1,711 research outputs found
Thermoelastic and structural properties of ionically conducting cerate perovskites: (II) SrCeO<sub>3</sub> between 1273 K and 1723 K
Thermodynamic grüneisen parameter and bond valence parameters for strontium cerate perovskite.</p
A common variant associated with dyslexia reduces expression of the KIAA0319 gene
This work was supported by the Wellcome Trust (MYD, SP, TSS, JCK, RWM, PC, SB, and APM), the Intramural Research Programs of the National Human Genome Research Institute (MYD and EDG) and National Cancer Institute (MPO), and the NIH/Ox-Cam Graduate Partnership Program (MYD).Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.PostprintPeer reviewe
The Design and Validation of the Quantum Mechanics Conceptual Survey
The Quantum Mechanics Conceptual Survey (QMCS) is a 12-question survey of
students' conceptual understanding of quantum mechanics. It is intended to be
used to measure the relative effectiveness of different instructional methods
in modern physics courses. In this paper we describe the design and validation
of the survey, a process that included observations of students, a review of
previous literature and textbooks and syllabi, faculty and student interviews,
and statistical analysis. We also discuss issues in the development of specific
questions, which may be useful both for instructors who wish to use the QMCS in
their classes and for researchers who wish to conduct further research of
student understanding of quantum mechanics. The QMCS has been most thoroughly
tested in, and is most appropriate for assessment of (as a posttest only),
sophomore-level modern physics courses. We also describe testing with students
in junior quantum courses and graduate quantum courses, from which we conclude
that the QMCS may be appropriate for assessing junior quantum courses, but is
not appropriate for assessing graduate courses. One surprising result of our
faculty interviews is a lack of faculty consensus on what topics should be
taught in modern physics, which has made designing a test that is valued by a
majority of physics faculty more difficult than expected.Comment: Submitted to Physical Review Special Topics: Physics Education
Researc
Mitigating agrichemicals from an artificial runoff event using a managed riverine wetland
We examined the mitigation efficiency of a managed riverine wetland amended with a mixture of suspended sediment, two nutrients (nitrogen and phosphorus), and three pesticides (atrazine, metolachlor, and permethrin) during a simulated agricultural runoff event. Hydrologic management of the 500 m-long, 25 mwide riverine wetland was done by adding weirs at both ends. The agrichemical mixture was amended to the wetland at the upstream weir simulating a four-hour, ~1 cm rainfall event from a 16 ha agricultural field. Water samples (1 L) were collected every 30 min within the first 4 h, then every 4 h until 48 h, and again on days 5, 7, 14, 21, and 28 post-amendment at distances of 0 m, 10 m, 40 m, 300 m and 500 m from the amendment point within the wetland for suspended solids, nutrient, and pesticide analyses. Peak sediment, nutrient, and pesticide concentrations occurred within 3 h of amendment at 0 m, 10 m, 40 m, and 300 m downstream and showed rapid attenuation of agrichemicals from the water column with 79–98%, 42–98%, and 63–98% decrease in concentrations of sediments, nutrients, and pesticides, respectively, within 48 h. By day 28, all amendments were near or below pre-amendment concentrations. Water samples at 500 m showed no changes in sediment or nutrient concentrations; pesticide concentrations peaked within 48 h but at ≤11% of upstream peak concentrations and had dissipated by day 28. Managed riverine wetlands≥1 ha and with hydraulic residence times of days to weeks can efficiently trap agricultural runoff during moderate (1 cm) late-spring and early-summer rainfall events, mitigating impacts to receiving rivers
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Stops making sense: translational trade-offs and stop codon reassignment
Background
Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature.
Results
In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences.
Conclusions
We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants
Eulerian simulation of the fluid dynamics of helicopter brownout
A computational model is presented that can be used to simulate the development of the dust cloud
that can be entrained into the air when a helicopter is operated close to the ground in desert or dusty
conditions. The physics of this problem, and the associated pathological condition known as ‘brownout’
where the pilot loses situational awareness as a result of his vision being occluded by dust suspended in the
flow around the helicopter, is acknowledged to be very complex. The approach advocated here involves
an approximation to the full dynamics of the coupled particulate-air system. Away from the ground, the
model assumes that the suspended particles remain in near equilibrium under the action of aerodynamic
forces. Close to the ground, this model is replaced by an algebraic sublayer model for the saltation and
entrainment process. The origin of the model in the statistical mechanics of a distribution of particles
governed by aerodynamic forces allows the validity of the method to be evaluated in context by comparing
the physical properties of the suspended particulates to the local properties of the flow field surrounding
the helicopter. The model applies in the Eulerian frame of reference of most conventional Computational
Fluid Dynamics codes and has been coupled with Brown’s Vorticity Transport Model. Verification of the
predictions of the coupled model against experimental data for particulate entrainment and transport in
the flow around a model rotor are encouraging. An application of the coupled model to analyzing the
differences in the geometry and extent of the dust clouds that are produced by single main rotor and
tandem-rotor configurations as they decelerate to land has shown that the location of the ground vortex
and the size of any regions of recirculatory flow, should they exist, play a primary role in governing the
extent of the dust cloud that is created by the helicopter
Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
A patient with a heterozygous variant of Creutzfeldt-Jakob disease (CJD) with a methionine/valine genotype at codon 129 of the prion protein gene was recently reported. Using an ultrasensitive and specific protein misfolding cyclic amplification–based assay for detecting variant CJD prions in cerebrospinal fluid, we discriminated this heterozygous case of variant CJD from cases of sporadic CJD
Identification of common genetic variation that modulates alternative splicing
Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function
Spasmogenic Effects of the Proteasome Inhibitor Carfilzomib on Coronary Resistance, Vascular Tone and Reactivity
Background: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides
heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated
in patients with recent myocardial infarction/unstable angina excluded from the safety trials.
Aimof Study: To test the effects of CFZ (10−9 to 10−7 mol/L) on vascular tone and reactivity in the isolated rabbit
heart and aorta.
Methods and Results: CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure
(CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the
highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic
strips with contraction plateau reached after 10 min. This spasmogenic effect doubled following ablation of the
endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin
II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and
nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreatedwith CFZ exhibited
impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-
dependent vasodilating agent, on the plateau of NA contraction (p b 0.05).
Conclusions: CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents.
Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over
50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent
mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior
history of coronary spasm
The Juvenile Justice Behavioral Health Services Cascade: A New Framework for Measuring Unmet Substance Use Treatment Services Needs Among Adolescent Offenders
Overview—Substance use and substance use disorders are highly prevalent among youth under juvenile justice (JJ) supervision, and related to delinquency, psychopathology, social problems, risky sex and sexually transmitted infections, and health problems. However, numerous gaps exist in the identification of behavioral health (BH) problems and in the subsequent referral, initiation and retention in treatment for youth in community justice settings. This reflects both organizational and systems factors, including coordination between justice and BH agencies.
Methods and Results—This paper presents a new framework, the Juvenile Justice Behavioral Health Services Cascade (“Cascade”), for measuring unmet substance use treatment needs to illustrate how the cascade approach can be useful in understanding service delivery issues and identifying strategies to improve treatment engagement and outcomes for youth under community JJ supervision. We discuss the organizational and systems barriers for linking delinquent youth to BH services, and explain how the Cascade can help understand and address these barriers. We provide a detailed description of the sequential steps and measures of the Cascade, and then offer an example of its application from the Juvenile Justice – Translational Research on Interventions for Adolescents in the Legal System project (JJ-TRIALS), a multi-site research cooperative funded by the National Institute on Drug Abuse.
Conclusion—As illustrated with substance abuse treatment, the Cascade has potential for informing and guiding efforts to improve behavioral health service linkages for adolescent offenders, developing and testing interventions and policies to improve interagency and cross-systems coordination, and informing the development of measures and interventions for improving the implementation of treatment in complex multisystem service settings
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