1,257 research outputs found
Lambda-Cold Dark Matter, Stellar Feedback, and the Galactic Halo Abundance Pattern
(Abridged) The hierarchical formation scenario for the stellar halo requires
the accretion and disruption of dwarf galaxies, yet low-metallicity halo stars
are enriched in alpha-elements compared to similar, low-metallicity stars in
dwarf spheroidal (dSph) galaxies. We address this primary challenge for the
hierarchical formation scenario for the stellar halo by combining chemical
evolution modelling with cosmologically-motivated mass accretion histories for
the Milky Way dark halo and its satellites. We demonstrate that stellar halo
and dwarf galaxy abundance patterns can be explained naturally within the LCDM
framework. Our solution relies fundamentally on the LCDM model prediction that
the majority of the stars in the stellar halo were formed within a few
relatively massive, ~5 x 10^10 Msun, dwarf irregular (dIrr)-size dark matter
halos, which were accreted and destroyed ~10 Gyr in the past. These systems
necessarily have short-lived, rapid star formation histories, are enriched
primarily by Type II supernovae, and host stars with enhanced [a/Fe]
abundances. In contrast, dwarf spheroidal galaxies exist within low-mass dark
matter hosts of ~10^9 Msun, where supernovae winds are important in setting the
intermediate [a/Fe] ratios observed. Our model includes enrichment from Type Ia
and Type II supernovae as well as stellar winds, and includes a
physically-motivated supernovae feedback prescription calibrated to reproduce
the local dwarf galaxy stellar mass - metallicity relation. We use
representative examples of the type of dark matter halos we expect to host a
destroyed ``stellar halo progenitor'' dwarf, a surviving dIrr, and a surviving
dSph galaxy, and show that their derived abundance patterns, stellar masses,
and gas masses are consistent with those observed for each type of system.Comment: 10 pages, 3 figures, version accepted by Ap
Quasiparticle transport in the vortex state of YBa_2Cu_3O_6.9
The effect of vortices on quasiparticle transport in cuprate superconductors
was investigated by measuring the low temperature thermal conductivity of
YBa_2Cu_3O_6.9 in magnetic fields up to 8 T. The residual linear term (as T \to
0) is found to increase with field, directly reflecting the occupation of
extended quasiparticle states. A study for different Zn impurity concentrations
reveals a good agreement with recent calculations for a d-wave superconductor,
thereby shedding light on the nature of scattering by both impurities and
vortices. It also provides a quantitative measure of the gap near the nodes.Comment: 4 pages, 2 included eps figures, significant new analysis wrt other
experiments, to appear in Phys Rev Lett 29 March 199
GRADE-ADOLOPMENT process to develop 24-hour movement behavior recommendations and physical activity guidelines for the under 5s in the United Kingdom, 2019
Background: This article summarizes the approach taken to develop UK Chief Medical Officers' physical activity guidelines for the Under 5s, 2019. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE)- Adaptation, Adoption, De Novo Development (ADOLOPMENT) approach was used, based on the guidelines from Canada and Australia, with evidence updated to February 2018. Recommendations were based on the associations between (1) time spent in sleep, sedentary time, physical activity, and 10 health outcomes and (2) time spent in physical activity and sedentary behavior on sleep outcomes (duration and latency). Results: For many outcomes, more time spent in physical activity and sleep (up to a point) was beneficial, as was less time spent in sedentary behavior. The authors present, for the first time, evidence in GRADE format on behavior type-outcome associations for infants, toddlers, and preschoolers. Stakeholders supported all recommendations, but recommendations on sleep and screen time were not accepted by the Chief Medical Officers; UK guidelines will refer only to physical activity. Conclusions: This is the first European use of GRADE-ADOLOPMENT to develop physical activity guidelines. The process is robust, rapid, and inexpensive, but the UK experience illustrates a number of challenges that should help development of physical activity guidelines in future
Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials
Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen
85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and
second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There
are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG.
These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naıĀØve adults. Subjects were vaccinated with BCG
alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety
and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG primeāMVA85A
boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination
was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when
administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were
compared with the previous long interval trial data, there were no significant differences in the magnitude of immune
responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The
clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses.
This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These
findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial
immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data
presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here
Brain structural differences in children with fetal alcohol spectrum disorder and its subtypes
IntroductionThe teratogenic effects of prenatal alcohol exposure (PAE) have been examined in animal models and humans. The current study extends the prior literature by quantifying differences in brain structure for individuals with a fetal alcohol spectrum disorder (FASD) compared to typically developing controls, as well as examining FASD subtypes. We hypothesized the FASD group would reveal smaller brain volume, reduced cortical thickness, and reduced surface area compared to controls, with the partial fetal alcohol syndrome (pFAS)/fetal alcohol syndrome (FAS) subtypes showing the largest effects and the PAE/alcohol-related neurodevelopmental disorder (ARND) subtype revealing intermediate effects.MethodsThe sample consisted of 123 children and adolescents recruited from a single site including children with a diagnosis of FASD/PAE (26 males, 29 females) and controls (34 males, 34 females). Structural T1-weighted MRI scans were obtained on a 3T Trio TIM scanner and FreeSurfer v7.2 was used to quantify brain volume, cortical thickness, and surface area. Analyses examined effects by subgroup: pFAS/FAS (N = 32, Mage = 10.7 years, SEage = 0.79), PAE/ARND (N = 23, Mage = 10.8, SEage = 0.94), and controls (N = 68, Mage = 11.1, SEage = 0.54).ResultsTotal brain volume in children with an FASD was smaller relative to controls, but subtype analysis revealed only the pFAS/FAS group differed significantly from controls. Regional analyses similarly revealed reduced brain volume in frontal and temporal regions for children with pFAS/FAS, yet children diagnosed with PAE/ARND generally had similar volumes as controls. Notable differences to this pattern occurred in the cerebellum, caudate, and pallidum where children with pFAS/FAS and PAE/ARND revealed lower volume relative to controls. In the subset of participants who had neuropsychological testing, correlations between volume and IQ scores were observed. Goodness-of-Fit analysis by age revealed differences in developmental patterns (linear vs. quadratic) between groups in some cases.DiscussionThis study confirmed prior results indicating decreased brain volume in children with an FASD and extended the results by demonstrating differential effects by structure for FASD subtypes. It provides further evidence for a complex role of PAE in structural brain development that is likely related to the cognitive and behavioral effects experienced by children with an FASD
GWAS on family history of Alzheimerās disease
Alzheimerās disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimerās dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (nā=ā74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (Pā<ā5āĆā10ā8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications
Why alternative teenagers self-harm: exploring the link between non-suicidal self-injury, attempted suicide and adolescent identity
Background:
The term āself-harmā encompasses both attempted suicide and non-suicidal self-injury (NSSI). Specific adolescent subpopulations such as ethnic or sexual minorities, and more controversially, those who identify as āAlternativeā (Goth, Emo) have been proposed as being more likely to self-harm, while other groups such as āJocksā are linked with protective coping behaviours (for example exercise). NSSI has autonomic (it reduces negative emotions) and social (it communicates distress or facilitates group ābondingā) functions. This study explores the links between such aspects of self-harm, primarily NSSI, and youth subculture.<p></p>
Methods:
An anonymous survey was carried out of 452 15 year old German school students. Measures included: identification with different youth cultures, i.e. Alternative (Goth, Emo, Punk), Nerd (academic) or Jock (athletic); social background, e.g. socioeconomic status; and experience of victimisation. Self-harm (suicide and NSSI) was assessed using Self-harm Behavior Questionnaire and the Functional Assessment of Self-Mutilation (FASM).<p></p>
Results:
An āAlternativeā identity was directly (rāāā0.3) and a āJockā identity inversely (rāāā-0.1) correlated with self-harm. āAlternativeā teenagers self-injured more frequently (NSSI 45.5% vs. 18.8%), repeatedly self-injured, and were 4ā8 times more likely to attempt suicide (even after adjusting for social background) than their non-Alternative peers. They were also more likely to self-injure for autonomic, communicative and social reasons than other adolescents.<p></p>
Conclusions:
About half of āAlternativeā adolescentsā self-injure, primarily to regulate emotions and communicate distress. However, a minority self-injure to reinforce their group identity, i.e. āTo feel more a part of a groupā
Compounds from an Unbiased Chemical Screen Reverse Both Er-to-Golgi Trafficking Defects and Mitochondrial Dysfunction in Parkinson's Disease Models
Ī±-Synuclein (Ī±-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because Ī±-syn dysfunction is associated with several neurodegenerative disorders, including Parkinsonās disease (PD). We previously created a yeast model of Ī±-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to Ī±-syn expression. We also uncovered a core group of proteins with diverse activities related to Ī±-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of Ī±-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress Ī±-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of Ī±-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced Ī±-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of Ī±-syn foci, re-established ER-to-Golgi trafficking and ameliorated Ī±-syn-mediated damage to mitochondria. They also corrected the toxicity of Ī±-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of Ī±-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (NS038372)Michael J. Fox Foundation for Parkinson's ResearchHoward Hughes Medical InstituteUnited States. National Institutes of Health (NS049221)American Parkinson Disease Association, Inc
Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa
There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter-gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6.Social Science and Humanities Research Council of Canada; NORAM; American-Scandinavian Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/73598/2010]; IGERT [DGE 0801634]; Hyde Family Foundations; Institute of Human Origins; National Science Foundation [BCS-9912465, BCS-0130713, BCS-0524087, BCS-1138073]; John Templeton Foundation to the Institute of Human Origins at Arizona State Universit
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