Solar Probe Plus (SPP) will be the first spacecraft to fly into the low solar corona. SPP’s main science goal is to determine the structure and dynamics of the Sun’s coronal magnetic field, ...understand how the solar corona and wind are heated and accelerated, and determine what processes accelerate energetic particles. Understanding these fundamental phenomena has been a top-priority science goal for over five decades, dating back to the 1958 Simpson Committee Report. The scale and concept of such a mission has been revised at intervals since that time, yet the core has always been a close encounter with the Sun. The mission design and the technology and engineering developments enable SPP to meet its science objectives to: (1) Trace the flow of energy that heats and accelerates the solar corona and solar wind; (2) Determine the structure and dynamics of the plasma and magnetic fields at the sources of the solar wind; and (3) Explore mechanisms that accelerate and transport energetic particles. The SPP mission was confirmed in March 2014 and is under development as a part of NASA’s Living with a Star (LWS) Program. SPP is scheduled for launch in mid-2018, and will perform 24 orbits over a 7-year nominal mission duration. Seven Venus gravity assists gradually reduce SPP’s perihelion from 35 solar radii (
R
S
) for the first orbit to
<
10
R
S
for the final three orbits. In this paper we present the science, mission concept and the baseline vehicle for SPP, and examine how the mission will address the key science questions
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated ...with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The NASA Radiation Belt Storm Probes (RBSP) mission addresses how populations of high energy charged particles are created, vary, and evolve in space environments, and specifically within Earth’s ...magnetically trapped radiation belts. RBSP, with a nominal launch date of August 2012, comprises two spacecraft making in situ measurements for at least 2 years in nearly the same highly elliptical, low inclination orbits (1.1×5.8 RE, 10
∘
). The orbits are slightly different so that 1 spacecraft laps the other spacecraft about every 2.5 months, allowing separation of spatial from temporal effects over spatial scales ranging from ∼0.1 to 5 RE. The uniquely comprehensive suite of instruments, identical on the two spacecraft, measures all of the particle (electrons, ions, ion composition), fields (
E
and
B
), and wave distributions (
d
E
and
d
B
) that are needed to resolve the most critical science questions. Here we summarize the high level science objectives for the RBSP mission, provide historical background on studies of Earth and planetary radiation belts, present examples of the most compelling scientific mysteries of the radiation belts, present the mission design of the RBSP mission that targets these mysteries and objectives, present the observation and measurement requirements for the mission, and introduce the instrumentation that will deliver these measurements. This paper references and is followed by a number of companion papers that describe the details of the RBSP mission, spacecraft, and instruments.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder. Two subtypes commonly present with a language disorder: semantic ...dementia (SemD) and progressive nonfluent aphasia (PNFA).
Patients meeting consensus criteria for PNFA and SemD who had volumetric MRI of sufficient quality to allow cortical thickness analysis were recruited from a tertiary referral clinic: 44 (11 pathologically confirmed) patients with SemD and 32 (4 pathologically confirmed) patients with PNFA and 29 age-matched and gender-matched healthy controls were recruited. Cortical thickness analysis was performed using the Freesurfer software tools.
Patients with SemD had significant cortical thinning in the left temporal lobe, particularly temporal pole, entorhinal cortex, and parahippocampal, fusiform, and inferior temporal gyri. A similar but less extensive pattern of loss was seen in the right temporal lobe and (with increasing severity) also in left orbitofrontal, inferior frontal, insular, and cingulate cortices. Patients with PNFA had involvement particularly of the left superior temporal lobe, inferior frontal lobe, and insula, and (with increasing severity) other areas in the left frontal, lateral temporal, and anterior parietal lobes. Similar patterns were seen in the pathologically confirmed cases. Patterns of cortical thinning differed between groups: SemD had significantly more cortical thinning in the temporal lobes bilaterally while PNFA had significantly more thinning in the frontal and parietal lobes.
The language variants of frontotemporal lobar degeneration have distinctive and significantly different patterns of cortical thinning. Increasing disease severity is associated with spread of cortical thinning and the pattern of spread is consistent with progression of clinical deficits.
Vegetable oils are being investigated as a potential source of environmentally favourable lubricants, due to a combination of biodegradability, renewability and excellent lubrication performance. Low ...oxidation and thermal stability, poor low-temperature properties and narrow range of available viscosities, however, limit their potential application as industrial lubricants. This review addresses oxidation as a limitation of vegetable oil-based lubricants. The basic mechanism of vegetable oil autoxidation is presented, along with methods used to monitor and analyse the products of oxidation. The potential impact of such oxidation products on lubrication performance is discussed. A brief discussion of methods used to assess and improve oxidation stability completes the review.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder.
We collected blood samples from a cohort of 225 patients with a diagnosis within ...the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease.
A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).
These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.
To address factors dictating similarities and differences between solar system radiation belts, we present comparisons between relativistic electron radiation belt spectra of all five strongly ...magnetized planets: Earth, Jupiter, Saturn, Uranus, and Neptune. We choose observed electron spectra with the highest intensities near ∼1 MeV and compare them against expectations based on the so‐called Kennel‐Petschek limit (KP). For evaluating the KP limit, we begin with a recently published relativistic formulation and then add several refinements of our own. Specifically, we utilized a more flexible analytic spectral shape that allows us to accurately fit observed radiation belt spectra, and we examine the differential characteristics of the KP limit. We demonstrate that the previous finding that KP‐limited spectra take on an E−1 shape in the nonrelativistic formulation is also roughly preserved with the relativistic formulation; this shape is observed at several of the planets studied. We also conclude that three factors limit the highest relativistic electron radiation belt intensities within solar system planetary magnetospheres: (1) plasma whistler mode interactions that limit differential spectral intensities to a differential Kennel‐Petschek limit (Earth, Jupiter, and Uranus), (2) the absence of robust acceleration processes associated with injection dynamics (Neptune), and (3) material interactions between the radiation electrons and clouds of gas and dust (Saturn).
Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study ...in mild to moderate AD.
The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.
No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.
Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status.
Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its ...removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.
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•Macrophage NCoR KO mice are protected from HFD-induced insulin resistance•NCoR deletion results in a paradoxical hyporesponsiveness to TLR4 signaling•Derepression of LXRs results in increased anti-inflammatory ω3 fatty acids•ω3 fatty acids inhibit enhancer/promoter activation at hyporesponsive genes
Loss of NcoR unexpectedly leads to an anti-inflammatory phenotype in mice, along with increased insulin sensitivity, due to derepression of LXR-regulated pathways. Activation of LXR stimulates production of anti-inflammatory palmitoleic and omega 3 fatty acids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to ...provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: "what does good quality haemodialysis look like?"The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want to - most of this is freely available online, at least in summary form.A few notes on the individual sections: 1. This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines "enough" dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term "eKt/V" is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient. 2. This section deals with "non-standard" dialysis, which basically means anything other than 3 times per week. For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per week - this is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here. 3. This section deals with membranes (the type of "filter" used in the dialysis machine) and "HDF" (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it's as good as but not better than regular dialysis. 4. This section deals with fluid removal during dialysis sessions: how to remove enough fluid without causing cramps and low blood pressure. Amongst other recommendations we advise close collaboration with patients over this. 5. This section deals with dialysate, which is the fluid used to "pull" toxins out of the blood (it is sometimes called the "bath"). The level of things like potassium in the dialysate is important, otherwise too much or too little may be removed. There is a section on dialysate buffer (bicarbonate) and also a section on phosphate, which occasionally needs to be added into the dialysate. 6. This section is about anticoagulation (blood thinning) which is needed to stop the circuit from clotting, but sometimes causes side effects. 7. This section is about certain safety aspects of dialysis, not seeking to replace well-established local protocols, but focussing on just a few where we thought some national-level guidance would be useful. 8. This section draws together a few aspects of dialysis which don't easily fit elsewhere, and which impact on how dialysis feels to patients, rather than the medical outcome, though of course these are linked. This is where home haemodialysis and exercise are covered. There is an appendix at the end which covers a few aspects in more detail, especially the mathematical ideas. Several aspects of dialysis are not included in this guideline since they are covered elsewhere, often because they are aspects which affect non-dialysis patients too. This includes: anaemia, calcium and bone health, high blood pressure, nutrition, infection control, vascular access, transplant planning, and when dialysis should be started.
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