A Transport Analysis of the BEEM Spectroscopy of Au/Si Schottky Barriers

A systematic transport study of the ballistic electron emission microscopy (BEEM) of Au/Si(100) and Au/Si(111) Schottky barriers for different thicknesses of the metal layer and different temperatures is presented. It is shown that the existing experimental data are compatible with a recently predicted bandstructure-induced non-forward electron propagation through the Au(111) layer.Comment: 5 pages, Latex-APS, 1 postscript figure, http://www.icmm.csic.es/Pandres/pedro.htm. Phys. Stat. Sol. (b) (to appear), HCIS-10 Conf, Berlin 199

Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases

Aim: Brain clusterin is known to be associated with the amyloid‐β deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases. Methods: Post‐mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL. Results: Immunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non‐phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid‐β in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL. Conclusions: Our results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states

Foot Bone in Vivo: Its Center of Mass and Centroid of Shape

This paper studies foot bone geometrical shape and its mass distribution and establishes an assessment method of bone strength. Using spiral CT scanning, with an accuracy of sub-millimeter, we analyze the data of 384 pieces of foot bones in vivo and investigate the relationship between the bone's external shape and internal structure. This analysis is explored on the bases of the bone's center of mass and its centroid of shape. We observe the phenomenon of superposition of center of mass and centroid of shape fairly precisely, indicating a possible appearance of biomechanical organism. We investigate two aspects of the geometrical shape, (i) distance between compact bone's centroid of shape and that of the bone and (ii) the mean radius of the same density bone issue relative to the bone's centroid of shape. These quantities are used to interpret the influence of different physical exercises imposed on bone strength, thereby contributing to an alternate assessment technique to bone strength.Comment: 9 pages, 4 figure

Symptoms associated with victimization in patients with schizophrenia and related disorders

Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization. Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20–29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios. Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples. Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments

Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas

Ablation of prion protein immunoreactivity by heating in saturated calcium hydroxide

<p>Abstract</p> <p>Background</p> <p>Prions, the infectious agents that cause transmissible spongiform encephalopathies (TSEs), are relatively resistant to destruction by physical, enzymatic, and chemical treatments. Hydrolysis in boiling saturated calcium hydroxide (limewater) utilizes inexpensive chemicals to digest protein components of offal. The purpose of this work was to determine if incubating brain material from scrapie-infected sheep in near-boiling saturated calcium hydroxide solution (Ca(OH)₂) would abolish immunoreactivity of the infectious prion (PrP^Sc) as determined by western blot.</p> <p>Findings</p> <p>After incubating for as few as 10 minutes in saturated calcium hydroxide at 99°C, immunoreactivity of protease resistant bands by western blot analysis is completely lost.</p> <p>Conclusion</p> <p>Boiling in limewater may offer an alternative for disposal of carcasses and enable alternative uses for rendered products from potentially infected carcasses.</p

Long-term monitoring in primary care for chronic kidney disease and chronic heart failure: a multi-method research programme

Background: Long-term monitoring is important in chronic condition management. Despite considerable costs of monitoring, there is no or poor evidence on how, what and when to monitor. The aim of this study was to improve understanding, methods, evidence base and practice of clinical monitoring in primary care, focusing on two areas: chronic kidney disease and chronic heart failure. Objectives: The research questions were as follows: does the choice of test affect better care while being affordable to the NHS? Can the number of tests used to manage individuals with early-stage kidney disease, and hence the costs, be reduced? Is it possible to monitor heart failure using a simple blood test? Can this be done using a rapid test in a general practitioner consultation? Would changes in the management of these conditions be acceptable to patients and carers? Design: Various study designs were employed, including cohort, feasibility study, Clinical Practice Research Datalink analysis, seven systematic reviews, two qualitative studies, one cost-effectiveness analysis and one cost recommendation. Setting: This study was set in UK primary care. Data sources: Data were collected from study participants and sourced from UK general practice and hospital electronic health records, and worldwide literature. Participant: The participants were NHS patients (Clinical Practice Research Datalink: 4.5 million patients), chronic kidney disease and chronic heart failure patients managed in primary care (including 750 participants in the cohort study) and primary care health professionals. Interventions: The interventions were monitoring with blood and urine tests (for chronic kidney disease) and monitoring with blood tests and weight measurement (for chronic heart failure). Main outcome measures: The main outcomes were the frequency, accuracy, utility, acceptability, costs and cost-effectiveness of monitoring. Results: Chronic kidney disease: serum creatinine testing has increased steadily since 1997, with most results being normal (83% in 2013). Increases in tests of creatinine and proteinuria correspond to their introduction as indicators in the Quality and Outcomes Framework. The Chronic Kidney Disease Epidemiology Collaboration equation had 2.7% greater accuracy (95% confidence interval 1.6% to 3.8%) than the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate. Estimated annual transition rates to the next chronic kidney disease stage are ≈ 2% for people with normal urine albumin, 3–5% for people with microalbuminuria (3–30 mg/mmol) and 3–12% for people with macroalbuminuria (> 30 mg/mmol). Variability in estimated glomerular filtration rate-creatinine leads to misclassification of chronic kidney disease stage in 12–15% of tests in primary care. Glycaemic-control and lipid-modifying drugs are associated with a 6% (95% confidence interval 2% to 10%) and 4% (95% confidence interval 0% to 8%) improvement in renal function, respectively. Neither estimated glomerular filtration rate-creatinine nor estimated glomerular filtration rate-Cystatin C have utility in predicting rate of kidney function change. Patients viewed phrases such as ‘kidney damage’ or ‘kidney failure’ as frightening, and the term ‘chronic’ was misinterpreted as serious. Diagnosis of asymptomatic conditions (chronic kidney disease) was difficult to understand, and primary care professionals often did not use ‘chronic kidney disease’ when managing patients at early stages. General practitioners relied on Clinical Commissioning Group or Quality and Outcomes Framework alerts rather than National Institute for Health and Care Excellence guidance for information. Cost-effectiveness modelling did not demonstrate a tangible benefit of monitoring kidney function to guide preventative treatments, except for individuals with an estimated glomerular filtration rate of 60–90 ml/minute/1.73 m2, aged < 70 years and without cardiovascular disease, where monitoring every 3–4 years to guide cardiovascular prevention may be cost-effective. Chronic heart failure: natriuretic peptide-guided treatment could reduce all-cause mortality by 13% and heart failure admission by 20%. Implementing natriuretic peptide-guided treatment is likely to require predefined protocols, stringent natriuretic peptide targets, relative targets and being located in a specialist heart failure setting. Remote monitoring can reduce all-cause mortality and heart failure hospitalisation, and could improve quality of life. Diagnostic accuracy of point-of-care N-terminal prohormone of B-type natriuretic peptide (sensitivity, 0.99; specificity, 0.60) was better than point-of-care B-type natriuretic peptide (sensitivity, 0.95; specificity, 0.57). Within-person variation estimates for B-type natriuretic peptide and weight were as follows: coefficient of variation, 46% and coefficient of variation, 1.2%, respectively. Point-of-care N-terminal prohormone of B-type natriuretic peptide within-person variability over 12 months was 881 pg/ml (95% confidence interval 380 to 1382 pg/ml), whereas between-person variability was 1972 pg/ml (95% confidence interval 1525 to 2791 pg/ml). For individuals, monitoring provided reassurance; future changes, such as increased testing, would be acceptable. Point-of-care testing in general practice surgeries was perceived positively, reducing waiting time and anxiety. Community heart failure nurses had greater knowledge of National Institute for Health and Care Excellence guidance than general practitioners and practice nurses. Health-care professionals believed that the cost of natriuretic peptide tests in routine monitoring would outweigh potential benefits. The review of cost-effectiveness studies suggests that natriuretic peptide-guided treatment is cost-effective in specialist settings, but with no evidence for its value in primary care settings. Limitations: No randomised controlled trial evidence was generated. The pathways to the benefit of monitoring chronic kidney disease were unclear. Conclusions: It is difficult to ascribe quantifiable benefits to monitoring chronic kidney disease, because monitoring is unlikely to change treatment, especially in chronic kidney disease stages G3 and G4. New approaches to monitoring chronic heart failure, such as point-of-care natriuretic peptide tests in general practice, show promise if high within-test variability can be overcome

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

Parkour as a donor sport for athletic development in youth team sports: insights through an ecological dynamics lens

Analyses of talent development in sport have identified that skill can be enhanced through early and continued involvement in donor sports which share affordances (opportunities for action) with a performer's main target sport. Aligning key ideas of the Athletic Skills Model and ecological dynamics theory, we propose how the sport of parkour could provide a representative and adaptive platform for developing athletic skill (e.g. coordination, timing, balance, agility, spatial awareness and muscular strength). We discuss how youth sport development programmes could be (re) designed to include parkour-style activities, in order to develop general athletic skills in affordance-rich environments. It is proposed that team sports development programmes could particularly benefit from parkour-style training since it is exploratory and adaptive nature shapes utilisation of affordances for innovative and autonomous performance by athletes. Early introduction to varied, relevant activities for development of athleticism and skill, in a diversified training programme, would provide impetus for a fundamental shift away from the early specialisation approach favoured by traditional theories of skill acquisition and expertise in sport