Measuring optical activity in the far-field from a racemic nanomaterial: Diffraction spectroscopy from plasmonic nanogratings

Recent progress in nanofabrication has redrawn the boundaries of the applicability of chiroptical (chiral optical) effects. Chirality, often expressed as a twist in biomolecules, is crucial for pharmaceuticals, where it can result in extremely different chemical properties. Because chiroptical effects are typically very weak in molecules, plasmonic nanomaterials are often proposed as a promising platform to significantly enhance these effects. Unfortunately, the ideal plasmonic nanomaterial has conflicting requirements: Its chirality should enhance that of the chiral molecules and yet it should have no chiroptical response on its own. Here, we propose a unique reconciliation to satisfy the requirements: A racemic plasmonic nanomaterial, consisting of equal amounts of opposite chiral unit cells. We show how diffraction spectroscopy can be used to unveil the presence of chirality in such racemic nanogratings in the far-field. Our experiments are supported by numerical simulations and yield a circular intensity difference of up to 15%. The physical origin is demonstrated by full wave simulations in combination with a Green's function-group-theory-based analysis. Contributions from Circular Dichroism in the Angular Distribution of Photoelectrons (CDAD) and pseudo/extrinsic chirality are ruled out. Our findings enable the far-field measurement and tuning of racemic nanomaterials, which is crucial for hyper-sensitive chiral molecular characterization.V. K. V. acknowledges support from the Royal Society through the University Research Fellowships. We acknowledge Royal Society grants CHG\R1\170067, PEF1\170015 and RGF\EA\180228, as well as STFC grant ST/R005842/1 and EPSRC grant EP/L015544/1. C. W. acknowledges financial support from Cancer Research UK (CRUK) Pioneer Award (C55962/A24669) and Wolfson College, Cambridge, UK. C. W. further acknowledges research support from S. Bohndiek, T. Wilkinson and G. Gordon. X. Z. and G. A. E. V. are grateful for the financial support from the FWO (G090017N) and KU Leuven internal research funds (C24/15/015)

Screening for asthma in Cantonese-speaking immigrant children

BACKGROUND: Asthma prevalence among Chinese immigrant children is poorly understood and attempts to screen these children have produced varied outcomes. We sought to learn how to improve screening for asthma in Chinese immigrant children. METHODS: Children (n = 152) were administered the Brief Pediatric Asthma Screen in either Cantonese or English, they then viewed and reacted to a video showing people wheezing and subsequently took a pulmonary function test. RESULTS: The diagnosed asthma prevalence for our study population was 27.0%, with another 5.3% having possible undiagnosed asthma. Very few children had spirometry findings below normal. In multivariate analysis, being native born (p = 0.002) and having a family history of asthma (p = 0.003) were statistically associated with diagnosis of asthma. After viewing the video, 35.6% of respondents indicated that the images differed from their conception of wheezing. Of four translations of the word "wheeze" no single word was chosen by a majority. CONCLUSION: Our findings suggest that asthma diagnoses are higher for Chinese children who were born in the US suggesting that desegregation of data might reveal at risk subpopulations. Care needs to be taken when diagnosing asthma for Cantonese speakers because of the centrality of the word wheeze and the challenges of translation

EZH2-mediated epigenetic repression of DNA repair in promoting breast tumor initiating cells

Members of the Polycomb-group (PcG) family of proteins, including EZH2 (enhancer of zeste homolog 2), are involved in establishing epigenetic silencing of developmental genes in adult and embryonic stem cells, and their deregulation has been implicated in cancer. In a recent report, EZH2-mediated epigenetic repression of DNA damage repair in breast tumor initiating cells (BTICs) was identified as a mechanism that could promote expansion of BTICs, and may contribute to cancer progression

Integrating Health Care for the Most Vulnerable: Bridging the Differences in Organizational Cultures Between US Hospitals and Community Health Centers

Policymakers have increasingly promoted health services integration to improve quality and efficiency. The US health care safety net, which comprises providers of health care to uninsured, Medicaid, and other vulnerable patients, remains a largely fragmented collection of providers. We interviewed leadership from safety net hospitals and community health centers in 5 US cities (Boston, MA; Denver, CO; Los Angeles, CA; Minneapolis, MN; and San Francisco, CA) throughout 2013 on their experiences with service integration. We identify conflicts in organizational mission, identity, and consumer orientation that have fostered reluctance to enter into collaborative arrangements. We describe how smaller scale initiatives, such as capitated model for targeted populations, health information exchange, and quality improvements led by health plans, can help bridge cultural differences to lay the groundwork for developing integrated care programs

A walking programme and a supervised exercise class versus usual physiotherapy for chronic low back pain: a single-blinded randomised controlled trial. (The Supervised Walking In comparison to Fitness Training for Back Pain (SWIFT) Trial)

BACKGROUND: Chronic low back pain (CLBP) is a persistent disabling condition with rising significant healthcare, social and economic costs. Current research supports the use of exercise-based treatment approaches that encourage people with CLBP to assume a physically active role in their recovery. While international clinical guidelines and systematic reviews for CLBP support supervised group exercise as an attractive first-line option for treating large numbers of CLBP patients at low cost, barriers to their delivery include space and time restrictions in healthcare settings and poor patient attendance. The European Clinical Guidelines have identified the need for research in the use of brief/minimal contact self-activation interventions that encourage participation in physical activity for CLBP. Walking may be an ideally suited form of individualized exercise prescription as it is easy to do, requires no special skills or facilities, and is achievable by virtually all ages with little risk of injury, but its effectiveness for LBP is unproven. METHODS AND DESIGN: This study will be an assessor-blinded randomized controlled trial that will investigate the difference in clinical effectiveness and costs of an individualized walking programme and a supervised general exercise programme compared to usual physiotherapy, which will act as the control group, in people with chronic low back pain. A sample of 246 patients will be recruited in Dublin, Ireland through acute general hospital outpatient physiotherapy departments that provide treatment for people with CLBP. Patients will be randomly allocated to one of the three groups in a concealed manner. The main outcomes will be functional disability, pain, quality of life, fear avoidance, back beliefs, physical activity, satisfaction and costs, which will be evaluated at baseline, and 3, 6 and 12 months [follow-up by pre-paid postage]. Qualitative telephone interviews and focus groups will be embedded in the research design to obtain feedback about participants' experiences of the interventions and trial participation, and to inform interpretation of the quantitative data. Planned analysis will be by intention to treat (quantitative data) and thematic analysis (qualitative data) DISCUSSION: The trial will evaluate the effectiveness of a walking programme and a supervised general exercise programme compared to usual physiotherapy in people with CLBP. TRIAL REGISTRATION: Current controlled trial ISRCTN1759209

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme

Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries in re-engineered native proteins has proved challenging. Wholesale modification of natural enzymes is potentially compromised by their intrinsic complexity, which often obscures the underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity by combining a robust de novo designed chassis with a design process that avoids atomistic mimicry of natural proteins. Here, we apply this method to the construction of a highly efficient, promiscuous, and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H2O2. The maquette exhibits kinetics that match and even surpass those of certain natural peroxidases, retains its activity at elevated temperature and in the presence of organic solvents, and provides a simple platform for interrogating catalytic intermediates common to natural heme-containing enzymes

Using the Autism-Spectrum Quotient to Discriminate Autism Spectrum Disorder from ADHD in Adult Patients With and Without Comorbid Substance Use Disorder

It is unknown whether the Autism-spectrum quotient (AQ) can discriminate between Autism Spectrum Disorder (ASD) and Attention Deficit and Hyperactivity Disorder (ADHD) with or without comorbid Substance Use Disorder (SUD). ANOVA’s were used to analyse the mean AQ (sub)scores of 129 adults with ASD or ADHD. We applied receiver operating characteristic (ROC) computations to assess discriminant power. All but one of the mean AQ (sub)scores were significantly higher for adults with ASD compared to those with ADHD. The SUD status in general was not significantly associated with AQ (sub)scores. On the Social Skills subscale patients with ASD and comorbid SUD showed less impairment than those without SUD. The cut-off score 26 yielded 73% correct classifications. The clinical use of the AQ in differentiating between ASD and ADHD is limited

High Throughput Microplate Respiratory Measurements Using Minimal Quantities Of Isolated Mitochondria

Recently developed technologies have enabled multi-well measurement of O2 consumption, facilitating the rate of mitochondrial research, particularly regarding the mechanism of action of drugs and proteins that modulate metabolism. Among these technologies, the Seahorse XF24 Analyzer was designed for use with intact cells attached in a monolayer to a multi-well tissue culture plate. In order to have a high throughput assay system in which both energy demand and substrate availability can be tightly controlled, we have developed a protocol to expand the application of the XF24 Analyzer to include isolated mitochondria. Acquisition of optimal rates requires assay conditions that are unexpectedly distinct from those of conventional polarography. The optimized conditions, derived from experiments with isolated mouse liver mitochondria, allow multi-well assessment of rates of respiration and proton production by mitochondria attached to the bottom of the XF assay plate, and require extremely small quantities of material (1–10 µg of mitochondrial protein per well). Sequential measurement of basal, State 3, State 4, and uncoupler-stimulated respiration can be made in each well through additions of reagents from the injection ports. We describe optimization and validation of this technique using isolated mouse liver and rat heart mitochondria, and apply the approach to discover that inclusion of phosphatase inhibitors in the preparation of the heart mitochondria results in a specific decrease in rates of Complex I-dependent respiration. We believe this new technique will be particularly useful for drug screening and for generating previously unobtainable respiratory data on small mitochondrial samples

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease