores) decreased from 56.11 at baseline to 46.85 at 12-weeks (p < 0.0001 from Wilcoxon signed rank test) and the depression severity decreased from 30.44 at baseline to 20.67 at 12-weeks (p < 0.0001 from Wilcoxon signed rank test). Thirty seven percent (10/27) were considered responders, as defined by a decrease in total PCL scores of at least 20 percent and 19% (5/27) were considered as responders as defined by a decrease in total BDI score of at least 50%.</p> <p>Conclusions</p> <p>The addition of aripiprazole contributed to a reduction in both PTSD and depression symptomatology in a population that has traditionally demonstrated poor pharmacological response. Further investigations, including double-blind, placebo-controlled studies, are essential to confirm and further demonstrate the benefit of aripiprazole augmentation in the treatment of military related PTSD.</p
Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
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On the price of morals in markets: an empirical study of the Swedish AP-Funds and the Norwegian Government Pension Fund
This study empirically analyses the exclusion of companies from investorsâ investment universe due to a
companyâs business model (sector-based exclusion) or due
to a companyâs violations of international norms (normbased exclusion). We conduct a time-series analysis of the performance implications of the exclusion decisions of two leading Nordic investors, Norwayâs Government Pension Fund-Global (GPFG) and Swedenâs AP-funds. We find that their portfolios of excluded companies do not generate an abnormal return relative to the fundsâ benchmark index. While the exclusion portfolios show higher risk than the respective benchmark, this difference is only statistically
significant for the case of GPFG. These findings suggest
that the exclusion of the companies generally does not
harm fundsâ performance. We interpret these findings as
indicative that with exclusionary screening, as practiced by the sample funds, asset owners can meet the ethical
objectives of their beneficiaries without compromising
financial returns
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