Infection Risk and Critical Period for the Postharvest Control of Gray Mold (Botrytis cinerea) on Blueberry in Chile.
Gray mold (Botrytis cinerea) is a major disease of blueberries (Vaccinium spp.), which require more than 15 days of shipment at 0°C to reach international markets. The aims of this study were (i) to determine the relative susceptibility of the flowering and fruiting stages, (ii) to determine the critical blueberry growth stages for postharvest gray mold control, and (iii) to determine the infection risks on the basis of weather conditions. The epiphytic colonization of B. cinerea of flowers and fruits was demonstrated in blueberry 'Brigitta' and 'Duke' in Antuco and Virquenco. In inoculated flowers and fruits in humid chambers at 20°C, full bloom and mature fruit stages were the most susceptible stages. Fungicide applications at the mature fruit stage appeared as the most critical period for gray mold control in stored fruits. The algorithm proposed, which was based on >6 h of wetness between 14 and 25°C, allowed the estimation of the periods of B. cinerea infection risk. A significant correlation between the B. cinerea infection risk and gray mold incidence in stored fruits was obtained (r = 0.96, P < 0.0001). Therefore, this algorithm has the potential to optimize fungicide applications under field conditions, but field validation of this algorithm remains to be determined.


Do incompatible arguments cause extensive processing in the evaluation of arguments? The role of congruence between argument compatibility and argument quality.
Previous studies have demonstrated that arguments incompatible with prior beliefs are subjected to more extensive refutational processing, scrutinized longer, and judged to be weaker than arguments compatible with prior beliefs. However, this study suggests whether extensive processing is implemented when evaluating arguments is not decided by argument compatibility, but by congruence between two evaluating tendencies elicited by both argument compatibility and argument quality. Consistent with this perspective, the results of two experiments show that relative to congruent arguments, participants judged arguments eliciting incongruent evaluating tendencies as less extreme in strength, spent more time, and felt more hesitant generating strength judgments for them. The results also show that it is mainly incongruent arguments, not congruent arguments, whose strength ratings were more closely associated with the perceived personal importance of the issue, which intensified the tendency to evaluate arguments depending on argument compatibility. These results suggest that it is the incongruity between argument compatibility and argument quality, and not simply the argument compatibility, that plays a more important role in activating an extensive processing in the evaluation of arguments.


Newly Identified DDT-Related Compounds Accumulating in Southern California Bottlenose Dolphins.
Nontargeted GC×GC-TOF/MS analysis of blubber from 8 common bottlenose dolphins (Tursiops truncatus) inhabiting the Southern California Bight was performed to identify novel, bioaccumulative DDT-related compounds and to determine their abundance relative to the commonly studied DDT-related compounds. We identified 45 bioaccumulative DDT-related compounds of which the majority (80%) is not typically monitored in environmental media. Identified compounds include transformation products, technical mixture impurities such as tris(chlorophenyl)methane (TCPM), the presumed TCPM metabolite tris(chlorophenyl)methanol (TCPMOH), and structurally related compounds with unknown sources, such as hexa- to octachlorinated diphenylethene. To investigate impurities in pesticide mixtures as possible sources of these compounds, we analyzed technical DDT, the primary source of historical contamination in the region, and technical Dicofol, a current use pesticide that contains DDT-related compounds. The technical mixtures contained only 33% of the compounds identified in the blubber, suggesting that transformation products contribute to the majority of the load of DDT-related contaminants in these sentinels of ocean health. Quantitative analysis revealed that TCPM was the second most abundant compound class detected in the blubber, following DDE, and TCPMOH loads were greater than DDT. QSPR estimates verified 4,4',4″-TCPM and 4,4'4,″-TCPMOH are persistent and bioaccumulative.


Bayesian detection of causal rare variants under posterior consistency.
Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.


NMR Reveals Light-Induced Changes in the Dynamics of a Photoswitchable Fluorescent Protein.
The availability of fluorescent proteins with distinct phototransformation properties is crucial for a wide range of applications in advanced fluorescence microscopy and biotechnology. To rationally design new variants optimized for specific applications, a detailed understanding of the mechanistic features underlying phototransformation is essential. At present, little is known about the conformational dynamics of fluorescent proteins at physiological temperature and how these dynamics contribute to the observed phototransformation properties. Here, we apply high-resolution NMR spectroscopy in solution combined with in situ sample illumination at different wavelengths to investigate the conformational dynamics of rsFolder, a GFP-derived protein that can be reversibly switched between a green fluorescent state and a nonfluorescent state. Our results add a dynamic view to the static structures obtained by x-ray crystallography. Including a custom-tailored NMR toolbox in fluorescent protein research provides new opportunities for investigating the effect of mutations or changes in the environmental conditions on the conformational dynamics of phototransformable fluorescent proteins and their correlation with the observed photochemical and photophysical properties.


Measuring quality outcomes across hospital systems: Using a claims data model for risk adjustment of mortality rates.
Healthcare delivery systems around the world are designing care through value-based models where value is defined as a function of quality of care outcomes and cost. Mortality is a sentinel outcome measure of quality of care, of fundamental importance to patients and providers. Discovery Health (DH), an administrative funder of healthcare in South Africa (SA), uses service claims data of client medical schemes to examine standardised mortality rates (SMRs) at condition level across hospital systems for the purpose of healthcare system improvement. To accurately examine and contrast variation in condition-level SMRs across acute hospital systems, this outcome metric needs to be risk-adjusted for patient characteristics that make mortality more, or less, likely to occur. This article describes and evaluates the validity of risk-adjustment methods applied to service claims data to accurately determine SMRs across hospital systems. While service claims data may have limitations regarding case risk adjustment, it is important that we do not lose the important opportunity to use claims data as a reliable proxy to comment on the quality of care within healthcare systems. This methodology is robust in its demonstration of variation of performance on mortality outcomes across hospital systems. For the measurement period January 2014 - December 2016, the average risk-adjusted SMRs across hospital systems where DH members were hospitalised for acute myocardial infarction, stroke, pneumonia and coronary artery bypass graft procedures were 9.7%, 8.0%, 5.3% and 3.2%, respectively. This exercise of transparently examining variation in SMRs at hospital system level is the first of its kind in SA's private sector. Our methodological exercise is used to establish a local pattern of variation of SMRs in the private sector as the base off which to scrutinise reasons for variation and off which to build quality of care improvement strategies. High-performing healthcare systems must seek out opportunities for learning and continuous improvement such as those offered by examining important quality of care outcome measures across hospitals.


Necrosis and apoptosis after retinal ischemia: involvement of NMDA-mediated excitotoxicity and p53.
Accumulated evidence has shown that apoptosis and necrosis contribute to neuronal death after ischemia. The present study was performed to study the temporal and spatial patterns of neuronal necrosis and apoptosis after ischemia in retina and to outline mechanisms underlying necrosis and apoptosis. Retinal ischemia was induced by increasing intraocular pressure to a range of 160 mm Hg to 180 mm Hg for 90 minutes in adult rats. The patterns of neuronal cell death were determined using light and electron microscopy and were visualized by TdT-dUTP nick-end labeling (TUNEL). The mRNA expression profile of p53 was examined using reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization histochemistry. Immunohistochemistry was performed using anti-p53, anti-microtubule associated protein-2, and anti-glial fibrillary acidic protein antibodies. Within 4 hours after ischemia, neurons in the inner nuclear cell layer (INL) and ganglion cell layer (GCL) underwent marked necrosis, made apparent by swelling of the cell body and mitochondria, early fenestration of the plasma membrane, and irregularly scattered condensation of nuclear chromatin. After 3 days, the INL and GCL neurons showed further degeneration through apoptosis marked by cell body shrinkage, aggregation, and condensation of nuclear chromatin. Apoptotic neurons were also observed sparsely in the outer nuclear cell layer. Intravitreal injections of MK-801 prevented early neuronal degeneration after ischemia. Of note, mRNA and protein levels of p53, the tumor suppressor gene known to induce apoptosis, were increased in the retinal areas undergoing apoptosis 1 to 3 days after ischemic injury. Ischemia produces the N-methyl-D-aspartate-mediated necrosis and slowly evolving apoptosis of neurons in the retina. The latter may depend on the expression of the p53 proapoptosis gene.


[Darunavir/cobicistat monotherapy. Experience in a tertiary hospital].
Ritonavir-boosted protease inhibitor (IP/r) monotherapy: darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r) monotherapy is only provided in the major treatment guidelines in pretreated patients to prevent toxicity associated with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), reduce costs and simplify antiretroviral treatment. To start IP/r monotherapy, according to GESIDA guidelines 2016, patients need to meet the following criteria: absence of chronic hepatitis B, plasma viral load <50 copies/ mL for at least 6 months and absence of protease inhibitors mutations or previous virologic failures to IP/r. Currently, there are no studies that evaluate the efficacy and safety of darunavir/cobicistat (DRV/COBI) monotherapy. This prospective study analyzed pretreated HIV patients with DRV/r monotherapy that were switched to DRV/COBI monotherapy. The aim of the study is to describe the effectiveness and safety of the DRV/COBI monotherapy. Seventy-eight patients were evaluated. Patients had a median of 31.29 months of DRV/r monotherapy before DRV/COBI monotherapy. Nine of the 78 patients developed "blips" (plasma viral load: 50-200 copies/ml) and four patients had plasma viral load ≥200 copies/mL. An 83.3% (65/78) of the patients remained with undetectable plasma viral load. As for safety, there were no significant differences in lipid profile, liver function (transaminases) and renal function between DRV/r and DRV/COBI monotherapy. DRV/COBI monotherapy seems to be effective and safe (lipid profile, liver and kidney function). However, it will be necessary to design specific studies comparing DRV/r vs DRV/COBI monotherapy to confirm these results.


Transcriptome dynamics of the stomatal lineage: birth, amplification, and termination of a self-renewing population.
Developmental transitions can be described in terms of morphology and the roles of individual genes, but also in terms of global transcriptional and epigenetic changes. Temporal dissections of transcriptome changes, however, are rare for intact, developing tissues. We used RNA sequencing and microarray platforms to quantify gene expression from labeled cells isolated by fluorescence-activated cell sorting to generate cell-type-specific transcriptomes during development of an adult stem-cell lineage in the Arabidopsis leaf. We show that regulatory modules in this early lineage link cell types that had previously been considered to be under separate control and provide evidence for recruitment of individual members of gene families for different developmental decisions. Because stomata are physiologically important and because stomatal lineage cells exhibit exemplary division, cell fate, and cell signaling behaviors, this dataset serves as a valuable resource for further investigations of fundamental developmental processes.


Implications of spiritual experiences to the understanding of mind-brain relationship.
While there has been a large increase in scientific studies on spirituality, there has been too few of studies of the core of spirituality: spiritual experiences (SE), which often involve altered states of consciousness, reports of anomalous experiences and of consciousness beyond the body. This paper argues that SE, although usually neglected in debates regarding mind-brain relationship (MBR), may provide the much needed enlargement of the empirical basis for advancing the understanding of the MBR. This paper briefly presents and discusses recent scientific investigations on some types of SE (meditative states, end of life and near death experiences, mediumship and alleged memories of previous lives) and their implications to MBR. Neurofunctional studies of SE have shown that they are related to but not necessarily caused by complex functional patterns in several brain areas. The study of meditative states, as voluntarily induced mind states that influence brain states has been a privileged venue to investigate top-down (mind over brain) causation. End of life and near death experiences offer cases of unexpected adequate mental function under severe brain damage and/or dysfunction. Scientific investigations of several types of SE have provided evidence against materialistic reductionist views of mind. The recent trend to scientifically investigate SE has already produced interesting and thought-provoking findings that deserve careful further exploration. Because of their potential implication, these findings may also contribute to the understanding of MBR, which remains an important, yet poorly explored way to investigate human nature.


Moon: electrical properties of the uppermost layers.
Presently available data on the electrical conductivity of the uppermost lunar surface layers are in accord with the presence of dry, powdered rocks in which the dielectric loss tangent is frequency-independent over several decades of frequency. These powders have typical direct-current conductivity values of about 10(-13) to 10(-16) mhos per meter and dielectric constants of about 3.0, depending on the packing. Thus the surface layers of the moon are likely to have an extremely low electrical conductivity. At high frequencies normal dielectric losses lead to much higher apparent conductivities that are frequency-dependent.


Foraging depth depicts resource partitioning and contamination level in a pelagic shark assemblage: Insights from mercury stable isotopes.
The decline of shark populations in the world ocean is affecting ecosystem structure and function in an unpredictable way and new ecological information is today needed to better understand the role of sharks in their habitats. In particular, the characterization of foraging patterns is crucial to understand and foresee the evolution of dynamics between sharks and their prey. Many shark species use the mesopelagic area as a major foraging ground but the degree to which different pelagic sharks rely on this habitat remains overlooked. In order to depict the vertical dimension of their trophic ecology, we used mercury stable isotopes in the muscle of three pelagic shark species (the blue shark Prionace glauca, the shortfin mako shark Isurus oxyrinchus and the smooth hammerhead shark Sphyrna zygaena) from the northeastern Pacific region. The Δ199Hg values, ranging from 1.40 to 2.13‰ in sharks, suggested a diet mostly based on mesopelagic prey in oceanic habitats. We additionally used carbon and nitrogen stable isotopes (δ13C, δ15N) alone or in combination with Δ199Hg values, to assess resource partitioning between the three shark species. Adding Δ199Hg resulted in a decrease in trophic overlap estimates compared to those based on δ13C/δ15N alone, demonstrating that multi-isotope modeling is needed for accurate trophic description of the three species. Mainly, it reveals that they forage at different average depths and that resource partitioning is mostly expressed through the vertical dimension within pelagic shark assemblages. Concomitantly, muscle total mercury concentration (THg) differed between species and increased with feeding depth. Overall, this study highlights the key role of the mesopelagic zone for shark species foraging among important depth gradients and reports new ecological information on trophic competition using mercury isotopes. It also suggests that foraging depth may play a pivotal role in the differences between muscle THg from co-occurring high trophic level shark species.


Index of tobacco control sustainability (ITCS): a tool to measure the sustainability of national tobacco control programmes.
To produce a tool to assess and guide sustainability of national tobacco control programmes. A two-stage process adapting the Delphi and Nominal group techniques. A series of indicators of tobacco control sustainability were identified in grantee/country advisor reports to The International Union Against Tuberculosis and Lung Disease under the Bloomberg Initiative to Reduce Tobacco Control (2007-2015). Focus groups and key informant interviews in seven low and middle-income countries (52 government and civil society participants) provided consensus ratings of the indicators' relative importance. Data were reviewed and the indicators were accorded relative weightings to produce the 'Index of Tobacco Control Sustainability' (ITCS). All 31 indicators were considered 'Critical' or 'Important' by the great majority of participants. There was consensus that a tool to measure progress towards tobacco control sustainability was important. The most critical indicators related to financial policies and allocations, a national law, a dedicated national tobacco control unit and civil society tobacco control network, a national policy against tobacco industry 'Corporate Social Responsibility' (CSR), national mortality and morbidity data, and national policy evaluation mechanisms. The 31 indicators were agreed to be 'critical' or 'important' factors for tobacco control sustainability. The Index comprises the weighted indicators as a tool to identify aspects of national tobacco control programmes requiring further development to augment their sustainability and to measure and compare progress over time. The next step is to apply the ITCS and produce tobacco control sustainability assessments.


Unrealistic optimism and the ethics of phase I cancer research.
One of the most pressing ethical challenges facing phase I cancer research centres is the process of informed consent. Historically, most scholarship has been devoted to redressing therapeutic misconception, that is, the conflation of the nature and goals of research with those of therapy. While therapeutic misconception continues to be a major ethical concern, recent scholarship has begun to recognise that the informed consent process is more complex than merely a transfer of information and therefore cannot be evaluated only according to how well an individual understands such information. Other components of decision-making operate independently of understanding and yet still may compromise the quality of informed consent. Notable among these components is unrealistic optimism, an event-specific belief that one has a better chance of receiving benefit than others similarly situated. In this article, we consider responses to interviews with parents who had recently completed an informed consent conference for enrolling their child in a phase I cancer clinical trial to examine how this influence manifests and how investigators might address it during informed consent.


densityCut: an efficient and versatile topological approach for automatic clustering of biological data.
Many biological data processing problems can be formalized as clustering problems to partition data points into sensible and biologically interpretable groups. This article introduces densityCut, a novel density-based clustering algorithm, which is both time- and space-efficient and proceeds as follows: densityCut first roughly estimates the densities of data points from a K-nearest neighbour graph and then refines the densities via a random walk. A cluster consists of points falling into the basin of attraction of an estimated mode of the underlining density function. A post-processing step merges clusters and generates a hierarchical cluster tree. The number of clusters is selected from the most stable clustering in the hierarchical cluster tree. Experimental results on ten synthetic benchmark datasets and two microarray gene expression datasets demonstrate that densityCut performs better than state-of-the-art algorithms for clustering biological datasets. For applications, we focus on the recent cancer mutation clustering and single cell data analyses, namely to cluster variant allele frequencies of somatic mutations to reveal clonal architectures of individual tumours, to cluster single-cell gene expression data to uncover cell population compositions, and to cluster single-cell mass cytometry data to detect communities of cells of the same functional states or types. densityCut performs better than competing algorithms and is scalable to large datasets. Data and the densityCut R package is available from https://bitbucket.org/jerry00/densitycut_dev : firstname.lastname@example.com or firstname.lastname@example.com or email@example.com Supplementary data are available at Bioinformatics online.


Cyclone disaster vulnerability and response experiences in coastal Bangladesh.
For generations, cyclones and tidal surges have frequently devastated lives and property in coastal and island Bangladesh. This study explores vulnerability to cyclone hazards using first-hand coping recollections from prior to, during and after these events. Qualitative field data suggest that, beyond extreme cyclone forces, localised vulnerability is defined in terms of response processes, infrastructure, socially uneven exposure, settlement development patterns, and livelihoods. Prior to cyclones, religious activities increase and people try to save food and valuable possessions. Those in dispersed settlements who fail to reach cyclone shelters take refuge in thatched-roof houses and big-branch trees. However, women and children are affected more despite the modification of traditional hierarchies during cyclone periods. Instinctive survival strategies and intra-community cooperation improve coping post cyclone. This study recommends that disaster reduction programmes encourage cyclone mitigation while being aware of localised realities, endogenous risk analyses, and coping and adaptation of affected communities (as active survivors rather than helpless victims).


Effects of synbiotic food consumption on metabolic status of diabetic patients: a double-blind randomized cross-over controlled clinical trial.
We are aware of no study indicating the effects of synbiotic food consumption on metabolic profiles, inflammation and oxidative stress among diabetic patients. The aim of the current study was to investigate the effects of synbiotic food consumption on metabolic profiles, hs-CRP and biomarkers of oxidative stress in diabetic patients. This randomized double-blinded cross-over controlled clinical trial was performed among 62 diabetic patients aged 35-70 y. After a 2-wk run-in period, subjects were randomly assigned to consume either a synbiotic (n = 62) or control food (n = 62) for 6 weeks. A 3-week washout period was applied following which subjects were crossed over to the alternate treatment arm for an additional 6 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 10(7) CFU), 0.04 g inulin (HPX) as prebiotic with 0.38 g isomalt, 0.36 g sorbitol and 0.05 g stevia as sweetener per 1 g. Control food (the same substance without probiotic bacteria and prebiotic inulin) was packed in identical 9-gram packages. Patients were asked to consume the synbiotic and control foods three times a day. Fasting blood samples were taken at baseline and after a 6-wk intervention to measure metabolic profiles, hs-CRP and biomarkers of oxidative stress. Consumption of a synbiotic food, compared to the control, resulted in a significant decrease in serum insulin levels (changes from baseline: -1.75 ± 0.60 vs. +0.95 ± 1.09 μIU/mL, P = 0.03). Although we failed to find a significant effect of synbiotic food consumption on total- and LDL-cholesterol levels and HOMA-IR, the effects on FPG (22.3 vs. 4.2 mg/dL, P = 0.09), serum triglycerides (45.9 vs. 20.6 mg/dL, P = 0.08) and HDL-cholesterol levels (3.1 vs. -2 mg/dL, P = 0.06) tended to be significant. A significant reduction in serum hs-CRP levels (-1057.86 ± 283.74 vs. 95.40 ± 385.38 ng/mL, P = 0.01) was found following the consumption of synbiotic food compared with the control group. Supplementation with the synbiotic food led to a significant increase in plasma total GSH (319.98 vs. 19.73 μmol/L, P < 0.001) and serum uric acid levels (+0.7 vs. -0.1 mg/dL, P = 0.04) compared to the control food. No significant effect of the synbiotic food was observed on plasma TAC levels. In conclusion, consumption of a synbiotic food for 6 weeks among diabetic patients had significant effects on serum insulin, hs-CRP, uric acid and plasma total GSH levels. www.irct.ir: IRCT201201195623N1.


Preparing for the Worst: Evidence that Older Adults Proactively Downregulate Negative Affect.
Previous studies have only investigated age-related differences in emotional processing and encoding in response to, not in anticipation of, emotional stimuli. In the current study, we investigated age-related differences in the impact of emotional anticipation on affective responses and episodic memory for emotional images. Young and older adults were scanned while encoding negative and neutral images preceded by cues that were either valid or invalid predictors of image valence. Participants were asked to rate the emotional intensity of the images and to complete a recognition task. Using multivariate behavioral partial least squares (PLS) analysis, we found that greater anticipatory recruitment of the amygdala, ventromedial prefrontal cortex (vmPFC), and hippocampus in older adults predicted reduced memory for negative than neutral images and the opposite for young adults. Seed PLS analysis further showed that following negative cues older adults, but not young adults, exhibited greater activation of vmPFC, reduced activation of amygdala, and worse memory for negative compared with neutral images. To the best of our knowledge, this is the first study to provide evidence that the "positivity effect" seen in older adults' memory performance may be related to the spontaneous emotional suppression of negative affect in anticipation of, not just in response to, negative stimuli.


Nonenzymatic glycosylation and the pathogenesis of diabetic complications.
Glucose chemically attaches to proteins and nucleic acids without the aid of enzymes. Initially, chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. Equilibrium is reached after several weeks, however, and further accumulation of these early nonenzymatic glycosylation products does not continue beyond that time. Subsequent reactions of the Amadori product slowly give rise to nonequilibrium advanced glycosylation end-products which continue to accumulate indefinitely on longer-lived molecules. Excessive formation of both types of nonenzymatic glycosylation product appears to be the common biochemical link between chronic hyperglycemia and a number of pathophysiologic processes potentially involved in the development of long-term diabetic complications. The major biological effects of excessive nonenzymatic glycosylation include: inactivation of enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated proteins and trapping of soluble proteins by glycosylated extracellular matrix (both may progress in the absence of glucose); decreased susceptibility to proteolysis; abnormalities of nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity.


HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing.
HIV up-regulates cell-surface expression of specific ligands for the activating NKG2D receptor, including ULBP-1, -2, and -3, but not MICA or MICB, in infected cells both in vitro and in vivo. However, the viral factor(s) involved in NKG2D ligand expression still remains undefined. HIV-1 Vpr activates the DNA damage/stress-sensing ATR kinase and promotes G(2) cell-cycle arrest, conditions known to up-regulate NKG2D ligands. We report here that HIV-1 selectively induces cell-surface expression of ULBP-2 in primary CD4(+) T lymphocytes by a process that is Vpr dependent. Importantly, Vpr enhanced the susceptibility of HIV-1-infected cells to NK cell-mediated killing. Strikingly, Vpr alone was sufficient to up-regulate expression of all NKG2D ligands and thus promoted efficient NKG2D-dependent NK cell-mediated killing. Delivery of virion-associated Vpr via defective HIV-1 particles induced analogous biologic effects in noninfected target cells, suggesting that Vpr may act similarly beyond infected cells. All these activities relied on Vpr ability to activate the ATR-mediated DNA damage/stress checkpoint. Overall, these results indicate that Vpr is a key determinant responsible for HIV-1-induced up-regulation of NKG2D ligands and further suggest an immunomodulatory role for Vpr that may not only contribute to HIV-1-induced CD4(+) T-lymphocyte depletion but may also take part in HIV-1-induced NK-cell dysfunction.


Candidate gene analysis for determinacy in pigeonpea (Cajanus spp.).
We report a likely candidate gene, CcTFL1, for determinacy in pigeonpea through candidate gene sequencing analysis, mapping, QTL analysis together with comparative genomics and expression profiling. Pigeonpea (Cajanus cajan) is the sixth most important legume crop grown on ~5 million hectares globally. Determinacy is an agronomically important trait selected during pigeonpea domestication. In the present study, seven genes related to determinacy/flowering pattern in pigeonpea were isolated through a comparative genomics approach. Single nucleotide polymorphism (SNP) analysis of these candidate genes on 142 pigeonpea lines found a strong association of SNPs with the determinacy trait for three of the genes. Subsequently, QTL analysis highlighted one gene, CcTFL1, as a likely candidate for determinacy in pigeonpea since it explained 45-96 % of phenotypic variation for determinacy, 45 % for flowering time and 77 % for plant height. Comparative genomics analysis of CcTFL1 with the soybean (Glycine max) and common bean (Phaseolus vulgaris) genomes at the micro-syntenic level further enhanced our confidence in CcTFL1 as a likely candidate gene. These findings have been validated by expression analysis that showed down regulation of CcTFL1 in a determinate line in comparison to an indeterminate line. Gene-based markers developed in the present study will allow faster manipulation of the determinacy trait in future breeding programs of pigeonpea and will also help in the development of markers for these traits in other related legume species.


[Character strengths and well-being in Japanese children and youth: creating good habits].
Character education in the US aims to establish good habits corresponding to good character. The purpose of this study was to determine the structure of character strengths and the relations among these strengths and wellbeing in Japanese children and youth. Peterson and Seligman (2004) developed a classification of character strengths called VIA-IS. We thought, however, that VIA-IS had too many items to use with school children. We selected 15 categories and developed a questionnaire for Japanese children and youth. Fourth to eighth grade students (N = 1,351) answered questionnaires in Study 1. We found four categories of character strengths, each of which consisted of 25 items: perseverance-honesty, courage-ideas, compassion-gratitude, and fairness-care. These categories were very similar to previous research findings which simplified the categories. In Study 2, we found a positive relationship among four categories of character strengths and well-being, which we called the hope scale, life satisfaction scale, subjective happiness scale, and social support scale. We discussed what additional research was needed for establishing good habits using our categories with children and youth in schools.


Ascorbic acid and rates of cognitive decline in Alzheimer's disease.
The brain maintains high levels of ascorbic acid (AA) despite a concentration gradient favoring diffusion from brain to peripheral tissues. Dietary antioxidants, including AA, appear to modify the risk of Alzheimer's disease (AD). The objective of this study was to test the hypothesis that neurodegeneration in AD is modified by brain levels of AA. Thirty-two patients with mild to moderate AD participated in a biomarker study involving standardized clinical assessments over one year. Cerebrospinal fluid (CSF) and serum were collected at baseline for AA and albumin content. Cognitive measures were collected at baseline and one year. CSF and plasma AA failed to predict cognitive decline independently, however, CSF: plasma AA ratio did. After adding CSF Albumin Index (an established marker of blood-brain barrier integrity) to the regression models the effect of CSF: plasma AA ratio as a predictor of cognitive decline was weakened. CSF: plasma AA ratio predicts rate of decline in AD. This relationship may indicate that the CSF: plasma AA ratio is an index of AA availability to the brain or may be an artifact of a relationship between blood-brain barrier impairment and neurodegeneration.


Antigenic and genetic characterization of influenza viruses isolated in Mozambique during the 2015 season.
Due to the high rate of antigenic variation of influenza virus, seasonal characterization of the virus is crucial to assess and monitor the emergence of new pathogenic variants and hence formulate effective control measures. However, no study has yet been conducted in Mozambique to assess genetic, antigenic and antiviral susceptibility profile of influenza virus. A subset of samples (n = 20) from influenza positive children detected in two hospitals in Maputo city during 2015 season as part of the implementation of influenza surveillance system, were selected. The following assays were performed on these samples: antigenic characterization by hemagglutination inhibition assay, genetic characterization by Sanger sequencing of hemagglutinin (HA) and neuraminidase (NA) and susceptibility to oseltamivir and zanamivir (NA inhibitors) by enzymatic assay. The A(H1N1)pdm09 subtype viruses remained closely related antigenically and genetically to the 2016 vaccine virus A/California/7/2009 and other widely distributed viruses belonging to genetic group 6B. The majority of influenza A(H3N2) viruses studied were antigenically similar to the 2016-2017 vaccine virus, A/Hong Kong/4801/2014, and their HA and NA gene sequences fell into genetic subclade 3C.2a being closely related to viruses circulating in southern Africa. The influenza B viruses were antigenically similar to the 2016 season vaccine virus and HA sequences of all three fell into the B/Yamagata-lineage, clade 3, but contained NA genes of the B/Victoria-lineage. All tested viruses were sensitive to oseltamivir and zanamivir. Overall, all Mozambican influenza A and B viruses were most closely related to Southern African viruses and all were sensitive to oseltamivir and zanamivir. These findings suggest the existence of an ecological niche of influenza viruses within the region and hence highlighting the need for joint epidemiologic and virologic surveillance to monitor the evolution of influenza viruses.


Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.
This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.


Mechanisms of relaxant action of nicardipine, a new Ca++-antagonist, on isolated dog cerebral and mesenteric arteries.
In helically-cut strips of cerebral and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, carbocyclic thromboxane A2 (cTxA2) or K+, the addition of nicardipine caused a dose-related relaxation. Nicardipine-induced relaxation was greater in cerebral than in mesenteric arteries when contracted with PGF2 alpha and cTxA2, but did not appreciably differ in the arteries contracted with K+. Cerebral arteries contracted with hemolysate and PGF2 alpha relaxed in response to nicardipine to a similar extent. The contractile response to PGF2 alpha was attenuated by pretreatment with nicardipine, the attenuation being greater in cerebral than in mesenteric arteries. Ca++-induced contractions in cerebral and mesenteric arteries previously exposed to Ca++-free media and depolarized by excess K+ were attenuated by nicardipine to a similar extent. PGF2 alpha-induced contractions of cerebral arteries exposed to Ca++-free media were attenuated by nicardipine, whereas those of mesenteric arteries were unaffected. Attenuations by nicardipine of the Ca++-induced contraction in PGF2 alpha-treated cerebral arteries were greater than those seen in mesenteric arteries. It may be concluded that nicardipine produces a greater relaxation of cerebral arteries than mesenteric arteries, possibly due to a greater inhibition of the Ca++-influx and to a decrease in the release of Ca++ from intracellular storage sites in cerebral arteries. As far as the concentrations used are concerned, nicardipine appears to attenuate the inward movement of Ca++ across cell membrane in mesenteric arterial smooth muscle, but not the release of intracellularly stored Ca++.


Public health literacy defined.
Public health literacy is an emerging concept necessary to understand and address the broad array of factors, such as climate change, globalization, and poverty, that influence the public's health. Whereas health literacy has traditionally been operationalized as an individual-level construct, public health literacy takes into account the complex social, ecologic, and systemic forces affecting health and well-being. However, public health literacy has not yet been fully articulated. This paper addresses this gap by outlining a broad, new definition of public health literacy. This definition was developed through an inductive analytic process conducted in 2007 by a multidisciplinary research team, and two expert-panel sessions were convened to assess the consensual validity of the emergent definition. Based on this process, public health literacy is defined as the degree to which individuals and groups can obtain, process, understand, evaluate, and act on information needed to make public health decisions that benefit the community. Three dimensions of public health literacy--conceptual foundations, critical skills, and civic orientation--and related competencies are also proposed. Public health literacy is distinct from individual-level health literacy, and together, the two types of literacy form a more comprehensive model of health literacy. A five-part agenda is offered for future research and action aimed at increasing levels of public health literacy.


The impact of cerebellar transcranial direct current stimulation (tDCS) on learning fine-motor sequences.
The cerebellum has been shown to be important for skill learning, including the learning of motor sequences. We investigated whether cerebellar transcranial direct current stimulation (tDCS) would enhance learning of fine motor sequences. Because the ability to generalize or transfer to novel task variations or circumstances is a crucial goal of real world training, we also examined the effect of tDCS on performance of novel sequences after training. In Study 1, participants received either anodal, cathodal or sham stimulation while simultaneously practising three eight-element key press sequences in a non-repeating, interleaved order. Immediately after sequence practice with concurrent tDCS, a transfer session was given in which participants practised three interleaved novel sequences. No stimulation was given during transfer. An inhibitory effect of cathodal tDCS was found during practice, such that the rate of learning was slowed in comparison to the anodal and sham groups. In Study 2, participants received anodal or sham stimulation and a 24 h delay was added between the practice and transfer sessions to reduce mental fatigue. Although this consolidation period benefitted subsequent transfer for both tDCS groups, anodal tDCS enhanced transfer performance. Together, these studies demonstrate polarity-specific effects on fine motor sequence learning and generalization.This article is part of the themed issue 'New frontiers for statistical learning in the cognitive sciences'.


Relative Susceptibility Among Alternative Host Species Prevalent in the Great Plains to Wheat streak mosaic virus.
Wild grasses, crops, and grassy weeds are known to host Wheat streak mosaic virus (WSMV) and its vector, the wheat curl mite (WCM). Their relative importance as a source of WSMV was evaluated. A survey of small-grain fields throughout Montana was conducted between 2008 and 2009. Cheatgrass was the most prevalent grassy weed and the most frequent viral host, with 6% infection by WSMV in 2008 (n = 125) and 15% in 2009 (n = 358). By mechanically inoculating plants with WSMV in the greenhouse, the highest susceptibility was found in rye brome (52.1%), jointed goatgrass (80.9%), and wild oat (53.9%. Quackgrass, not previously reported as a host, was susceptible to WSMV (12.7%). Mite transmission efficiency from susceptible grass species was lower than from wheat, and grass species must be a host for both WSMV and the WCM to serve as a virus source. WCM transmission was more efficient than mechanical transmission. Overall, results indicate that grass species can serve as a viral reservoir, regional variation in a weed species' susceptibility to WSMV cannot explain geographic variation in epidemic intensity, and crop species and closely related weeds (e.g., jointed goatgrass) remain the best reservoirs for both WSMV and the WCM.


Is Continuous Flow Superior to Pulsatile Flow in Single Ventricle Mechanical Support? Results from a Large Animal Pilot Study.
Durable mechanical support in situations of physiologic single ventricle has been met with little success so far, particularly in small children. We created an animal model to investigate whether pulsatile or continuous flow would be superior. Three 1 month old sheep (10-16 kg) were instrumented. Via sternotomy and with cardiopulmonary bypass, a large ventricular septal defect and atrial septal defect were created. The left ventricle was cannulated using a Berlin Heart inflow cannula. This was connected sequentially to a continuous flow device (Thoratec HeartMate X, Pleasanton, CA) and to a pulsatile device (Berlin Heart Excor, The Woodlands, TX). Outflow was via a Y-graft to both aorta and pulmonary artery, striving for equal flow to both. Atrial filling pressures were controlled with volume infusions over a wide range. Under comparable loading conditions, significantly higher maximum flow was obtained by HeartMate X than by Excor (4.95 ± 1.27 L/min [range, 3.84-6.34 L/min] for HeartMate X vs. 1.80 ± 0.85 L/min [range, 1.01-2.7 L/min] for Excor; p < 0.05). Judging from this limited animal study, in single ventricle scenarios, continuous flow devices may achieve higher pump flows than pulsatile devices when provided with similar filling pressures. Their clinical use should be investigated. More extensive experimental studies are needed.


Colony-stimulating factor-1 mediates macrophage-related neural damage in a model for Charcot-Marie-Tooth disease type 1X.
Previous studies in our laboratory have shown that in models for three distinct forms of the inherited and incurable nerve disorder, Charcot-Marie-Tooth neuropathy, low-grade inflammation implicating phagocytosing macrophages mediates demyelination and perturbation of axons. In the present study, we focus on colony-stimulating factor-1, a cytokine implicated in macrophage differentiation, activation and proliferation and fostering neural damage in a model for Charcot-Marie-Tooth neuropathy 1B. By crossbreeding a model for the X-linked form of Charcot-Marie-Tooth neuropathy with osteopetrotic mice, a spontaneous null mutant for colony-stimulating factor-1, we demonstrate a robust and persistent amelioration of demyelination and axon perturbation. Furthermore, functionally important domains of the peripheral nervous system, such as juxtaparanodes and presynaptic terminals, were preserved in the absence of colony-stimulating factor-1-dependent macrophage activation. As opposed to other Schwann cell-derived cytokines, colony-stimulating factor-1 is expressed by endoneurial fibroblasts, as revealed by in situ hybridization, immunocytochemistry and detection of β-galactosidase expression driven by the colony-stimulating factor-1 promoter. By both light and electron microscopic studies, we detected extended cell-cell contacts between the colony-stimulating factor-1-expressing fibroblasts and endoneurial macrophages as a putative prerequisite for the effective and constant activation of macrophages by fibroblasts in the chronically diseased nerve. Interestingly, in human biopsies from patients with Charcot-Marie-Tooth type 1, we also found frequent cell-cell contacts between macrophages and endoneurial fibroblasts and identified the latter as main source for colony-stimulating factor-1. Therefore, our study provides strong evidence for a similarly pathogenic role of colony-stimulating factor-1 in genetically mediated demyelination in mice and Charcot-Marie-Tooth type 1 disease in humans. Thus, colony-stimulating factor-1 or its cognate receptor are promising target molecules for treating the detrimental, low-grade inflammation of several inherited neuropathies in humans.


Changes in association of the Xenopus origin recognition complex with chromatin on licensing of replication origins.
During late mitosis and early G1, a series of proteins are assembled onto replication origins that results in them becoming 'licensed' for replication in the subsequent S phase. In Xenopus this first involves the assembly onto chromatin of the Xenopus origin recognition complex XORC, and then XCdc6, and finally the RLF-M component of the replication licensing system. In this paper we examine changes in the way that XORC associates with chromatin in the Xenopus cell-free system as origins become licensed. Restricting the quantity of XORC on chromatin reduced the extent of replication as expected if a single molecule of XORC is sufficient to specify a single replication origin. During metaphase, XOrc1 associated only weakly with chromatin. In early interphase, XOrc1 formed a strong complex with chromatin, as evidenced by its resistance to elution by 200 mM salt, and this state persisted when XCdc6 was assembled onto the chromatin. As a consequence of origins becoming licensed the association of XOrc1 and XCdc6 with chromatin was destabilised, and XOrc1 became susceptible to removal from chromatin by exposure to either high salt or high Cdk levels. At this stage the essential function for XORC and XCdc6 in DNA replication had already been fulfilled. Since high Cdk levels are required for the initiation of DNA replication, this 'licensing-dependent origin inactivation' may contribute to mechanisms that prevent re-licensing of replication origins once S phase has started.


Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.


8-oxodGTP incorporation by DNA polymerase beta is modified by active-site residue Asn279.
To understand how the active site of a DNA polymerase might modulate the coding of 8-oxo-7,8-dihydrodeoxyguanine (8-oxodG), we performed steady-state kinetic analyses using wild-type DNA polymerase beta (pol beta) and two active-site mutants. We compared the coding of these polymerases by calculating the ratio of efficiencies for incorporation of dATP and dCTP opposite 8-oxodG and for incorporation of 8-oxodGTP opposite dA and dC. For wild-type pol beta, there is a 2:1 preference for incorporation of dCTP over dATP opposite 8-oxodG using a 5'-phosphorylated 4-base gap substrate. Mutation of either Asn279 or Arg283 to alanine has almost no effect on the ratio. 8-OxodGTP is preferentially incorporated opposite a template dA (24:1) by wild-type pol beta; mutation of Asn279 to alanine results dramatic change whereby there is preferential incorporation of 8-oxodGTP opposite dC (14:1). This suggests that interactions of 8-oxodGTP with Asn279 in the polymerase active site may alter the conformation of 8-oxodGTP and therefore alter its misincorporation.


Metabolomic Quality Assessment of EDTA Plasma and Serum Samples.
Handling and processing of blood can significantly alter the molecular composition and consistency of biobank samples and can have a major impact on the identification of biomarkers. It is thus crucial to identify tools to determine the quality of samples to be used in biomarker discovery studies. In this study, a non-targeted gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) metabolomic strategy was used with the aim of identifying quality markers for serum and plasma biobank collections lacking proper documentation of preanalytical handling. The effect of postcentrifugation delay was examined in serum stored in tubes with gel separation plugs and ethylenediaminetetraacetic acid (EDTA) plasma in tubes with or without gel separation plugs. The change in metabolic pattern was negligible in all sample types processed within 3 hours after centrifugation regardless of whether the samples were kept at 4°C or 22°C. After 8 and 24 hours postcentrifugation delay before aliquoting, there was a pronounced increase in the number of affected metabolites, as well as in the magnitude of the observed changes. No protective effect on the metabolites was observed in gel-separated EDTA plasma samples. In a separate series of experiments, lactate and glucose levels were determined in plasma to estimate the effect of precentrifugation delay. This separate experiment indicates that the lactate to glucose ratio may serve as a marker to identify samples with delayed time to centrifugation. Although our data from the untargeted GC-TOFMS analysis did not identify any specific markers, we conclude that plasma and serum metabolic profiles remain quite stable when plasma and serum are centrifuged and separated from the blood cells within 3 hours.


Isolated cranial distortion mimicking caput succedenum from amniotic band disruption without any neurological abnormality.
This report describes a term newborn with isolated distortion in the left parietal bone without any other visible congenital anomaly, due to amniotic band disruption. A skull x-ray, ultrasound scan and subsequent MRI scan of the brain did not show any apparent distortion apart from depression and concavity in the left parietal bone. The purpose of this case report is to raise awareness of this possible, mild outcome of this little-known entity, which may mimic caput succedaneum (moulding of the presenting part in the birth canal during natural delivery), and to provide a historical and embryological background.


Absence of Female-Typical Pheromone-Induced Hypothalamic Neural Responses and Kisspeptin Neuronal Activity in α-Fetoprotein Knockout Female Mice.
Pheromones induce sexually dimorphic neuroendocrine responses, such as LH secretion. However, the neuronal network by which pheromones are converted into signals that will initiate and modulate endocrine changes remains unclear. We asked whether 2 sexually dimorphic populations in the anteroventral periventricular and periventricular nuclei that express kisspeptin and tyrosine hydroxylase (TH) are potential candidates that will transduce the olfactory signal to the neuroendocrine system. Furthermore, we assessed whether this transduction is sensitive to perinatal actions of estradiol by using female mice deficient in α-fetoprotein (AfpKO), which lack the protective actions of Afp against maternal estradiol. Wild-type (WT) and AfpKO male and female mice were exposed to same- versus opposite-sex odors and the expression of Fos (the protein product of the immediate early gene c-Fos) was analyzed along the olfactory projection pathways as well as whether kisspeptin, TH, and GnRH neurons are responsive to opposite-sex odors. Male odors induced a female-typical Fos expression in target forebrain sites of olfactory inputs involved in reproduction in WT, but not in AfpKO females, whereas female odors induced a male-typical Fos expression in males of both genotypes. In WT females, opposite-sex odors induced Fos in kisspeptin and TH neurons, whereas in AfpKO females and WT males, only a lower, but still significant, Fos expression was observed in TH but not in kisspeptin neurons. Finally, opposite-sex odors did not induce any significant Fos expression in GnRH neurons of both sexes or genotypes. Our results strongly suggest a role for fetal estrogen in the sexual differentiation of neural responses to sex-related olfactory cues.


Plasma acetate turnover and oxidation.
Plasma acetate turnover and oxidation were determined in 11 healthy subjects by the constant infusion of a trace amount of [1-14C]acetate for 6 h. The subjects ages ranged from 22 to 57 yr. There was a positive correlation (P less than 0.001) between plasma acetate concentration and turnover rate, and a negative correlation (P less than 0.001) between turnover and age. The plasma acetate concentration in the subjects 22--28 yr old was 0.17 vs. 0.13 mM (P less than 0.02) in subjects 40--57 yr old. The plasma acetate turnover rate was also greater in the younger age group (8.23 +/- 0.66 vs. 4.98 +/- 0.64 mumol/min . kg, P less than 0.01). Approximately 90% of the plasma acetate turnover was immediately oxidized to CO2 in both age groups, however, 13.2 +/- 0.89% of the CO2 output in the younger group was derived from plasma acetate oxidation compared to 7.9 +/- 0.94% in the older group (P less than 0.01). The mean plasma acetate concentration, turnover, and oxidation in six cancer patients 47--63 yr old were similar to the values observed in the age-matched healthy subjects. Uptake or output of acetate by various tissues was measured by arterial-venous plasma acetate concentration differences. In seven of eight subjects undergoing elective surgery, the arterial-portal venous concentration difference was negative, which indicated that the gastrointestinal tract can contribute to plasma acetate production. Uptake of plasma acetate by both the leg and liver appeared to be dictated by the arterial acetate concentration. Net production of acetate by both the leg and liver was most often observed at arterial plasma acetate concentrations less than 0.08 mM.


Spinal muscular atrophy: a timely review.
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.


Expression and functional analysis of voltage-activated Na+ channels in human prostate cancer cell lines and their contribution to invasion in vitro.
Ion channels are important for many cellular functions and disease states including cystic fibrosis and multidrug resistance. Previous work in the Dunning rat model of prostate cancer has suggested a relationship between voltage-activated Na+ channels (VASCs) and the invasive phenotype in vitro. The objectives of this study were to 1) evaluate the expression of VASCs in the LNCaP and PC-3 human prostate cancer cell lines by Western blotting, flow cytometry, and whole-cell patch clamping, 2) determine their role in invasion in vitro using modified Boyden chambers with and without a specific blocker of VASCs (tetrodotoxin). A 260-kd protein representing VASCs was found only in the PC-3 cell line, and these were shown to be membrane expressed on flow cytometry. Patch clamping studies indicated that functional VASCs were present in 10% of PC-3 cells and blocking these by tetrodotoxin (600 nmol/L) reduced their invasiveness by 31% (P = 0.02) without affecting the invasiveness of the LNCaP cells. These results indicate that the reduction of invasion is a direct result of VASC blockade and not a nonspecific action of the drug. This is the first report of VASCs in a human prostatic cell line. VASCs are present in PC-3 but not LNCaP cells as determined by both protein and functional studies. Tetrodotoxin reduced the invasiveness of PC-3 but not LNCaP cells, and these data suggest that ion channels may play an important functional role in tumor invasion.


A comprehensive overview of targeted therapy in metastatic renal cell carcinoma.
Chemotherapy and immunotherapy failed to deliver decisive results in the systemic treatment of metastatic renal cell carcinoma. Agents representing the current standards operate on members of the RAS signal transduction pathway. Sunitinib (targeting vascular endothelial growth factor), temsirolimus (an inhibitor of the mammalian target of rapamycin - mTOR) and pazopanib (a multi-targeted receptor tyrosine kinase inhibitor) are used in the first line of recurrent disease. A combination of bevacizumab (inhibition of angiogenesis) plus interferon α is also first-line therapy. Second line options include everolimus (another mTOR inhibitor) as well as tyrosine kinase inhibitors for patients who previously received cytokine. We review the results of clinical investigations focusing on survival benefit for these agents. Additionally, trials focusing on new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and monoclonal antibodies including velociximab are also discussed. In addition to published outcomes we also include follow-up and interim results of ongoing clinical trials. In summary, we give a comprehensive overview of current advances in the systemic treatment of metastatic renal cell carcinoma.


Persistent HIV antigenaemia and decline of HIV core antibodies associated with transition to AIDS.
Sequential serum samples from 13 homosexual men who seroconverted for antibodies to human immunodeficiency virus (HIV) were tested for HIV antigen. In one of these men, who developed the acquired immune deficiency syndrome (AIDS), HIV antigenaemia preceded the onset of AIDS by more than a year and persisted throughout the course of the disease. This antigenaemia was accompanied by the disappearance of IgG antibody reactivity to the major HIV core protein p24. In none of the 12 others, who all remained without serious disease, were serum concentrations of HIV antigen detected, except on one occasion in one man. All their serum samples showed strong IgG antibody reactivity to p24. Nine children who were infected with HIV in 1981 by plasma transfusion from a single donor were also followed up for HIV antigenaemia. HIV antigen was almost constantly present in the serum (26 of 28 samples) of five children who developed AIDS related complex or AIDS and less often in the serum (four of 10 samples) of four children who remained free of symptoms. The two children who developed AIDS showed a virtual absence of antibody reactivity to p24. These results indicate that increased HIV gene expression is a contributing factor to the development of AIDS and also provide evidence for a switch from latent to active HIV infection.


Engineered cell-adhesive nanoparticles nucleate extracellular matrix assembly.
Tissue engineering aims to regenerate new biological tissue for replacing diseased or injured tissues. We propose a new approach to accelerate the deposition of cell-secreted matrix proteins into extracellular matrix fibrils. We examined whether dynamic substrates with nanoscale ligand features allowing for alpha5beta1 integrin recruiting, cellular tension generation, and alpha5beta1 integrin mobility would enhance fibronectin matrix assembly in a ligand model system that is routinely not sufficient for its induction. To this end, we developed biodynamic substrates consisting of cell adhesive fragment from the 9th and 10th type repeats of fibronectin (FNf ) functionalized to 100 nm prefabricated albumin nanoparticles (ANPs). FNf-ANPs modulated cellular spreading processes, promoting the development of stellate or dendritic morphologies. Concomitant with the spreading, FNf-ANPs rapidly recruited beta1 integrins to focal contacts and promoted the migration of beta1 integrins centripetally from the cell periphery toward the center. FNf-ANPs stimulated the deposition of secreted fibronectin into matrix fibrils; FNf, the key ligand alone, was not sufficient for fibronectin fibrillogenesis. When FNf-ANPs were displayed from "immobilized" substrates, abolishing any mobility of ligated beta1 integrins, fibronectin matrix assembly was abrogated, implicating the role of dynamic matrix display on matrix assembly. Receptor ligation of FNf-ANPs via noncontractile adhesions was not sufficient to stimulate fibrillogenesis, and Rho-kinase inhibitors abolished fibronectin matrix deposition. Our approach highlights the possibility of engineering integrin-based extracellular matrix assembly using nanotechnology, which may have implications for improved biomaterials for wound repair and basic understanding of matrix remodeling within pathogenesis and biomedicine.


Exploiting Unlabeled Data in CNNs by Self-Supervised Learning to Rank.
For many applications the collection of labeled data is expensive laborious. Exploitation of unlabeled data during training is thus a long pursued objective of machine learning. Self-supervised learning addresses this by positing an auxiliary task (different, but related to the supervised task) for which data is abundantly available. In this paper, we show how ranking can be used as a proxy task for some regression problems. As another contribution, we propose an efficient backpropagation technique for Siamese networks which prevents the redundant computation introduced by the multi-branch network architecture. We apply our framework to two regression problems: Image Quality Assessment (IQA) and Crowd Counting. For both we show how to automatically generate ranked image sets from unlabeled data. Our results show that networks trained to regress to the ground truth targets for labeled data and to simultaneously learn to rank unlabeled data obtain significantly better, state-of-the-art results for both IQA and crowd counting. In addition, we show that measuring network uncertainty on the self-supervised proxy task is a good measure of informativeness of unlabeled data. This can be used to drive an algorithm for active learning and we show that this reduces labeling effort by up to 50 percent.


By land, air, and sea: hemipteran diversity through the genomic lens.
Thanks to a recent spate of sequencing projects, the Hemiptera are the first hemimetabolous insect order to achieve a critical mass of species with sequenced genomes, establishing the basis for comparative genomics of the bugs. However, as the most speciose hemimetabolous order, there is still a vast swathe of the hemipteran phylogeny that awaits genomic representation across subterranean, terrestrial, and aquatic habitats, and with lineage-specific and developmentally plastic cases of both wing polyphenisms and flightlessness. In this review, we highlight opportunities for taxonomic sampling beyond obvious pest species candidates, motivated by intriguing biological features of certain groups as well as the rich research tradition of ecological, physiological, developmental, and particularly cytogenetic investigation that spans the diversity of the Hemiptera.


Pest categorisation of Phenacoccus solenopsis.
The EFSA Panel on Plant Health performed a pest categorisation of Phenacoccus solenopsis (Hemiptera: Pseudococcidae) for the European Union (EU) territory. This species is not included in EU Commission Implementing Regulation 2019/2072. P. solenopsis is native to North America and has spread to all continents except Antarctica. It has recently been reported from Cyprus, Greece and Italy. This mealybug is a polyphagous pest, feeding on about 300 plant species. It usually feeds on aerial plant parts, especially new growth, but also occurs on roots, and is often associated with ants. It is an economically important pest of ornamentals, such as hibiscus and lantana, glasshouse vegetable crops, mainly bell pepper, tomato and eggplant, and field crops, such as cotton. Large populations cause die-back and reduction in yield. Adult and immature P. solenopsis could enter the EU with imported fresh fruit, vegetables and cut flowers, although the main pathway of introduction is likely to be plants for planting. Host availability and climate suitability indicate that most of the EU would be suitable for establishment. The main natural dispersal stage is the first instar, which crawls over the plant or may be dispersed further by wind and animals. All stages may be transported over longer distances in trade. Phytosanitary measures are available and should prevent further introductions and slow the spread within the EU. P. solenopsis is under official control in Cyprus and has recently been reported in Greece and Italy. Assuming that these reports reflect a limited distribution, and P. solenopsis shortly comes under official control, it would satisfy all the criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union quarantine pest.


Sun protection factor: meaning and controversies.
The Sun Protection Factor (SPF) is the most important data to quantify the effectiveness of a sunscreen, being universally accepted. The method is based on determining the minimum erythematous dose (MED), defined as the smallest amount of energy required for triggering the erythema, in areas of protected and unprotected skin. The SPF value is then calculated as the ratio between the MED of protected and unprotected skin. The first publication of a method for determining the SPF was presented in 1978 by the U.S. FDA agency, followed by other publications of FDA and other international regulatory agencies. Although considered the reference method for quantification of sunscreen efficacy of topical products, there are controversies in literature about the method for determining the SPF and the implications of the real conditions of use in the protection achieved in practice by users.


Interleukin-1 in monocyte activation phenotypes in systemic juvenile idiopathic arthritis: Observations from a clinical trial of rilonacept, an interleukin-1 inhibitor.
Systemic juvenile idiopathic arthritis (sJIA) is a childhood rheumatic disease of unknown origin. Dysregulated innate immunity is implicated in disease pathology. We investigated if IL-1 inhibition affects circulating cytokines and monocyte gene expression. CD14+ monocytes from patients in the RAPPORT trial were analyzed by RT-PCR for expression of IL1B and transcription factors associated with monocyte activation. Serum IL-1ra decreased with treatment, and IL-18BP transiently increased. Serum levels of IL-1β, IL-6, IL-10 and IL-18 were unchanged. IRF5 and STAT6 were decreased, and PPARG was increased, independent of clinical response, and may represent a skew toward a PPARG-driven M2-like phenotype. IL1B expression was decreased in early clinical responders. A transient increase in STAT1, and a decrease in SOCS1 preceded the reduction in IL1B in early clinical responders. Changes in IL1B/STAT1/SOCS1 could be associated with crosstalk between IL-1 and IFN pathways in sJIA. These transcriptional changes might be useful as drug response biomarkers.


Prospective associations between beverage intake during the midlife and subclinical carotid atherosclerosis: The Study of Women's Health Across the Nation.
The potential impacts of beverage intake during the midlife on future subclinical atherosclerosis among women are unclear. The aim of this study was to evaluate the prospective associations between the intakes of eight beverage groups and subclinical carotid atherosclerosis in midlife women. Data came from the Study of Women's Health Across the Nation, a multicenter, multiethnic, and prospective cohort study. A total of 1,235 midlife women had measures of subclinical carotid atherosclerosis and repeatedly beverage intake data collected using a validated food frequency questionnaire. Beverages were aggregated into eight groups, including coffee, tea, sugar-sweetened beverages, artificially sweetened beverages, fruit juices, whole milk, milk with lower fat content, and alcoholic beverages. The associations of beverage intake with common carotid artery intima-media thickness (CCA-IMT) and adventitial diameter (CCA-AD) were estimated using linear models; the associations with carotid plaque were estimated using log-binomial models. Coffee intake was associated with CCA-IMT in an inverted J-shaped pattern. After adjusting for covariates, women with >0 to <1 cup/day and 1 to <2 cups/day of coffee intake had a 0.031 mm (95% CI: 0.012, 0.051) and a 0.027 mm (95% CI: 0.005, 0.049) larger CCA-IMT, respectively, than coffee non-drinkers. Women who consumed ≥2 cups/day of coffee did not have significantly different CCA-IMT than non-drinkers. There was an inverse linear association between moderate alcoholic beverages intake and CCA-IMT (P-trend = 0.014). Whole milk intake had inverted U-shaped associations with CCA-IMT and carotid plaque. No significant associations were found between other beverage groups and subclinical atherosclerosis. In midlife women, occasional coffee intake may be associated with more subclinical atherosclerosis while moderate alcoholic beverages intake may be associated with less subclinical atherosclerosis. Future work should focus on the determination of the optimal beverage intake profile for maximum cardiovascular benefits in midlife women.


Sweet Emotion: The Role of Odor-induced Context in the Search Advantage for Happy Facial Expressions.
The current study investigated the extent to which the concurrent presentation of pleasant and unpleasant odors could modulate the perceptual saliency of happy facial expressions in an emotional visual search task. Whilst a search advantage for happy faces was found in the no odor and unpleasant odor conditions, it was abolished under the pleasant odor condition. Furthermore, phasic properties of visual search performance revealed the malleable nature of this happiness advantage. Specifically, attention towards happy faces was optimized at the start of the visual search task for participants presented with pleasant odors, but diminished towards the end. This pattern was reversed for participants in the unpleasant odor condition. These patterns occur through the emotion-inducing capacities of odors and highlight the circumstances in which top-down factors can override perceptually salient facial features in emotional visual search.


Active disruption of an RNA-protein interaction by a DExH/D RNA helicase.
All aspects of cellular RNA metabolism and the replication of many viruses require DExH/D proteins that manipulate RNA in a manner that requires nucleoside triphosphates. Although DExH/D proteins have been shown to unwind purified RNA duplexes, most RNA molecules in the cellular environment are complexed with proteins. It has therefore been speculated that DExH/D proteins may also affect RNA-protein interactions. We demonstrate that the DExH protein NPH-II from vaccinia virus can displace the protein U1A from RNA in an active adenosine triphosphate-dependent fashion. NPH-II increases the rate of U1A dissociation by more than three orders of magnitude while retaining helicase processivity. This indicates that DExH/D proteins can effectively catalyze protein displacement from RNA and thereby participate in the structural reorganization of ribonucleoprotein assemblies.


Trigonelline-induced neurite outgrowth in human neuroblastoma SK-N-SH cells.
Extension of dendrites and axons in neurons may compensate and rescue damaged neuronal networks in the dementia brain. Our aim is to isolate and identify constituents of coffee beans exhibiting neurite outgrowth activity. Among the extracts of raw and roasted coffee beans, a methanol fraction of the ethanol extract (1 microg/ml) of raw beans increased significantly the percentage of cells with neurites in human neuroblastoma SK-N-SH cells. Among subfractions of this methanol fraction was a basic fraction (5 microg/ml) which exhibited significant neurite outgrowth activity. Finally, trigonelline in the basic fraction was identified to be active as far neurite extension was concerned. Treatment with trigonelline (30 microM) increased the percentage of cells with neurites at 3 and 6 d after treatment. In addition, the number of neurites reacting positively to phosphorylated neurofilament-H was increased by treatment with 30 microM trigonelline for 6 d, suggesting enhancement of axonal extension. These results show that trigonelline promotes functional neurite outgrowth.


Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi.
The problems of Plasmodium falciparum infection in pregnant women have been described in numerous sub-Saharan African countries, but the frequency of parasitemia at the first antenatal visit and risk factors for infection have not been fully investigated. During a prospective antimalarial treatment and prophylaxis trial in pregnant women in Malawi (three groups receiving a chloroquine regimen and one group receiving a mefloquine regimen), we examined women at their first antenatal clinic visit to evaluate these issues and to verify that subjects in the study treatment/prevention arms were similar. Among 4,127 women with enrollment blood smear results, 1,836 (44.5%) were parasitemic. The highest infection rates and densities were observed in primigravidas (66% infected, geometric mean parasite density [GMPD] = 1,588 parasites/mm3 of whole blood), followed by second pregnancies (46% infected, GMPD = 615 parasites/mm3) and subsequent pregnancies (29% infected, GMPD = 238 parasites/mm3), (P < 10(-6) for both infection prevalence and density, by chi-square test for trend). Significant risk factors for parasitemia at first antenatal clinic visit in a multivariate model included low gravidity, high transmission season, no use of prophylaxis before first antenatal clinic visit, young age (< 20 years), human immunodeficiency virus (HIV) infection, low hematocrit, short stature, and second trimester (compared with third trimester). Women in the different treatment arms of the study were generally similar in many characteristics; statistically significant differences, where present, were small. Targeting malaria control efforts to women in their first or second pregnancy and during the high transmission season will be an important strategy to reach most parasitemic women and minimize resource expenditure. Women infected with HIV had a 55% increased risk of parasitemia at their first antenatal clinic visit and may represent an additional important risk group whose numbers may be increasing and who may benefit from identification and management for malaria.


Variation in Pea (Pisum sativum L.) Seed Quality Traits Defined by Physicochemical Functional Properties.
Pea is one of the most produced and consumed pulse crops around the world. The study of genetic variability within pea germplasm is an important tool to identify outstanding accessions with optimal functional and nutritional qualities. In the present study, a collection of 105 pea accessions was analysed for physicochemical properties, pasting viscosity, and basic composition parameters. While pasting viscosities were negatively correlated to hydration capacity, cooking time, and basic composition, a positive correlation was found between the hydration capacity and the basic composition parameters. Basic composition (protein, fibre, fat, and resistant starch) parameters were further evaluated regarding seed trait morphology, namely, seed shape, colour, and surface. Allelic characterisation at the r and rb genetic loci was performed in a subgroup of 32 accessions (3 phenotyped as smooth and 29 as rough seeded), revealing that none of the initially classified rough-seeded accessions were rb mutants, 19 were r mutants, and 13 were neither r nor rb. Despite their initial phenotypic classification, the 13 accessions genetically classified as smooth behaved differently (p < 0.05) to the 19 r mutants in terms of physicochemical properties, pasting viscosity, and basic composition parameters. Using multivariate analysis of the most discriminatory parameters for the food-related traits studied, the best-performing accessions at functional and nutritional levels were identified for future plant breeding to improve field pea production and consumption.


Prevalence of cytomegalovirus antibodies in blood donors at the National Blood Transfusion Centre, Nairobi.
Cytomegalovirus (CMV) infection in susceptible patients is associated with serious morbidity and a high mortality. Transmission of cytomegalovirus infection through blood transfusion is markedly reduced by transfusion of CMV seronegative blood products, or by transfusion of leucodepleted blood products. To determine the prevalence CMV IgG and IgM antibodies among blood donors at the National Blood Transfusion Services (NBTS), Nairobi. Cross-sectional descriptive study. Four hundred participants were recruited from blood donors at the NBTS and testing was done at the Kenyatta National Hospital (KNH) immunology laboratories and the NBTC. Social demographic data and the CMV serologic status for the participants was determined and documented as being positive or negative for immunoglobulin G (IgG) and immunoglobulin M (IgM). The age, gender, marital status, education level and geographical area of residence of the participants were documented. Corresponding results of HIV, hepatitis B antigen, hepatitis C antibody from the patients were obtained from the NBTS. Majority of the blood donors recruited were male at 57.9%. Most blood donors were aged 16-20 years (42.5%) and only 17.2% were above 30 years of age. Unmarried blood donors, those with secondary school education and an income between Kshs 5000 (US $67) and KShs 50,000 (US$ 667) monthly were the majority at 78.5%, 54.8% and 66.1% respectively. Sexually active blood donors constituted 60.5% of the donors recruited. Positivity for transfusion transmissible infections (TTI) tested was 1.3%, 0.3%, 2.3% and 1.0% for human immunodeficiency virus (HIV), syphilis, hepatitis B and hepatitis C respectively. Anti- CMV IgG and IgM positivity was 97.0%, (95% CI 96.45-97.53%), and 3.6% (95% CI 1.7-5.2%), respectively. There was no statistical difference between different ages, marital status, salary, individual's sexuality in the prevalence of CMV antibodies. However females had a higher prevalence of CMV antibodies. There is a very high prevalence of cytomegalovirus antibodies among blood donors at the NBTS, with virtually all blood donors having been exposed to the virus. Since the CMV remains latent within leucocytes after infection inspite of the prescence of antibodies in seropositive individuals, leucoreduction of blood products is recommended before transfusion to seronegative susceptible patients. In Kenya, susceptible groups of patients include very low birthweight babies, patients with acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus infections (HIV) patients, patients on myelosuppressive cancer therapy and recipients of kidney transplants. Further studies are recomended to determine the prevalence of CMV antibodies in these patients in order to establish the magnitude of the demand for CMV safe blood.


May-thurner syndrome: a case report.
May-Thurner Syndrome (MTS) or iliac vein compression syndrome is caused by compression of the left common iliac vein by the right common iliac artery. This obstruction may cause leg swelling, varicosities, deep venous thrombosis, chronic venous stasis ulcers, or more serious complications, such as pulmonary embolism. Iliac vein compression can be assessed with computed tomography (CT) and iliac venography. The goals of treatment are to reduce symptoms and to reduce the risk of complications. Stent placement is an alternative method to a direct surgical approach. We present a case of MTS, treated with stent placement.


Differential proteomic analyses of cataracts from rat models of type 1 and 2 diabetes.
To identify differential changes in proteins and metabolites underlying "fast" type 1 (T1DC) and "slow" type 2 (T2DC) diabetic cataract (DC) formation in rat. Rat models of types 1 and 2 diabetes consisted of streptozotocin injection without and with high-fat diet, respectively. Cataract progression was examined weekly. At week 6, total protein changes were comparatively and quantitatively assessed by two-dimensional differential in-gel electrophoresis (2-D DIGE) coupled with mass spectrometry, and relevant metabolic changes were examined. Differences in high molecular weight (HMW) crystallin species between diabetic and control lenses were similarly identified. Cataracts were morphologically different and progressed more slowly in T2DC versus T1DC. αA-crystallin, βB2-crystallin, and βA4-crystallin were significantly decreased in both DC types versus control. αB-crystallin was increased while βB1-crystallin was markedly decreased in T2DC. In T1DC, γB-crystallin and γS-crystallin fragmentation were increased. High-fat diet by itself had little impact, except for lowering γS-crystallin fragmentation. Despite significantly decreased opacity, a greater decrease in intermediate filaments (IFs) and more HMW crystallin species were observed in T2DC versus T1DC. However, aldose reductase expression and activity and sorbitol levels were increased to a greater extent in T1DC, while reduced glutathione (GSH) and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) levels were decreased to a greater extent and adenosine triphosphate (ATP) level was much lower in T1DC versus T2DC. The results suggest that osmotic damage, GSH loss, and decreased ATP production might be important pathological mechanisms in T1DC formation, whereas crystallin modification and cross-linking/aggregation as well as IF degradation may play more crucial roles in T2DC formation.


Biofilm accumulation model that predicts antibiotic resistance of Pseudomonas aeruginosa biofilms.
A computer model of biofilm dynamics was adapted to incorporate the activity of an antimicrobial agent on bacterial biofilm. The model was used to evaluate the plausibility of two mechanisms of biofilm antibiotic resistance by qualitative comparison with data from a well-characterized experimental system (H. Anwar, J. L. Strap, and J. W. Costerton, Antimicrob. Agents Chemother. 36:1208-1214, 1992). The two mechanisms involved either depletion of the antibiotic by reaction with biomass or physiological resistance due to reduced bacterial growth rates in the biofilm. Both mechanisms predicted the experimentally observed resistance of 7-day-old Pseudomonas aeruginosa biofilms compared with that of 2-day-old ones. A version of the model that incorporated growth rate-dependent killing predicted reduced susceptibility of thicker biofilms because oxygen was exhausted within these biofilms, leading to very slow growth in part of the biofilm. A version of the model that incorporated a destructive reaction of the antibiotic with biomass likewise accounted for the relative resistance of thicker biofilms. Resistance in this latter case was due to depletion of the antibiotic in the bulk fluid rather than development of a gradient in the antibiotic concentration within the biofilm. The modeling results predicted differences between the two cases, such as in the survival profiles within the biofilm, that could permit these resistance mechanisms to be experimentally distinguished.


Characterization of muscle ankyrin repeat proteins in human skeletal muscle.
Muscle ankyrin repeat proteins (MARPs) are a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. In cardiac muscle, cardiac ankyrin repeat protein (CARP) and diabetes-related ankyrin repeat protein (DARP) reportedly redistribute from binding sites on titin to the nucleus following a prolonged stretch. However, it is unclear whether ankyrin repeat domain protein 2 (Ankrd 2) shows comparable stretch-induced redistribution to the nucleus. We measured the following in rested human skeletal muscle: 1) the absolute amount of MARPs and 2) the distribution of Ankrd 2 and DARP in both single fibers and whole muscle preparations. In absolute amounts, Ankrd 2 is the most abundant MARP in human skeletal muscle, there being ~3.1 µmol/kg, much greater than DARP and CARP (~0.11 and ~0.02 µmol/kg, respectively). All DARP was found to be tightly bound at cytoskeletal (or possibly nuclear) sites. In contrast, ~70% of the total Ankrd 2 is freely diffusible in the cytosol [including virtually all of the phosphorylated (p)Ankrd 2-Ser99 form], ~15% is bound to non-nuclear membranes, and ~15% is bound at cytoskeletal sites, likely at the N2A region of titin. These data are not consistent with the proposal that Ankrd 2, per se, or pAnkrd 2-Ser99 mediates stretch-induced signaling in skeletal muscle, dissociating from titin and translocating to the nucleus, because the majority of these forms of Ankrd 2 are already free in the cytosol. It will be necessary to show that the titin-associated Ankrd 2 is modified by stretch in some as-yet-unidentified way, distinct from the diffusible pool, if it is to act as a stretch-sensitive signaling molecule.


Addressing uncertainties in the ERICA Integrated Approach.
Like any complex environmental problem, ecological risk assessment of the impacts of ionising radiation is confounded by uncertainty. At all stages, from problem formulation through to risk characterisation, the assessment is dependent on models, scenarios, assumptions and extrapolations. These include technical uncertainties related to the data used, conceptual uncertainties associated with models and scenarios, as well as social uncertainties such as economic impacts, the interpretation of legislation, and the acceptability of the assessment results to stakeholders. The ERICA Integrated Approach has been developed to allow an assessment of the risks of ionising radiation, and includes a number of methods that are intended to make the uncertainties and assumptions inherent in the assessment more transparent to users and stakeholders. Throughout its development, ERICA has recommended that assessors deal openly with the deeper dimensions of uncertainty and acknowledge that uncertainty is intrinsic to complex systems. Since the tool is based on a tiered approach, the approaches to dealing with uncertainty vary between the tiers, ranging from a simple, but highly conservative screening to a full probabilistic risk assessment including sensitivity analysis. This paper gives on overview of types of uncertainty that are manifest in ecological risk assessment and the ERICA Integrated Approach to dealing with some of these uncertainties.


Self-assessment of the outcome of early medical abortion versus clinic follow-up in India: a randomised, controlled, non-inferiority trial.
The need for multiple clinical visits remains a barrier to women accessing safe legal medical abortion services. Alternatives to routine clinic follow-up visits have not been assessed in rural low-resource settings. We compared the effectiveness of standard clinic follow-up versus home assessment of outcome of medical abortion in a low-resource setting. This randomised, controlled, non-inferiority trial was done in six health centres (three rural, three urban) in Rajasthan, India. Women seeking early medical abortion up to 9 weeks of gestation were randomly assigned (1:1) to either routine clinic follow-up or self-assessment at home. Randomisation was done with a computer-generated randomisation sequence, with a block size of six. The study was not blinded. Women in the home-assessment group were advised to use a pictorial instruction sheet and take a low-sensitivity urine pregnancy test at home, 10-14 days after intake of mifepristone, and were contacted by a home visit or telephone call to record the outcome of the abortion. The primary (non-inferiority) outcome was complete abortion without continuing pregnancy or need for surgical evacuation or additional mifepristone and misoprostol. The non-inferiority margin for the risk difference was 5%. All participants with a reported primary outcome and who followed the clinical protocol were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01827995. Between April 23, 2013, and May 15, 2014, 731 women were recruited and assigned to clinic follow-up (n=366) or home assessment (n=365), of whom 700 were analysed for the main outcomes (n=336 and n=364, respectively). Complete abortion without continuing pregnancy, surgical intervention, or additional mifepristone and misoprostol was reported in 313 (93%) of 336 women in the clinic follow-up group and 347 (95%) of 364 women in the home-assessment group (difference -2·2%, 95% CI -5·9 to 1·6). One case of haemorrhage occurred in each group (rate of adverse events 0·3% in each group); no other adverse events were noted. Home assessment of medical abortion outcome with a low-sensitivity urine pregnancy test is non-inferior to clinic follow-up, and could be introduced instead of a clinic follow-up visit in a low-resource setting.


CABE: A Cloud-Based Acoustic Beamforming Emulator for FPGA-Based Sound Source Localization.
Microphone arrays are gaining in popularity thanks to the availability of low-cost microphones. Applications including sonar, binaural hearing aid devices, acoustic indoor localization techniques and speech recognition are proposed by several research groups and companies. In most of the available implementations, the microphones utilized are assumed to offer an ideal response in a given frequency domain. Several toolboxes and software can be used to obtain a theoretical response of a microphone array with a given beamforming algorithm. However, a tool facilitating the design of a microphone array taking into account the non-ideal characteristics could not be found. Moreover, generating packages facilitating the implementation on Field Programmable Gate Arrays has, to our knowledge, not been carried out yet. Visualizing the responses in 2D and 3D also poses an engineering challenge. To alleviate these shortcomings, a scalable Cloud-based Acoustic Beamforming Emulator (CABE) is proposed. The non-ideal characteristics of microphones are considered during the computations and results are validated with acoustic data captured from microphones. It is also possible to generate hardware description language packages containing delay tables facilitating the implementation of Delay-and-Sum beamformers in embedded hardware. Truncation error analysis can also be carried out for fixed-point signal processing. The effects of disabling a given group of microphones within the microphone array can also be calculated. Results and packages can be visualized with a dedicated client application. Users can create and configure several parameters of an emulation, including sound source placement, the shape of the microphone array and the required signal processing flow. Depending on the user configuration, 2D and 3D graphs showing the beamforming results, waterfall diagrams and performance metrics can be generated by the client application. The emulations are also validated with captured data from existing microphone arrays.


Multifractal analysis of the 137Cs fallout pattern in Austria resulting from the Chernobyl accident.
The cumulative deposition of the 137Cs fallout in Austria resulting from the passage of the Chernobyl cloud has been investigated by applying correlation dimension and hyperbolic frequency distribution methods. For the analysis, a total of 1,881 deposition values were used, which were collected by the Federal Environmental Agency of Austria and the Federal Ministry of Health, representing all available measurements of 137Cs in soil made in Austria after the Chernobyl accident. From these data a hyperbolic exponent for the frequency distribution of 4.0 and a set of fractal correlation dimensions, which decrease from 1.426 +/- 0.022 (for the whole network) to 0.706 +/- 0.047 (for 137Cs values > or = 100 kBq m(-2)), were derived, thus confirming that the fallout pattern can be described as a multifractal.