Cancer-selective, single agent chemoradiosensitising gold nanoparticles

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics

Contrasting Genetic Structure in Two Co-Distributed Species of Old World Fruit Bat

The fulvous fruit bat (Rousettus leschenaulti) and the greater short-nosed fruit bat (Cynopterus sphinx) are two abundant and widely co-distributed Old World fruit bats in Southeast and East Asia. The former species forms large colonies in caves while the latter roots in small groups in trees. To test whether these differences in social organization and roosting ecology are associated with contrasting patterns of gene flow, we used mtDNA and nuclear loci to characterize population genetic subdivision and phylogeographic histories in both species sampled from China, Vietnam and India. Our analyses from R. leschenaulti using both types of marker revealed little evidence of genetic structure across the study region. On the other hand, C. sphinx showed significant genetic mtDNA differentiation between the samples from India compared with China and Vietnam, as well as greater structuring of microsatellite genotypes within China. Demographic analyses indicated signatures of past rapid population expansion in both taxa, with more recent demographic growth in C. sphinx. Therefore, the relative genetic homogeneity in R. leschenaulti is unlikely to reflect past events. Instead we suggest that the absence of substructure in R. leschenaulti is a consequence of higher levels of gene flow among colonies, and that greater vagility in this species is an adaptation associated with cave roosting

Prevalence of foot pain across an international consortium of population based cohorts.

OBJECTIVE: Despite the potential burden of foot pain, some of the most fundamental epidemiological questions surrounding the foot remain poorly explored. The prevalence of foot pain has proved difficult to compare across existing studies due to variations in case definitions. The objective of this study was to investigate the prevalence of foot pain in a number of international population-based cohorts using original data and to explore differences in the case definitions used. METHODS: Foot pain variables were examined in five cohorts (the Chingford Women Study, the Johnston County Osteoarthritis Project, the Framingham Foot Study, the Clinical Assessment Study of the Foot and the North West Adelaide Health Study). One foot pain question was chosen from each cohort based on its similarity to the American College of Rheumatology (ACR) pain question. RESULTS: The precise definition of foot pain varied between the cohorts. The prevalence of foot pain ranged from 13 to 36% and was lowest within the cohort that used a case definition specific to pain, compared to the four remaining cohorts that included components of pain, aching or stiffness. Foot pain was generally more prevalent in women, the obese and generally increased with age, being much lower in younger participants (20-44 years). CONCLUSION: Foot pain is common and is associated with female sex, older age and obesity. The prevalence of foot pain is likely affected by the case definition used, therefore consideration must be given for future population studies to use consistent measures of data collection. This article is protected by copyright. All rights reserved

Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention

Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention. Methods Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank. Findings In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution. Interpretation Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification. Funding National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.This study was supported by funding from National Health and Medical Research Council (NHMRC) grant APP1062227. Supported in part by the Victorian Government’s OIS Program. M.I. was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). G.A. was supported by an NHMRC Early Career Fellowship (no. 1090462). N.J.S., C.P.N. and B.K. are supported by the British Heart Foundation and N.J.S. is a NIHR Senior Investigator. R.S.P. is supported by the British Heart Foundation (FS/14/76/30933). The MRC/BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council [MR/L003120/1], British Heart Foundation [RG/13/13/30194], and UK National Institute for Health Research Cambridge Biomedical Research Centre. J.D. is a British Heart Foundation Professor and NIHR Senior Investigator

Developmental Transcriptional Networks Are Required to Maintain Neuronal Subtype Identity in the Mature Nervous System

During neurogenesis, transcription factors combinatorially specify neuronal fates and then differentiate subtype identities by inducing subtype-specific gene expression profiles. But how is neuronal subtype identity maintained in mature neurons? Modeling this question in two Drosophila neuronal subtypes (Tv1 and Tv4), we test whether the subtype transcription factor networks that direct differentiation during development are required persistently for long-term maintenance of subtype identity. By conditional transcription factor knockdown in adult Tv neurons after normal development, we find that most transcription factors within the Tv1/Tv4 subtype transcription networks are indeed required to maintain Tv1/Tv4 subtype-specific gene expression in adults. Thus, gene expression profiles are not simply “locked-in,” but must be actively maintained by persistent developmental transcription factor networks. We also examined the cross-regulatory relationships between all transcription factors that persisted in adult Tv1/Tv4 neurons. We show that certain critical cross-regulatory relationships that had existed between these transcription factors during development were no longer present in the mature adult neuron. This points to key differences between developmental and maintenance transcriptional regulatory networks in individual neurons. Together, our results provide novel insight showing that the maintenance of subtype identity is an active process underpinned by persistently active, combinatorially-acting, developmental transcription factors. These findings have implications for understanding the maintenance of all long-lived cell types and the functional degeneration of neurons in the aging brain

Incidence of self-reported brain injury and the relationship with substance abuse: findings from a longitudinal community survey

<p>Abstract</p> <p>Background</p> <p>Traumatic or serious brain injury (BI) has persistent and well documented adverse outcomes, yet 'mild' or 'moderate' BI, which often does not result in hospital treatment, accounts for half the total days of disability attributed to BI. There are currently few data available from community samples on the incidence and correlates of these injuries. Therefore, the study aimed to assess the 1) incidence of self-reported mild (not requiring hospital admission) and moderate (admitted to hospital)) brain injury (BI), 2) causes of injury 3) physical health scores and 4) relationship between BI and problematic alcohol or marijuana use.</p> <p>Methods</p> <p>An Australian community sequential-cohort study (cohorts aged 20-24, 40-44 and 60-64 years at wave one) used a survey methodology to assess BI and substance use at baseline and four years later.</p> <p>Results</p> <p>Of the 7485 wave one participants, 89.7% were re-interviewed at wave two. There were 56 mild (230.8/100000 person-years) and 44 moderate BI (180.5/100000 person-years) reported between waves one and two. Males and those in the 20-24 year cohort had increased risk of BI. Sports injury was the most frequent cause of BI (40/100) with traffic accidents being a greater proportion of moderate (27%) than mild (7%) BI. Neither alcohol nor marijuana problems at wave one were predictors of BI. BI was not a predictor of developing substance use problems by wave two.</p> <p>Conclusions</p> <p>BI were prevalent in this community sample, though the incidence declined with age. Factors associated with BI in community samples differ from those reported in clinical samples (e.g. typically traumatic brain injury with traffic accidents the predominate cause). Further, detailed evaluation of the health consequences of these injuries is warranted.</p

Plastisol Foaming Process. Decomposition of the Foaming Agent, Polymer Behavior in the Corresponding Temperature Range and Resulting Foam Properties

The decomposition of azodicarbonamide, used as foaming agent in PVC - plasticizer (1/1) plastisols was studied by DSC. Nineteen different plasticizers, all belonging to the ester family, two being polymeric (polyadipates), were compared. The temperature of maximum decomposition rate (in anisothermal regime at 5 K min-1 scanning rate), ranges between 434 and 452 K. The heat of decomposition ranges between 8.7 and 12.5 J g -1. Some trends of variation of these parameters appear significant and are discussed in terms of solvent (matrix) and viscosity effects on the decomposition reactions. The shear modulus at 1 Hz frequency was determined at the temperature of maximum rate of foaming agent decomposition, and differs significantly from a sample to another. The foam density was determined at ambient temperature and the volume fraction of bubbles was used as criterion to judge the efficiency of the foaming process. The results reveal the existence of an optimal shear modulus of the order of 2 kPa that corresponds roughly to plasticizer molar masses of the order of 450 ± 50 g mol-1. Heavier plasticizers, especially polymeric ones are too difficult to deform. Lighter plasticizers such as diethyl phthalate (DEP) deform too easily and presumably facilitate bubble collapse

Searching for Heavy Charged Higgs Boson with Jet Substructure at the LHC

We study the heavy charged Higgs boson (from 800 GeV to 1500 GeV in this study) in production associated with a top quark at the LHC with the collision energy $\sqrt{s}=14$ TeV. Such a heavy charged Higgs boson can dominantly decay into a top quark and a bottom quark due to its large Yukawa couplings, like in MSSM. To suppress background events and to confirm the signal, we reconstruct the mass bumps of the heavy charged Higgs boson and the associated top quark. For this purpose, we propose a hybrid-R reconstruction method which utilizes the top tagging technique, a jet substructure technique developed for highly boosted massive particles. By using the full hadronic mode of $p p \to H^{\pm} t \to t tb$ as a test field, we find that this method can greatly reduce the combinatorics in the full reconstruction and can successfully reduce background events down to a controlled level. The sensitivity of LHC to the heavy charged Higgs boson with two $b$ taggings is studied and a $9.5\sigma$ significance can be achieved when $m_{H^\pm} =1 \textrm{TeV}$.Comment: 27 pages, 10 figures, 7 tables; v2: some typos corrected and references added; v3: discussion added, Fig.10 and Table7 updated, version published in JHE