662 research outputs found
The Development of an After-School Program for Youth Placed At-Risk: A Collaborative Approach
Educators, program practitioners, and potential community partners may enjoy this presentation on a collaborative approach to improving the lives of youth that have been placed at-risk within and outside of a Title I elementary schoolâs after-school program. By combining resources, expertise, and disciplines, the program works to develop well-rounded and personally and socially responsible children through academic enrichment, sport-based youth development, and parental engagement
Lessons Learned from an After-School Program: Building Personal and Social Responsibility
Drawing from the physical activity and positive youth development literatures, this paper describes a novel after-school effort designed to enhance youthsâ life skill development outcomes across school, family, and community settings. This program, which is derived from the Teaching Personal and Social Responsibility (TPSR) model, is a university-assisted effort serving 1st through 5th graders attending a low-income elementary school. As a part of this modelâs approach, pre-service physical education teachers engage in a yearlong course sequence and practicum that enables them to deliver the program. University graduate students and faculty then provide ongoing support, facilitation, and training to the pre-service teachers at the same time they conduct field-based research on the effort. The preliminary data indicate that the program can successfully impact several teaching and life skill development outcomes. However, additional interventions appear to be needed to extend youthsâ outcomes to settings outside of the program
Targeted chromosomal deletions and inversions in zebrafish
Zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) provide powerful platforms for genome editing in plants and animals. Typically, a single nuclease is sufficient to disrupt the function of protein-coding genes through the introduction of microdeletions or insertions that cause frameshifts within an early coding exon. However, interrogating the function of cis-regulatory modules or noncoding RNAs in many instances requires the excision of this element from the genome. In human cell lines and invertebrates, two nucleases targeting the same chromosome can promote the deletion of intervening genomic segments with modest efficiencies. We have examined the feasibility of using this approach to delete chromosomal segments within the zebrafish genome, which would facilitate the functional study of large noncoding sequences in a vertebrate model of development. Herein, we demonstrate that segmental deletions within the zebrafish genome can be generated at multiple loci and are efficiently transmitted through the germline. Using two nucleases, we have successfully generated deletions of up to 69 kb at rates sufficient for germline transmission (1%-15%) and have excised an entire lincRNA gene and enhancer element. Larger deletions (5.5 Mb) can be generated in somatic cells, but at lower frequency (0.7%). Segmental inversions have also been generated, but the efficiency of these events is lower than the corresponding deletions. The ability to efficiently delete genomic segments in a vertebrate developmental system will facilitate the study of functional noncoding elements on an organismic level
Does inbreeding contribute to pregnancy loss in Thoroughbred horses?
Background: Excessive inbreeding increases the probability of uncovering homozygous recessive genotypes and has been associated with an increased risk of retained placenta and lower semen quality. No genomic analysis has investigated the association between inbreeding levels and pregnancy loss. Objectives: This study compared genetic inbreeding coefficients (F) of naturally occurring Thoroughbred Early Pregnancy Loss (EPLs), Mid and Late term Pregnancy Loss (MLPL), and Controls. The F value was hypothesised to be higher in cases of pregnancy loss (EPLs and MLPLs) than Controls. Study design: Observational case-control study. Methods: Allantochorion and fetal DNA from EPL (n=37, gestation age 14-65 days), MLPL (n=94, gestational age 70 daysâ24 hours post parturition) and Controls (n=58) were genotyped on the Axiom Equine 670K SNP Genotyping Array. Inbreeding coefficients using Runs Of Homozygosity (FROH) were calculated using PLINK software. ROHs were split into size categories to investigate the recency of inbreeding. Results: MLPLs had significantly higher median number of ROH (188 interquartile range (IQR), 180.8-197.3), length of ROH (3.10, IQR 2.93-3.33), and total number of ROH (590.8, IQR 537.3-632.3), and FROH (0.26, IQR 0.24-0.28) when compared with the Controls and the EPLs (p<0.05). There was no significant difference in any of the inbreeding indices between the EPLs and Controls. The MLPLs had a significantly higher proportion of long (>10 Mb) ROH (2.5%, IQR 1.6-3.6) than the Controls (1.7%, IQR 0.6-2.5), p=0.001. No unique ROHs were found in the EPL or MLPL populations. Limitations: SNP-array data does not allow analysis of every base in the sequence. Conclusions: This first study of the effect of genomic inbreeding levels on pregnancy loss showed that inbreeding is a contributor to MLPL, but not EPL in the UK Thoroughbred population. Mating choices remain critical, because inbreeding may predispose to MLPL by increasing the risk of homozygosity for specific lethal allele(s)
Prion infection impairs cholesterol metabolism in neuronal cells
Conversion of prion protein (PrPC) into a pathological isoform (PrPSc) during prion infection occurs in lipid rafts and is dependent on cholesterol. Here, we show that prion infection increases the abundance of cholesterol transporter, ATP-binding cassette transporter type A1 (ATP-binding cassette transporter type A1), but reduces cholesterol efflux from neuronal cells leading to the accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was confirmed in prion-infected mice. Mechanistically, conversion of PrPC to the pathological isoform led to PrPSc accumulation in rafts, displacement of ABCA1 from rafts and the cell surface, and enhanced internalization of ABCA1. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression with liver X receptor agonist or overexpression of heterologous ABCA1 reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, which plays an important role in the pathogenesis of prion infection in neuronal cells
Birth and Evolution of Isolated Radio Pulsars
We investigate the birth and evolution of Galactic isolated radio pulsars. We
begin by estimating their birth space velocity distribution from proper motion
measurements of Brisken et al. (2002, 2003). We find no evidence for
multimodality of the distribution and favor one in which the absolute
one-dimensional velocity components are exponentially distributed and with a
three-dimensional mean velocity of 380^{+40}_{-60} km s^-1. We then proceed
with a Monte Carlo-based population synthesis, modelling the birth properties
of the pulsars, their time evolution, and their detection in the Parkes and
Swinburne Multibeam surveys. We present a population model that appears
generally consistent with the observations. Our results suggest that pulsars
are born in the spiral arms, with a Galactocentric radial distribution that is
well described by the functional form proposed by Yusifov & Kucuk (2004), in
which the pulsar surface density peaks at radius ~3 kpc. The birth spin period
distribution extends to several hundred milliseconds, with no evidence of
multimodality. Models which assume the radio luminosities of pulsars to be
independent of the spin periods and period derivatives are inadequate, as they
lead to the detection of too many old simulated pulsars in our simulations.
Dithered radio luminosities proportional to the square root of the spin-down
luminosity accommodate the observations well and provide a natural mechanism
for the pulsars to dim uniformly as they approach the death line, avoiding an
observed pile-up on the latter. There is no evidence for significant torque
decay (due to magnetic field decay or otherwise) over the lifetime of the
pulsars as radio sources (~100 Myr). Finally, we estimate the pulsar birthrate
and total number of pulsars in the Galaxy.Comment: 27 pages, including 15 figures, accepted by Ap
Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease
Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity
Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuroblastoma cells
The misfolding and aggregation of the largely disordered protein, α-synuclein, is a central pathogenic event that occurs in the synucleinopathies, a group of neurodegenerative disorders that includes Parkinson's disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated α-synuclein are unresolved. Here, we studied the pathogenicity of misfolded α-synuclein produced using the protein misfolding cyclic amplification (PMCA) assay. To do this, previous publishedmethodswere adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded α-synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded α-synuclein. To investigate whether such an interaction can impact the properties of α-synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show that CA both accelerates the rate ofα-synuclein fibrillization and produces species that harbourenhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live nontransgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed that misfoldedα-synucleincauses hyperactive mitochondrial respiration without causing any functional deficit.These datagive strong support for the mitochondrion as a target for misfolded α-synuclein and reveal persistent, hyperactive respiration as a potential upstream pathogenic event associated with the synucleinopathies
Strange homelands: encountering the migrant on the contemporary Greek stage
This article examines three examples from recent Greek theatre which stage experiences of migrants and refugees against the backdrop of Greeceâs growing internationalism and multiculturalism. In allowing migrants to author their own narratives of border-crossing and encountering their new âhomelandâ, those theatrical endeavours, I argue, attempt to break the monologism of Greek theatre and monolithic understandings of national identity thus opening up spaces for encountering diverse voices. In acknowledging the risks and tensions underpinning the migrantâs presence on stage, the article also applies pressure to questions of encounter, authenticity, representation and self-expression of migratory subjects and interrogates some ways in which they navigate their precarious space of belonging and author themselves in the context of contemporary Greek theatre
Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the UK and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR)
- âŠ