Interphase cytogenetics of hematological cancer: comparison of classical karyotyping and in situ hybridization using a panel of eleven chromosome specific DNA probes.
Numerical chromosome aberrations were detected in hematological cancers by nonradioactive in situ hybridization (ISH) procedures, using centromere specific probes for chromosomes 1, 7, 8, 9, 10, 11, 16, 17, 18, X, and Y. All 15 cases could be evaluated by ISH for these 11 probes. Our experiments show that in seven of these randomly selected leukemia bone marrow cell suspensions numerical aberrations for one or two chromosomes could be detected by this method. The results of ISH on interphase nuclei and in some cases on metaphase preparations were compared with karyotyping data. Seven cases of chromosomal aberrations observed with ISH (three for monosomy and four for trisomy) were confirmed by this classical cytogenetic technique, whereas in five instances an aberration was found only with ISH (twice for monosomy, twice for trisomy, and one disomy for the Y-probe). One case of a trisomy for chromosome 1 observed by ISH on interphase nuclei could be explained by a marker chromosome, a finding that was further substantiated by ISH on metaphase spreads. In this case double-target ISH on interphase cells with the probes for chromosomes 1 and 16 strongly suggested a translocation between these chromosomes. Also, in one case a marker chromosome could be characterized as a translocation between chromosomes 7 and 17. In this latter case the cytogenetic examinations revealed only monosomy for chromosomes 7 and 17 in addition to noncharacterized marker chromosomes. Our results indicate that the nonradioactive ISH procedure in combination with chromosome specific repetitive centromeric probes is a powerful tool for studying both numerical and structural chromosomal aberrations in interphase nuclei of leukemias. It may therefore become a valuable and routine diagnostic tool in addition to the existing karyotyping procedures.


Chiral differentiation of d- and l-isoleucine using permethylated β-cyclodextrin: infrared multiple photon dissociation spectroscopy, ion-mobility mass spectrometry, and DFT calculations.
Chiral differentiation of protonated isoleucine (Ile) using permethylated β-cyclodextrin (perCD) in the gas-phase was studied using infrared multiple photon dissociation (IRMPD) spectroscopy, ion-mobility, and density functional theory (DFT) calculations. The gaseous protonated non-covalent complexes of perCD and d-Ile or l-Ile produced by electrospray ionization were interrogated by laser pulses in the wavenumber region of 2650 to 3800 cm-1. The IRMPD spectra showed remarkably different IR spectral features for the d-Ile or l-Ile and perCD non-covalent complexes. However, drift-tube ion-mobility experiments provided only a small difference in their collision cross-sections, and thus a limited separation of the d- and l-Ile complexes. DFT calculations revealed that the chiral distinction of the d- and l-complexes by IRMPD spectroscopy resulted from local interactions of the protonated Ile with perCD. Furthermore, the theoretical results showed that the IR absorption spectra of higher energy conformers (by ∼13.7 kcal mol-1) matched best with the experimentally observed IRMPD spectra. These conformers are speculated to be formed from kinetic-trapping of the solution-phase conformers. This study demonstrated that IRMPD spectroscopy provides an excellent platform for differentiating the subtle chiral difference of a small amino acid in a cyclodextrin-complexation environment; however, drift-tube ion-mobility did not have sufficient resolution to distinguish the chiral difference.


Polyhydroxybutyrate, a biodegradable thermoplastic, produced in transgenic plants.
Polyhydroxybutyrate (PHB), a high molecular weight polyester, is accumulated as a storage carbon in many species of bacteria and is a biodegradable thermoplastic. To produce PHB by genetic engineering in plants, genes from the bacterium Alcaligenes eutrophus that encoded the two enzymes required to convert acetoacetyl-coenzyme A to PHB were placed under transcriptional control of the cauliflower mosaic virus 35S promoter and introduced into Arabidopsis thaliana. Transgenic plant lines that contained both genes accumulated PHB as electron-lucent granules in the cytoplasm, nucleus, and vacuole; the size and appearance of these granules were similar to the PHB granules that accumulate in bacteria.


Yield, Insect-Derived Ear Injury, and Aflatoxin Among Developmental and Commercial Maize Hybrids Adapted to the North American Subtropics.
The development of maize (Zea mays L.) hybrids that are adapted to subtropical areas of North America should consider yield potential under heat and moisture stress, and reduced susceptibility to insect herbivory and disease. To aid in this process, maize hybrids (43 developmental and seven non-Bt commercial hybrids) were evaluated for severity of ear injury to Helicoverpa zea (Boddie) and Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), susceptibility to Aspergillus flavus (Link) (Deuteromycetes: Moniliales), and yield. In subtropical Corpus Christi and College Station, TX, field experiments conducted over three years revealed significant differences among maize hybrids with the rank of the selected measurements differing across the two locations. When the location by maize hybrid interaction was not significant, variation across the main factors of maize hybrid genetics (in all cases) and location (in some cases) was detected. In 2014, a significant location by maize hybrid interaction in yield but not aflatoxin and ear injury were likely associated with differences in weather between locations. In Corpus Christi in 2015, a location by maize hybrid interaction was detected for ear injury only. Overall, experimental maize hybrids, containing the inbred line Tx777, displayed partial resistance to insect derived ear injury in both locations, and some hybrid testcrosses exhibited low rates of aflatoxin accumulation while maintaining relatively high yields. Tx777 was selected from populations originating in Bolivia and adapted to subtropical climates. The most promising hybrid testcrosses had lower ear injury and aflatoxin accumulation, and good yield under varying heat and moisture stress at the two subtropical maize growing areas in this study.


Self-administration of injectable contraception: a systematic review and meta-analysis.
Depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) may facilitate self-administration and expand contraceptive access. To inform WHO guidelines on self-care interventions, we conducted a systematic review and meta-analysis comparing self-administration versus provider administration of injectable contraception on outcomes of pregnancy, side effects/adverse events, contraceptive uptake, contraceptive continuation, self-efficacy/empowerment and social harms. We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, LILACS and EMBASE in September 2018 for peer-reviewed studies comparing women who received injectable contraception with the option of self-administration with women who received provider-administered injectable contraception on at least one outcome of interest. Risk of bias was assessed using the Cochrane tool for randomised controlled trials (RCTs) and the Evidence Project tool for non-randomised studies. Meta-analysis was conducted using random-effects models to generate pooled estimates of relative risk (RR). Six studies with 3851 total participants met the inclusion criteria: three RCTs and three controlled cohort studies. All studies examined self-injection of DMPA-SC; comparison groups were either provider-administered DMPA-SC or provider-administered intramuscular DMPA. All studies followed women through 12 months of contraceptive coverage and measured (dis)continuation of injectable contraception. Meta-analysis found higher rates of continuation with self-administration compared with provider administration in three RCTs (RR: 1.27, 95% CI 1.16 to 1.39) and three controlled cohort studies (RR: 1.18, 95% CI 1.10 to 1.26). Four studies reported pregnancies; all showed no difference across study arms. Four studies reported side effects/adverse events; while two controlled cohort studies showed increased injection site reactions with self-administration, no other side effects increased with self-administration. One study found no difference in social harms. No studies reported measuring uptake or self-efficacy/empowerment. A growing evidence base suggests that self-administration of DMPA-SC can equal or improve contraceptive continuation rates compared with provider administration. This benefit comes without notable increases in pregnancy or safety concerns. Self-injection of DMPA-SC is a promising approach to increasing contraceptive use.


Longitudinal study of regional cerebral blood flow changes in depression after stroke.
We studied 60 patients longitudinally to examine relations between regional cerebral blood flow and depressive states after stroke. Poststroke depressive states were assessed by the Zung Self-Rating Depression Scale (SDS). Regional cerebral blood flow was measured using the 133xenon inhalation method with patients in the resting state on the same day as the SDS assessment. All patients were followed for an average of 14 months after the initial assessment. Severity of depression was inversely correlated with regional cerebral blood flow values in the parieto-occipital regions of the right hemisphere and in the anterior temporal region of the left hemisphere at the initial evaluation. Patients with lesions in left frontal or right parieto-occipital regions were more depressive in comparison with those with other brain lesions. Follow-up study showed significant inverse correlations between changes in SDS score and changes in regional cerebral blood flow at all scalp sites. Furthermore, higher inverse correlations were observed at specific brain regions in each hemisphere, including the parietal and parieto-occipital regions of the right hemisphere and the anterior temporal and inferior frontal regions of the left hemisphere. This relation was independent of recovery from neurological deficits. These results suggest that dysfunction of specific cortical and subcortical regions in both hemispheres asymmetrically contributes to depressive state after stroke.


The woodchuck: a model for therapeutic vaccination against hepadnaviral infection.
Interferon-alpha and nucleoside analogues are available for the treatment of chronic hepatitis B virus (HBV) infection but do not lead to a satisfactory result. New findings about the immunological control of HBV during acute infection suggest the pivotal role of T-cell mediated immune responses. Several preclinical and clinical trials were undertaken to explore the possibility of stimulating specific immune responses in chronically infected animals and patients by vaccination. However, vaccination with commercially available HBV vaccines in patients and immunization in woodchucks with core or surface proteins of woodchuck hepatitis virus (WHV) did not result in effective control of HBV and WHV infection, suggesting that new formulations of therapeutic vaccines are needed. Some new approaches combining antiviral treatments with nucleoside analogues, DNA vaccines and protein vaccines were tested in the woodchuck model. It could be shown that therapeutic vaccinations are able to stimulate specific B- and T-cell responses and to achieve transient suppression of viral replication. These results suggest the great potential of therapeutic vaccination in combination with antivirals to reach an effective and sustained control of HBV infection.


Fatty acid synthase inhibitor C75 ameliorates experimental colitis.
Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD.


Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate.
Limited information is available regarding epigenomic events mediating initiation and progression of tobacco-induced lung cancers. In this study, we established an in vitro system to examine epigenomic effects of cigarette smoke in respiratory epithelia. Normal human small airway epithelial cells and cdk-4/hTERT-immortalized human bronchial epithelial cells (HBEC) were cultured in normal media with or without cigarette smoke condensate (CSC) for up to 9 months under potentially relevant exposure conditions. Western blot analysis showed that CSC mediated dose- and time-dependent diminution of H4K16Ac and H4K20Me3, while increasing relative levels of H3K27Me3; these histone alterations coincided with decreased DNA methyltransferase 1 (DNMT1) and increased DNMT3b expression. Pyrosequencing and quantitative RT-PCR experiments revealed time-dependent hypomethylation of D4Z4, NBL2, and LINE-1 repetitive DNA sequences; up-regulation of H19, IGF2, MAGE-A1, and MAGE-A3; activation of Wnt signaling; and hypermethylation of tumor suppressor genes such as RASSF1A and RAR-beta, which are frequently silenced in human lung cancers. Array-based DNA methylation profiling identified additional novel DNA methylation targets in soft-agar clones derived from CSC-exposed HBEC; a CSC gene expression signature was also identified in these cells. Progressive genomic hypomethylation and locoregional DNA hypermethylation induced by CSC coincided with a dramatic increase in soft-agar clonogenicity. Collectively, these data indicate that cigarette smoke induces 'cancer-associated' epigenomic alterations in cultured respiratory epithelia. This in vitro model may prove useful for delineating early epigenetic mechanisms regulating gene expression during pulmonary carcinogenesis.


Historical changes in population structure during rice breeding programs in the northern limits of rice cultivation.
The rice local population was clearly differentiated into six groups over the 100-year history of rice breeding programs in the northern limit of rice cultivation over the world. Genetic improvements in plant breeding programs in local regions have led to the development of new cultivars with specific agronomic traits under environmental conditions and generated the unique genetic structures of local populations. Understanding historical changes in genome structures and phenotypic characteristics within local populations may be useful for identifying profitable genes and/or genetic resources and the creation of new gene combinations in plant breeding programs. In the present study, historical changes were elucidated in genome structures and phenotypic characteristics during 100-year rice breeding programs in Hokkaido, the northern limit of rice cultivation in the world. We selected 63 rice cultivars to represent the historical diversity of this local population from landraces to the current breeding lines. The results of the phylogenetic analysis demonstrated that these cultivars clearly differentiated into six groups over the history of rice breeding programs. Significant differences among these groups were detected in five of the seven traits, indicating that the differentiation of the Hokkaido rice population into these groups was correlated with these phenotypic changes. These results demonstrated that breeding practices in Hokkaido have created new genetic structures for adaptability to specific environmental conditions and breeding objectives. They also provide a new strategy for rice breeding programs in which such unique genes in local populations in the world can explore the genetic potentials of the local populations.


Notos - a galaxy tool to analyze CpN observed expected ratios for inferring DNA methylation types.
DNA methylation patterns store epigenetic information in the vast majority of eukaryotic species. The relatively high costs and technical challenges associated with the detection of DNA methylation however have created a bias in the number of methylation studies towards model organisms. Consequently, it remains challenging to infer kingdom-wide general rules about the functions and evolutionary conservation of DNA methylation. Methylated cytosine is often found in specific CpN dinucleotides, and the frequency distributions of, for instance, CpG observed/expected (CpG o/e) ratios have been used to infer DNA methylation types based on higher mutability of methylated CpG. Predominantly model-based approaches essentially founded on mixtures of Gaussian distributions are currently used to investigate questions related to the number and position of modes of CpG o/e ratios. These approaches require the selection of an appropriate criterion for determining the best model and will fail if empirical distributions are complex or even merely moderately skewed. We use a kernel density estimation (KDE) based technique for robust and precise characterization of complex CpN o/e distributions without a priori assumptions about the underlying distributions. We show that KDE delivers robust descriptions of CpN o/e distributions. For straightforward processing, we have developed a Galaxy tool, called Notos and available at the ToolShed, that calculates these ratios of input FASTA files and fits a density to their empirical distribution. Based on the estimated density the number and shape of modes of the distribution is determined, providing a rational for the prediction of the number and the types of different methylation classes. Notos is written in R and Perl.


Predictors and impact of second-line chemotherapy for advanced non-small cell lung cancer in the United States: real-world considerations for maintenance therapy.
: Recent clinical trials incorporating maintenance chemotherapy into the initial treatment of advanced non-small cell lung cancer (NSCLC) have highlighted the benefits of exposing patients to second-line therapies. We, therefore, determined the predictors and impact of second-line chemotherapy administration in a contemporary, diverse NSCLC population. : We performed a retrospective analysis of consecutive patients diagnosed with stage IV NSCLC from 2000 to 2007 at clinical facilities associated with the University of Texas Southwestern Medical Center. Demographic, disease, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression. : A total of 406 patients in this cohort received first-line chemotherapy and were included in the analysis. Mean age was 59 years, 28% were women, and 59% were white. Among these patients, 197 (49%) received second-line chemotherapy. Among those patients who had not progressed after four to six cycles of first-line chemotherapy, 67% received second-line chemotherapy. Receipt of second-line chemotherapy was significantly associated with patient insurance type (p = 0.007), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.005) but was not associated with patient age, gender, race, histology, or year of diagnosis. In a multivariate model, second-line chemotherapy administration remained associated with insurance type (p = 0.003), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.008). The number of cycles of first-line chemotherapy and administration of second-line chemotherapy were associated with overall survival in both univariate and multivariate analyses. : In this unselected, contemporary, and diverse cohort of patients with advanced NSCLC, 67% of individuals whose disease had not progressed after four to six cycles of first-line chemotherapy eventually received second-line chemotherapy. Markers of socioeconomic status, symptom burden, and response to and tolerance of first-line chemotherapy were associated with receipt of second-line chemotherapy. These factors may assist in the selection of patients most likely to benefit from maintenance chemotherapy.


Explaining the social patterning of lung function in adulthood at different ages: the roles of childhood precursors, health behaviours and environmental factors.
Lung function successfully predicts subsequent health. Although lung function is known to decline over age, little is known about changes in association with socioeconomic status (SES) throughout life, and whether explanatory factors for association vary with age or patterns for non smokers. Analyses were based on data on 24 500 participants aged ≥18 years from the 1995, 1998 and 2003 Scottish Health Surveys who were invited to provide 1 s forced expiratory volume (FEV1) and forced vital capacity (FVC) lung measurements. Sex-stratified multiple linear regression assessed lung function-SES (occupational social class) associations and attenuation by covariates in three age groups (2003 data (n=7928)). The FEV1-SES patterns were clear (p<0.001) and constant over time. Relative to the least disadvantaged, FEV1 in the most disadvantaged was lower by 0.28 L in men and 0.20 L in women under 40 years compared with differences of 0.51 L in men and 0.25 L in women over 64 years (p(interaction)<0.001 men, p(interaction)=0.004 women). The greatest attenuation of these results was seen by height, parental social class and smoking, especially among the under 65s. Second-hand smoke exposure and urban/rural residence had some impact among older groups. Adjusting for physical activity and weight had little effect generally. Similar patterns were seen for FVC and among never smokers. We found cross-sectional evidence that SES disparity in lung function increases with age, especially for men. Our findings indicate that early-life factors may predict inequity during younger adulthood, with environmental factors becoming more important at older ages.


The load independence of the end-systolic pressure-length relationship of the heart.
The end-systolic pressure-volume relationship is the state of the art in the measurement of myocardial contractility. This index is load-independent and relatively independent of heart rate. In this study the load-independent character of the end-systolic pressure-length (ESPL) relationship was evaluated in dogs under general anaesthesia. The results indicated that the ESPL is pre- and afterload-independent, since the comparative values of ESPL from afterloaded and reduced preload contractions did not differ significantly (N = 75; P = 0.5993). The application of the ESPL relationship as a means of describing the function of the heart as a muscle as well as a pump is discussed.


Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice.
Although morphine induces both analgesia and dependence through mu-opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K(+) (GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out ((-/-)) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3(-/-) mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3(-/-) mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3(-/-) mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3(-/-) mice by ablation of adrenergic fibers using the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate.


Controlling Light Harvesting with Light.
When exposed to intense sunlight, all organisms performing oxygenic photosynthesis implement various photoprotective strategies to prevent potentially lethal photodamage. The rapidly responding photoprotective mechanisms, occurring in the light-harvesting pigment-protein antennae, take effect within tens of seconds, while the dramatic and potentially harmful light intensity fluctuations manifest also on shorter time scales. Here we show that, upon illumination, individual phycobilisomes from Synechocystis PCC 6803, which, in vivo under low-light conditions, harvest solar energy, and have the built-in capacity to switch rapidly and reversibly into light-activated energy-dissipating states. Simultaneously measured fluorescence intensity, lifetime, and spectra, compared with a multicompartmental kinetic model, revealed that essentially any subunit of a phycobilisome can be quenched, and that the core complexes were targeted most frequently. Our results provide the first evidence for fluorescence blinking from a biologically active system at physiological light intensities and suggest that the light-controlled switches to intrinsically available energy-dissipating states are responsible for a novel type of photoprotection in cyanobacteria. We anticipate other photosynthetic organisms to employ similar strategies to respond instantly to rapid solar light intensity fluctuations. A detailed understanding of the photophysics of photosynthetic antenna complexes is of great interest for bioinspired solar energy technologies.


Generation of few-cycle infrared pulses from a degenerate dual-pump OPCPA.
A degenerate dual-pump optical parametric chirped-pulse amplifier (OPCPA) for generation of few-cycle intense pulses centered at 1.6 μm is theoretically investigated. By adding the optimized linear chirp to the two pump pulses from Ti:sapphire source and carefully adjusting the delays between the two pumps and seed, the long- and short-wavelength components of the seed pulse are efficiently amplified during the parametric process. Our simulations show that a broadband spectrum spanning from 1.3 μm to 2.1 μm is attained with a conversion efficiency of 22.6%. Signal pulse with a near transform-limited (TL) duration of 10.1 fs can be achieved by simply removing the linear chirp from the output signal. Besides, the compressed signal beam manifests good quality both spectrally and temporally, which allows tightly focusing the signal beam for further use.


Patents of drugs extracted from Brazilian medicinal plants.
Plants synthesise a vast repertoire of chemicals with various biological activities. Brazilian enormous botanical diversity facilitates the development of novel ethical drugs for the treatment of diseases in humans. To present therapeutic patent applications comprising Brazilian native plants published in the 2003-2008 period in light of legal aspects of patentability of biodiversity and public health concerns. Therapeutic patent applications related to Brazilian medicinal plants available at both the European Patent Office and the Brazilian National Institute of Industrial Property databases were reviewed. Twenty-five patents are presented, most of which concern inflammatory, allergic, parasitic, infectious or digestive diseases, including extracts from Carapa guianensis, Copaifera genus, Cordia verbenacea, Erythrina mulungu, Physalis angulata and other pharmaceutical compositions with antileishmanial, antimalarial or trypanocidal activity. Brazilian research centres and universities are responsible for most of these inventions.


End-point impedance measurements across dominant and nondominant hands and robotic assistance with directional damping.
The goal of this paper is to perform end-point impedance measurements across dominant and nondominant hands while doing airbrush painting and to use the results for developing a robotic assistance scheme. We study airbrush painting because it resembles in many ways manual welding, a standard industrial task. The experiments are performed with the 7 degrees of freedom KUKA lightweight robot arm. The robot is controlled in admittance using a force sensor attached at the end-point, so as to act as a free-mass and be passively guided by the human. For impedance measurements, a set of nine subjects perform 12 repetitions of airbrush painting, drawing a straight-line on a cartoon horizontally placed on a table, while passively moving the airbrush mounted on the robot's end-point. We measure hand impedance during the painting task by generating sudden and brief external forces with the robot. The results show that on average the dominant hand displays larger impedance than the nondominant in the directions perpendicular to the painting line. We find the most significant difference in the damping values in these directions. Based on this observation, we develop a "directional damping" scheme for robotic assistance and conduct a pilot study with 12 subjects to contrast airbrush painting with and without robotic assistance. Results show significant improvement in precision with both dominant and nondominant hands when using robotic assistance.


The association between muscle strength and activity limitations in patients with the hypermobility type of Ehlers-Danlos syndrome: the impact of proprioception.
The patients diagnosed with Ehlers-Danlos Syndrome Hypermobility Type (EDS-HT) are characterized by pain, proprioceptive inacuity, muscle weakness, potentially leading to activity limitations. In EDS-HT, a direct relationship between muscle strength, proprioception and activity limitations has never been studied. The objective of the study was to establish the association between muscle strength and activity limitations and the impact of proprioception on this association in EDS-HT patients. Twenty-four EDS-HT patients were compared with 24 controls. Activity limitations were quantified by Health Assessment Questionnaire (HAQ), Six-Minute Walk test (6MWT) and 30-s chair-rise test (30CRT). Muscle strength was quantified by handheld dynamometry. Proprioception was quantified by movement detection paradigm. In analyses, the association between muscle strength and activity limitations was controlled for proprioception and confounders. Muscle strength was associated with 30CRT (r = 0.67, p = <0.001), 6MWT (r = 0.58, p = <0.001) and HAQ (r = 0.63, p= <0.001). Proprioception was associated with 30CRT (r = 0.55, p < 0.001), 6MWT (r = 0.40, p = <0.05) and HAQ (r = 0.46, p < 0.05). Muscle strength was found to be associated with activity limitations, however, proprioceptive inacuity confounded this association. Muscle strength is associated with activity limitations in EDS-HT patients. Joint proprioception is of influence on this association and should be considered in the development of new treatment strategies for patients with EDS-HT. Implications for rehabilitation Reducing activity limitations by enhancing muscle strength is frequently applied in the treatment of EDS-HT patients. Although evidence regarding treatment efficacy is scarce, the current paper confirms the rationality that muscle strength is an important factor in the occurrence of activity limitations in EDS-HT patients. Although muscle strength is the most dominant factor that is associated with activity limitations, this association is confounded by proprioception. In contrast to common belief proprioception was not directly associated with activity limitations but confounded this association. Controlling muscle strength on the bases of proprioceptive input may be more important for reducing activity limitations than just enhancing sheer muscle strength.


Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia.
In patients with sickle cell anemia, fetal hemoglobin (HbF) concentrations vary by 2 orders of magnitude. This variance may be a result of heterogeneity in gene regulatory elements; accordingly, we searched for single nucleotide polymorphisms (SNPs) that might identify this variation. More than 180 SNPs were studied in 38 genes in 280 sickle cell anemia patients. The strongest association with HbF was found with SNPs near a QTL previously localized on chromosome 6q22.3-q23.2. Initially, two SNPs were identified in intergenic portions of this QTL and were associated with about a 20% difference in percent HbF. Subsequently, we genotyped 44 additional SNPs in the genomic region between 136.1 Mb and 137.5 Mb on chromosome 6q. Twelve SNPs, associated with a 20%-30% difference in HbF concentrations, were located in the introns of four genes, PDE7B, MAP7, MAP3K5 and PEX7. In K562 cells, the p38-MAPK pathway has been associated with the activation of gamma-globin gene expression by histone deacetylase inhibitors. Haplotypes C-T-T-T in MAP7 and T-C-C in PEX7 were significantly associated with increases in concentration of HbF, both showing strong dominance. Genetic elements abutting the 6q22.3-q23.2 QTL, may harbor trans-acting elements that help modulate baseline HbF level in sickle cell anemia.


Altered synaptic transmission in the hippocampus of transgenic mice with enhanced central nervous systems expression of interleukin-6.
Elevated levels of the inflammatory cytokine interleukin-6 (IL-6) occur in a number of CNS disorders. However, little is known about how this condition affects CNS neuronal function. Transgenic mice that express elevated levels of IL-6 in the CNS show cognitive changes, increased propensity for hippocampal seizures and reduced number of inhibitory interneurons, suggesting that elevated levels of IL-6 can cause neuroadaptive changes that alter hippocampal function. To identify these neuroadaptive changes, we measured the levels of protein expression using Western blot analysis and synaptic function using field potential recordings in hippocampus from IL-6 transgenic mice (IL-6 tg) and their non-transgenic (non-tg) littermates. Western blot analysis showed enhanced levels of the GFAP and STAT3 in the IL-6 tg hippocampus compared with the non-tg hippocampus, but no difference for several other proteins. Field potential recordings of synaptic transmission at the Schaffer collateral to CA1 synapse showed enhanced dendritic excitatory postsynaptic potentials and somatic population spikes in the CA1 region of hippocampal slices from IL-6 tg mice compared with slices from non-tg littermate controls. No differences were observed for several forms of short-term and long-term synaptic plasticity between hippocampal slices from IL-6 tg and non-tg mice. These results demonstrate that elevated levels of IL-6 can alter mechanisms involved in the excitability of hippocampal neurons and synapses, an effect consistent with recent evidence indicating that elevated production of IL-6 plays an important role in conditions associated with seizure activity and in other impairments observed in CNS disorders with a neuroinflammatory component.


Semiconductor lasers without population inversion.
We propose a new scheme for lasing without population inversion that utilizes interferences in double-quantum-well intersubband transitions. In contrast to the previous inversionless laser schemes based on atomic systems, the new proposal permits us to use band-gap engineering to choose the subband energies, coupling strengths, and decay rates, as desired, and permits us to create a laser system that does not require population inversion. We present detailed calculations on a specific scheme and discuss possible extensions.


Low sideband guided-mode resonant filter.
A guided-mode resonant filter with low sideband reflections is proposed. It is shown that, for serious reduction of out-of band reflectance, the combination of waveguide-grating filter design with conventional antireflective stack design methods is not adequate. To achieve symmetrical low sideband reflectances, independent control of various layer thicknesses is necessary. At a given illumination angle with appropriate control of the waveguide thickness, a specific resonant grating filter is designed whose out-of-band reflectance on both sides of the resonant peak is well below 10(-4). Even 50 nm away from the peak, on both sides, the out-of-band reflectance remains below 10(-3). Analysis of the variation in the main manufacturing parameters indicates that such filters can be reliably produced with present-day technologies.


Oral supplementation with melon superoxide dismutase extract promotes antioxidant defences in the brain and prevents stress-induced impairment of spatial memory.
The purpose of this study was to investigate the effect of antioxidant ingestion on stress-induced impairment of cognitive memory. Male C57BL/6 mice were divided into four groups as follows: (1) control mice (C mice) fed in a normal cage without immobilization; (2) restraint-stressed (RS mice) fed in a small cage; (3) vitamin E mice (VE mice), mice were fed in a small cage with a diet supplemented with vitamin E; (4) GliSODin mice (GS mice) fed in a small cage with a diet supplemented with GliSODin. RS, VE and GS mice were exposed to 12 h of immobilization daily. Five weeks later, spatial learning was measured using the Morris Water Maze (MWM) test. After water maze testing, we performed immunohistochemical analysis using 4-hydroxy-2-noneral (4-HNE) and an anti-Ki67 antibody. 4-HNE is a marker of lipid peroxidation. RS mice showed impaired spatial learning performance and an increased number of 4-HNE-positive cells in the granule cell layer (GCL) of the hippocampal dentate gyrus when compared to C mice. Moreover, RS mice showed a decreased number of Ki67-positive cells in the subgranular zone (SGZ). GS mice showed better spatial learning memory than RS mice. The number of 4-HNE-positive cells in the GCL of GS mice was significantly less than that of RS mice. The number of Ki67-positive cells in the SGZ of GS mice was significantly greater than that of RS mice. These finding suggests that GliSODin prevents stress-induced impairment of cognitive function and maintains neurogenesis in the hippocampus through antioxidant activity.


Culture kinetics of glycolytic enzyme induction, glucose utilization, and thymidine incorporation of extended-exposure phytohemagglutinin-stimulated human lymphocytes.
Glycolytic enzyme activity is significantly (P less than 0.05) induced between 24 and 48 hours of incubation in phytohemagglutinin-stimulated human lymphocytes. Nonstimulated cultured cells do not show this induction although these cells have an approximate daily doubling of thymidine incorporation. Maximal glycolytic enzyme activity is reached between 96 and 120 hours of culture in stimulated cells (3.5-fold increase) and maintained until at least 168 hours. There is no significant induction of the hexosemonophosphate shunt or the TCA cycle during seven-day transformation. Induction of glucose utilization becomes significantly (P less than 0.05) greater in stimulated as compared to nonstimulated cultures between 48 and 72 hours of culture and is significantly elevated for at least an additional 96 hours. There is a 17% increase in total protein in the stimulated cells after 24 hours of culture and higher levels of protein content are then maintained over the control. Thymidine incorporation is significantly greater in stimulated cells from 24-144 hours of culture but is not significantly different from the nonstimulated cells at 168 hours (P = 0.98) although glycolytic enzyme activity remains elevated in the stimulated cells. There is a greater enzyme induction of the latter phase of glycolysis during transformation and this phenomenon continues in extended cultures. Increases in glycolytic enzyme activity during mitogenesis appear to be an intrinsic phenomenon independent of cell proliferation and glucose transport. The mitogen-induced increase in the activity of the glycolytic enzymes accompanies blastogenesis and the sustained elevated activity of these enzymes to be related to the high metabolic rate of transformed cells.


Deep Convolutional Neural Networks for Image Classification: A Comprehensive Review.
Convolutional neural networks (CNNs) have been applied to visual tasks since the late 1980s. However, despite a few scattered applications, they were dormant until the mid-2000s when developments in computing power and the advent of large amounts of labeled data, supplemented by improved algorithms, contributed to their advancement and brought them to the forefront of a neural network renaissance that has seen rapid progression since 2012. In this review, which focuses on the application of CNNs to image classification tasks, we cover their development, from their predecessors up to recent state-of-the-art deep learning systems. Along the way, we analyze (1) their early successes, (2) their role in the deep learning renaissance, (3) selected symbolic works that have contributed to their recent popularity, and (4) several improvement attempts by reviewing contributions and challenges of over 300 publications. We also introduce some of their current trends and remaining challenges.


Breast cancer among young U.S. women in relation to oral contraceptive use.
While most studies have found no association between oral contraceptive use and breast cancer, several studies of younger women have reported an association with long-term oral contraceptive use. PURPOSE. We studied the relationship of patterns of oral contraceptive use to breast cancer risk among younger women. These women have had oral contraceptives available their entire reproductive lives and are now entering the breast cancer-prone years. A population-based, case-control study of breast cancer was conducted in three counties in western Washington State among women born in 1945 or later, ages 21-45. Case patients were 747 women with breast cancer diagnosed in 1983-1990 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. Control subjects were 961 women identified by random-digit telephone dialing. Subjects were interviewed in person, using pictures of brands of oral contraceptives and calendars of life events as recall aids. There was no increased incidence of breast cancer associated with ever having used oral contraceptives. Because only 8% of this cohort had never used oral contraceptives, short-term users (< 1 year) were combined with never users as the reference group for further analyses. A small increased risk of breast cancer was associated with long duration of oral contraceptive use (odds ratio for > or = 10 years = 1.3; 95% confidence interval [CI] = 0.9-1.9; P for trend = .03), particularly among women aged 35 years or younger (odds ratio for > or = 10 years = 1.7; 95% CI = 0.9-3.1). Breast cancer was also modestly related to oral contraceptive use early in reproductive life (odds ratio for use within 5 years of menarche = 1.3; 95% CI = 1.0-1.8; P for trend = .04) and to use of high-progestin-potency oral contraceptives for at least 1 year (odds ratio = 1.5; 95% CI = 1.1-2.1). These associations were adjusted for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. The associations were not further confounded by case-control differences in education, religion, breast feeding of offspring, or infertility; in oral contraceptive contraindications, indications, or complications; or in measures of breast cancer detection such as mammography or breast biopsy. Long-term oral contraceptive use among young women or use beginning near menarche may be associated with a small excess breast cancer risk, possibly due to susceptibility to genetic damage in breast epithelial cells at ages of high breast cell proliferative activity. Future studies should investigate whether the patterns of risk we reported are present as this cohort ages.


Non-angiogenic tumours unveil a new chapter in cancer biology.
The term 'angiogenesis' was coined in 1787 and the role of vessels in cancer has been studied ever since. In 1971 Folkman introduced the hypothesis, until now widely accepted, that tumour growth is strictly dependent on angiogenesis. However, the discovery that tumours can also grow without angiogenesis by exploiting pre-existing vessels, both in humans and more recently in mice, has demonstrated that this is not always the case. These observations highlight a new aspect of the interaction between vessels and tumours and demonstrate the existence of a previously unrecognized group of tumours that grow without angiogenesis and whose biology is, so far, largely unknown.


Association of fragmented QRS complex with myocardial reperfusion in acute ST-elevated myocardial infarction.
In this study, we aimed to evaluate the relationship between TIMI myocardial perfusion (TMP) grade, as an indicator of myocardial reperfusion, and fragmented QRS (fQRS) in standard 12-lead electrocardiogram. Also, we evaluate fQRS is an additional indicator of myocardial reperfusion. One hundred patients admitted with first STEMI to Coronary Intensive Care Unit and who were used thrombolytic therapy was included in this retrospective study. Standard 12-lead electrocardiogram records of patients simultaneous with coronary angiography (second day) were assessed and analysed for the presence of fQRS. Also, coronary angiography images were analyzed to identify the infarct related artery, TIMI grade of infarct related artery and TMP grade of infarct related artery. The patients with fQRS demonstrated a significantly lower TMP grade, TIMI grade and ejection fraction compared with the non-fQRS patients (P = 0.004, P = 0.003, P = 0.02 respectively). The patients with inadequate myocardial reperfusion demonstrated a significantly higher fQRS compared with the adequate myocardial reperfusion patients. (56.9% versus 23.5%, P = 0.002 respectively). On correlation analysis, there was a significant negative correlation between fQRS and left ventricular ejection fraction (r = -232, P = 0.02) TMP grade and adequate myocardial reperfusion (TMP 3) showed significant negative correlation with fQRS (r = -0.370, P = 0.000; r = -0.318, P = 0.001 respectively). Presence of fragmented QRS in STEMI patients was associated with inadequate myocardial reperfusion and it can be used as a simple, noninvasive parameter to evaluate myocardial reperfusion.


Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet.
Developing atherosclerotic lesions in hypercholesterolemic rabbits are depleted in zinc, while iron accumulates. This study examined the influence of zinc supplementation on the development of atherosclerosis and used isotope dilution gas chromatography-mass spectrometry techniques to measure biomarkers of oxidative lipid damage in atherosclerotic rabbit aorta. Our previous method for F(2)-isoprostane measurement was adapted to include the quantitation of cholesterol oxidation products in the same sample. Two groups of New Zealand white rabbits were fed a high cholesterol (1% w/w) diet and one group was also supplemented with zinc (1 g/kg) for 8 weeks. Controls were fed a normal diet. Zinc supplementation did not significantly alter the increase in total plasma cholesterol levels observed in animals fed high cholesterol. However, in cholesterol-fed animals zinc supplementation significantly reduced the accumulation of total cholesterol levels in aorta which was accompanied by a significant reduction in average aortic lesion cross-sectional areas of the animals. Elevated levels of cholesterol oxidation products (5,6-alpha and beta cholesterol epoxides, 7beta-hydroxycholesterol, 7-ketocholesterol) in aorta and total F(2)-isoprostanes in plasma and aorta of rabbits fed a cholesterol diet were significantly decreased by zinc supplementation. Our data indicate that zinc has an antiatherogenic effect, possibly due to a reduction in iron-catalyzed free radical reactions.


Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.
To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss. For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3-4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS). Participants (age=51 years; 88% men; body mass index=31.3 kg/m2; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (-38.9% proportionally), as compared with MED (-19.6% proportionally; p=0.035 weight loss adjusted) and HDG (-12.2% proportionally; p<0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all). The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half. NCT03020186.


Companion animal parasitology: a clinical perspective.
In recent years there have been many changes to the ways that clinical veterinary science is conducted and nowhere is this more evident than in companion animal practice. Veterinarians working with pet dogs and cats are facing new challenges associated with the emergence and re-emergence of parasitic diseases. Some, such as Neospora caninum, have been recently recognised; others like Giardia and Cryptosporidium have been reported with increasing frequency, in part as a result of laboratory tests with improved sensitivity and specificity. In many regions, the emergence of parasitic diseases has been a consequence of pet travel and exotic diseases pose a unique diagnostic challenge for the veterinarian, as the index of suspicion for these conditions may be absent. The ranges of certain vector-borne diseases such as babesiosis, hepatozoonosis, ehrlichiosis, leishmaniasis and dirofilariasis are extending due to ecological and climatic changes and enhanced by animals with subclinical infection returning home from endemic areas. In companion animal practice, veterinarians have the additional responsibility of providing accurate information about the zoonotic transmission of parasite infections from pets, especially to those most vulnerable such as children, the elderly and the immunocompromised. Effective education is vital to allay public concerns and promote responsible pet ownership.


Conflict between genetic and phenotypic differentiation: the evolutionary history of a 'lost and rediscovered' shorebird.
Understanding and resolving conflicts between phenotypic and genetic differentiation is central to evolutionary research. While phenotypically monomorphic species may exhibit deep genetic divergences, some morphologically distinct taxa lack notable genetic differentiation. Here we conduct a molecular investigation of an enigmatic shorebird with a convoluted taxonomic history, the White-faced Plover (Charadrius alexandrinus dealbatus), widely regarded as a subspecies of the Kentish Plover (C. alexandrinus). Described as distinct in 1863, its name was consistently misapplied in subsequent decades until taxonomic clarification ensued in 2008. Using a recently proposed test of species delimitation, we reconfirm the phenotypic distinctness of dealbatus. We then compare three mitochondrial and seven nuclear DNA markers among 278 samples of dealbatus and alexandrinus from across their breeding range and four other closely related plovers. We fail to find any population genetic differentiation between dealbatus and alexandrinus, whereas the other species are deeply diverged at the study loci. Kentish Plovers join a small but growing list of species for which low levels of genetic differentiation are accompanied by the presence of strong phenotypic divergence, suggesting that diagnostic phenotypic characters may be encoded by few genes that are difficult to detect. Alternatively, gene expression differences may be crucial in producing different phenotypes whereas neutral differentiation may be lagging behind.


Go-stimuli proportion influences response strategy in a sustained attention to response task.
The sustained attention to response task (SART) usefulness as a measure of sustained attention has been questioned. The SART may instead be a better measure of other psychological processes and could prove useful in understanding some real-world behaviours. Thirty participants completed four Go/No-Go response tasks much like the SART, with Go-stimuli proportions of .50, .65, .80 and .95. As Go-stimuli proportion increased, reaction times decreased while both commission errors and self-reported task-related thoughts increased. Performance measures were associated with task-related thoughts but not task-unrelated thoughts. Instead of faster reaction times and increased commission errors being due to absentmindedness or perceptual decoupling from the task, the results suggested participants made use of two competing response strategies, in line with a response strategy or response inhibition perspective of SART performance. Interestingly, performance measures changed in a nonlinear manner, despite the linear Go proportion increase. A threshold may exist where the prepotent motor response becomes more pronounced, leading to the disproportionate increase in response speed and commission errors. This research has implications for researchers looking to employ the SART and for more applied contexts where the consequences of response inhibition failures can be serious.


Activation of inactive plasma renin by plasma and tissue kallikreins.
1. Normal human plasma contains a proactivator of inactive renin. The pro-activator is activated at physiological pH in plasma that has been pretreated with acid. This activation in vitro leads to the conversion of inactive renin into the active form with simultaneous generation of kallikrein activity. 2. The endogenous activator of inactive renin has the same pH profile and inhibitor spectrum as plasma kallikrein. 3. Inactive renin can also be activated by exposure of plasma to exogenous trypsin, and in normal plasma the quantities of inactive renin that are activated after acidification and with trypsin are identical. Prekallikrein (Fletcher factor)-deficient plasma, however, has much lower renin activity after acidification than with trypsin. Thus acid activation of inactive renin depends on plasma prekallikrein, whereas the action of trypsin is independent of prekallikrein. 4. Highly purified tissue (pancreatic) kallikrein, in a concentration of less than 2 X 10(-8) mol/l, activates inactive renin that has been isolated from plasma by ion-exchange chromatography. In this respect it is at least 100 times more potent than trypsin. 5. It is therefore possible that plasma and/or tissue (renal) kallikreins are also involved in the activation of inactive renin in vivo.


Homeostatic pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during chronic itch development.
The epidermal barrier is thought to protect sensory nerves from overexposure to environmental stimuli, and barrier impairment leads to pathological conditions associated with itch, such as atopic dermatitis (AD). However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. Here we show that epidermal nerves are contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of chronic itch caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we found that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs in the normal skin, whereas this process was disturbed during chronic itch development. Furthermore, aberrant Ca2+ increases in epidermal nerves were induced in association with the disturbed pruning. Finally, TRPA1 inhibition suppressed aberrant Ca2+ increases in epidermal nerves and itch. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to aberrant activation of epidermal nerves and pathological itch.


Information bounds and optimal analysis of dynamic single molecule measurements.
Time-resolved single molecule fluorescence measurements may be used to probe the conformational dynamics of biological macromolecules. The best time resolution in such techniques will only be achieved by measuring the arrival times of individual photons at the detector. A general approach to the estimation of molecular parameters based on individual photon arrival times is presented. The amount of information present in a data set is quantified by the Fisher information, thereby providing a guide to deriving the basic equations relating measurement uncertainties and time resolution. Based on these information-theoretical considerations, a data analysis algorithm is presented that details the optimal analysis of single-molecule data. This method natively accounts and corrects for background photons and cross talk, and can scale to an arbitrary number of channels. By construction, and with corroboration from computer simulations, we show that this algorithm reaches the theoretical limit, extracting the maximal information out of the data. The bias inherent in the algorithm is considered and its implications for experimental design are discussed. The ideas underlying this approach are general and are expected to be applicable to any information-limited measurement.


External Locus of Control but not Self-Esteem Predicts Increasing Social Anxiety Among Bullied Children.
Elevated social anxiety is more likely among bullied children than those who have not been bullied but it is not inevitable and may be influenced by cognitive factors. Lower self-esteem and more external locus of control are associated with bullying and social anxiety but the impact of these factors over time among bullied children is less clear. Children from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) reported bullying experiences at age 8 (n = 6,704) and were categorized according to level of bullying exposure. The impact of self-esteem and locus of control on social anxiety was assessed up to age 13 across the bullying exposure groups using multi-group latent growth curve analysis. Complete data was available for 3,333 participants. More external locus of control was associated with a steeper increase in social anxiety among severely bullied children [B = .249, p = .025]. Although self-esteem at age 8 was associated with existing social anxiety it did not predict later increases in social anxiety. These results indicate that beliefs about lack of personal control among severely bullied children may contribute to increasing social anxiety over time. Exploring related cognitions may be helpful in this potentially vulnerable group.


Maternal adaptation to high-altitude pregnancy: an experiment of nature--a review.
A long and productive history of studies at high altitude has demonstrated that chronic hypoxia plays a key role in the aetiology of intrauterine growth restriction (IUGR) and pre-eclampsia. Susceptibility to altitude-associated IUGR varies among high-altitude populations in relation to their duration of altitude exposure, with multigenerational residents demonstrating one-third the birth weight fall present in shorter-resident groups. Higher uteroplacental blood flow during pregnancy in multigenerational high-altitude residents suggests that such population differences are due, at least in part, to differences in maternal vascular responses to pregnancy. We hypothesize that natural selection acting on hypoxia-inducible factor (HIF)-targeted or -regulatory genes has enabled maternal vascular adaptation to pregnancy in long-resident high-altitude groups. Preliminary evidence in support of this hypothesis demonstrates that the potent HIF-targeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by pregnancy and chronic hypoxia in Andean vs European residents of high altitude. Andeans show the normal, pregnancy-associated fall in ET-1 levels previously reported at low altitude, whereas Europeans have higher ET-1 levels and little pregnancy-associated change, like pre-eclamptic women. Single nucleotide polymorphisms (SNPs) in the ET-1 gene also differ in Andeans compared with low-altitude populations. We conclude that high altitude serves as an experiment of nature for elucidating genetic factors underlying susceptibility to complications of pregnancy and fetal life. Such studies may be important for identifying persons at risk for these complications at any altitude.


Time to recanalisation in patients with cerebral venous thrombosis under anticoagulation therapy.
Few studies have investigated the rates of recanalisation after cerebral venous thrombosis (CVT). Our objective was to investigate the recanalisation rate and to identify predictors of recanalisation in patients with CVT. We included 102 patients with confirmed first-ever, non-septic CVT. All patients received anticoagulation for 12 months or until complete recanalisation. To assess recanalisation, patients underwent MR venography every 3 months until partial or complete recanalisation or for 12 months after diagnosis. We conducted two parallel analyses of complete recanalisation versus partial and no recanalisation versus any recanalisation. As a secondary objective we explored the influence of recanalisation on outcome and recurrent events. We calculated the probability of recanalisation using Kaplan-Meier analysis and conducted multivariate analysis using a Cox model. The mean age of patients was 33.5±11 years (80 (78.4%) women). Survival analysis indicated that 50% of the patients had any recanalisation (grades I, II and III) by 64 days and complete recanalisation (grade III) by 169 days. Adjusted Cox proportional model revealed that age <50 years (HR=11.5 95% CI=1.58 to 84.46, p=0.01) and isolated superior sagittal sinus thrombosis (HR=0.39, 95% CI=0.14 to 1.04, p=0.05) predict complete recanalisation, while age <50 years (HR=4.79; 95% CI=1.69 to 13.5, p=0.003) predicts any recanalisation. Patients with complete recanalisation had a greater chance of good functional outcome (HR=5.17; 95% CI=2.8 to 9.53, p<0.001). We found that recanalisation occurs over time, until month 11. Complete recanalisation may influence functional outcome.


Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression.
Histone deacetylases (HDACs) modulate chromatin structure and transcription, but little is known about their function in mammalian development. HDAC1 was implicated previously in the repression of genes required for cell proliferation and differentiation. Here we show that targeted disruption of both HDAC1 alleles results in embryonic lethality before E10.5 due to severe proliferation defects and retardation in development. HDAC1-deficient embryonic stem cells show reduced proliferation rates, which correlate with decreased cyclin-associated kinase activities and elevated levels of the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). Similarly, expression of p21 and p27 is up-regulated in HDAC1-null embryos. In addition, loss of HDAC1 leads to significantly reduced overall deacetylase activity, hyperacetylation of a subset of histones H3 and H4 and concomitant changes in other histone modifications. The expression of HDAC2 and HDAC3 is induced in HDAC1-deficient cells, but cannot compensate for loss of the enzyme, suggesting a unique function for HDAC1. Our study provides the first evidence that a histone deacetylase is essential for unrestricted cell proliferation by repressing the expression of selective cell cycle inhibitors.


GIMI: the past, the present and the future.
In keeping with the theme of this year's e-Science All Hands Meeting--past, present and future--we consider the motivation for, the current status of, and the future directions for, the technologies developed within the GIMI (Generic Infrastructure for Medical Informatics) project. This analysis provides insights into how some key problems in data federation may be addressed. GIMI was funded by the UK's Technology Strategy Board with the intention of developing a service-oriented framework to facilitate the secure sharing and aggregation of heterogeneous data from disparate sources to support a range of healthcare applications. The project, which was led by the University of Oxford, involved collaboration from the National Cancer Research Institute Informatics Initiative, Loughborough University, University College London, t+ Medical, Siemens Molecular Imaging and IBM UK.


Protective effects of Phaseolus vulgaris lectin against viral infection in Drosophila.
Phytohemagglutinin (PHA) isolated from the family of Phaseolus vulgaris beans is a promising agent against viral infection; however, it has not yet been demonstrated in vivo. We herein investigated this issue using Drosophila as a host. Adult flies were fed lectin approximately 12 h before they were subjected to a systemic viral infection. After a fatal infection with Drosophila C virus, death was delayed and survival was longer in flies fed PHA-P, a mixture of L4, L3E1, and L2E2, than in control unfed flies. We then examined PHA-L4, anticipating subunit L as the active form, and confirmed the protective effects of this lectin at markedly lower concentrations than PHA-P. In both experiments, lectin feeding reduced the viral load prior to the onset of fly death. Furthermore, we found a dramatic increase in the levels of the mRNAs of phagocytosis receptors in flies after feeding with PHA-L4 while a change in the levels of the mRNAs of antimicrobial peptides was marginal. We concluded that P. vulgaris PHA protects Drosophila against viral infection by augmenting the level of host immunity.


Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland.
Urea cycle disorders (UCDs) are a group of rare inherited metabolic disorders. Affected individuals often present with hyperammonemic encephalopathy (HE) and have an increased risk of severe neurologic disease and early death. The study aims to provide epidemiologic data and to describe the disease manifestation and short-term outcome. Cross-border surveillance of newly diagnosed patients with UCDs - below 16 years of age - was performed from July 2012 to June 2015 in Germany and Austria and from January 2012 to December 2015 in Switzerland. Inquiries were sent monthly to all Pediatric Departments in Germany and Switzerland, and quarterly to the Austrian Metabolic Group. In addition, data were collected via a second source (metabolic laboratories) in all three countries. Between July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality. Cross-border surveillance is a powerful tool to identify patients with UCDs demonstrating that (1) the cumulative incidence of UCDs is lower than originally suggested, (2) the mortality rate is still high in patients with neonatal onset of symptoms, and (3) onset type and peak plasma ammonium concentration predict mortality.


First-principles definition and measurement of planetary electromagnetic-energy budget.
The imperative to quantify the Earth's electromagnetic-energy budget with an extremely high accuracy has been widely recognized but has never been formulated in the framework of fundamental physics. In this paper we give a first-principles definition of the planetary electromagnetic-energy budget using the Poynting-vector formalism and discuss how it can, in principle, be measured. Our derivation is based on an absolute minimum of theoretical assumptions, is free of outdated notions of phenomenological radiometry, and naturally leads to the conceptual formulation of an instrument called the double hemispherical cavity radiometer (DHCR). The practical measurement of the planetary energy budget would require flying a constellation of several dozen planet-orbiting satellites hosting identical well-calibrated DHCRs.


Bioinformatic discovery of novel bioactive peptides.
Short synthetic oligopeptides based on regions of human proteins that encompass functional motifs are versatile reagents for understanding protein signaling and interactions. They can either mimic or inhibit the parent protein's activity and have been used in drug development. Peptide studies typically either derive peptides from a single identified protein or (at the other extreme) screen random combinatorial peptides, often without knowledge of the signaling pathways targeted. Our objective was to determine whether rational bioinformatic design of oligopeptides specifically targeted to potentially signaling-rich juxtamembrane regions could identify modulators of human platelet function. High-throughput in vitro platelet function assays of palmitylated cell-permeable oligopeptides corresponding to these regions identified many agonists and antagonists of platelet function. Many bioactive peptides were from adhesion molecules, including a specific CD226-derived inhibitor of inside-out platelet signaling. Systematic screens of this nature are highly efficient tools for discovering short signaling motifs in molecular signaling pathways.


Immunization with cholera toxin B subunit induces high-level protection in the suckling mouse model of cholera.
Cholera toxin (CT) is the primary virulence factor responsible for severe cholera. Vibrio cholerae strains unable to produce CT show severe attenuation of virulence in animals and humans. The pentameric B subunit of CT (CTB) contains the immunodominant epitopes recognized by antibodies that neutralize CT. Although CTB is a potent immunogen and a promising protective vaccine antigen in animal models, immunization of humans with detoxified CT failed to protect against cholera. We recently demonstrated however that pups reared from mice immunized intraperitoneally (IP) with 3 doses of recombinant CTB were well protected against a highly lethal challenge dose of V. cholerae N16961. The present study investigated how the route and number of immunizations with CTB could influence protective efficacy in the suckling mouse model of cholera. To this end female mice were immunized with CTB intranasally (IN), IP, and subcutaneously (SC). Serum and fecal extracts were analyzed for anti-CTB antibodies by quantitative ELISA, and pups born to immunized mothers were challenged orogastrically with a lethal dose of V. cholerae. Pups from all immunized groups were highly protected from death by 48 hours (64-100% survival). Cox regression showed that percent body weight loss at 24 hours predicted death by 48 hours, but we were unable to validate a specific amount of weight loss as a surrogate marker for protection. Although CTB was highly protective in all regimens, three parenteral immunizations showed trends toward higher survival and less weight loss at 24 hours post infection. These results demonstrate that immunization with CTB by any of several routes and dosing regimens can provide protection against live V. cholerae challenge in the suckling mouse model of cholera. Our data extend the results of previous studies and provide additional support for the inclusion of CTB in the development of a subunit vaccine against V. cholerae.


Optical gain, spontaneous and stimulated emission of surface plasmon polaritons in confined plasmonic waveguide.
We develop a theoretical model to compute the local density of states in a confined plasmonic waveguide. Based on this model, we derive a simple formula with a clear physical interpretation for the lifetime modification of emitters embedded in the waveguide. The gain distribution within the active medium is then computed following the formalism developed in a recent work [Phys. Rev. B 78, 161401 (2008)], by taking rigorously into account the pump irradiance and emitters lifetime modifications in the system. We finally apply this formalism to describe gain-assisted propagation in a dielectric-loaded surface plasmon polariton waveguide.


Prognostic significance of Gleason pattern in patients with Gleason score 7 prostate carcinoma.
In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5). The authors studied 412 patients (mean postoperative follow-up, 33 months) with GS 7 tumors treated with radical prostatectomy at a single Australian campus between November 1989 and December 2002. The chi-square test, Kaplan-Meier method, and Cox proportional hazards analyses were used to evaluate the correlation between primary GP 4 and tertiary GP 5 with the occurrence of adverse pathologic features and disease recurrence. In this cohort, 307 patients (75%) had primary GP 3 tumors, 105 (25%) had primary GP 4 tumors, and 17 (2.3%) had a tertiary element of high-grade tumor (GP 5). Patients with primary GP 4 tumors displayed higher rates of seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary GP 5, had significantly shorter times to disease recurrence. Univariate analysis demonstrated that primary GP 4 (P = 0.0003) and tertiary GP 5 (P < 0.0001) were strong predictors of disease recurrence. Primary GP 4 (P = 0.0122) remained an independent predictor of disease recurrence on stepwise multivariate analysis. Primary GP 4 tumors represented an aggressive subset of GS 7 prostate carcinomas. Primary GP was an easily accessible and clinically relevant predictor of disease recurrence in patients with GS 7 prostate carcinoma.


Resilience in inpatient palliative care nursing: a qualitative systematic review.
Nurses in inpatient palliative care are frequently exposed to death and dying in addition to common stressors found in other nursing practice. Resilience may mitigate against stress but remains ill-defined and under-researched in the specialist palliative care setting. The aim of this systematic review was to understand resilience from the perspectives of inpatient palliative care nurses. A thematic synthesis of qualitative studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Academic Search Ultimate, Cumulative Index to Nursing and Allied Health Literature, Medline Complete, PsycINFO and Scopus. The review stages were searching for relevant literature, selecting relevant papers, data extraction, critical appraisal and thematic synthesis. Eight studies revealed 10 subthemes, 3 descriptive themes and 1 analytical theme: resilience occurs when nurses incorporate stressful aspects of their personal or professional lives into a coherent narrative that enhances their ability to cope with the demands of their role. Palliative care nursing is more stressful if patients or situations remind nurses of personal experiences. Nurses cope better with adequate support; however, coping does not necessarily imply increased resilience. Resilience occurs when nurses cognitively process their experiences, articulate their thoughts and feelings into a coherent narrative, and construct a sense of meaning or purpose. Future research could explore how nurses understand resilience and how it could be enhanced in the palliative care inpatient setting. With resilience, nurses may remain in the profession longer and improve the quality of care when they do.


Timing and tempo of primate speciation.
Published molecular clocks for primates are used to estimate typical divergence times for phylogroups (1.6 Ma), species (3.3 Ma), sister species (2.7 Ma), genera (8.9 Ma) and sister genera (8.6 Ma). Significant median differences exist between major groups (infraorders and superfamilies) for various divergence times. These data are employed to estimate typical maximum duration of speciation. Typical primate values (1.1 Ma) suggest this process to be faster than is characteristic of many vertebrates. However, after considering divergence times for hybridizing congeneric and confamilial primates, this value is likely only to estimate the commencement of prezygotic isolating mechanisms, rather than the completion of reproductive isolation. Thus, speciation typically takes around 1.0 Ma to more than 4.0 Ma to occur, depending on whether prezygotic or post-zygotic isolating mechanisms are emphasized. Typical primate genus age is around 5.3 Ma, but we note differences among major groups. In light of these estimates, the classification of humans and chimpanzees is reconsidered using a molecular yardstick approach. Three taxonomic frameworks may flow from molecular analyses, all of them having major implications for understanding the evolution of humans and chimpanzees.


Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model.
Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.


Risk factor model to predict venous thromboembolism in hospitalized medical patients.
The Joint Commission requires that all medical inpatients be assessed for venous thromboembolism (VTE) risk, but available risk stratification tools have never been validated. We conducted a retrospective cohort study of patients age ≥18 years, admitted to 374 US hospitals in 2004-2005, with a primary diagnosis of pneumonia, heart failure, chronic obstructive pulmonary disease (COPD), stroke, and urinary tract infection, and length of stay ≥3 days. Subjects were randomly assigned (80/20) to a derivation or validation set. We then assessed VTE (International Classification of Diseases, Ninth Revision [ICD-9] code plus diagnostic test plus treatment), patient demographics, 21 potential risk factors, and other comorbidities. We created a VTE risk stratification tool using multivariable regression modeling and applied it to the validation sample. Of 242,738 patients, 612 (0.25%) patients fulfilled our criteria for VTE during hospitalization, and an additional 440 (0.18%) were readmitted for VTE within 30 days (overall incidence of 0.43%). In the multivariable model, age, sex, and 10 additional risk factors were associated with VTE. The strongest risk factors were inherited thrombophilia (OR 4.00), length of stay ≥6 days (OR 3.22), inflammatory bowel disease (OR 3.11), central venous catheter (OR 1.87), and cancer. In the validation set, the model had a c-statistic of 0.75 (95% CI 0.71, 0.78). Deciles of predicted risk ranged from 0.11% to 1.46% with observed risk over the same deciles from 0.17% to 1.81%. The risk of symptomatic VTE in general medical patients is low. A risk factor model can identify those at sufficient risk to warrant pharmacologic prophylaxis.


Effect of gravity and microgravity on intracranial pressure.
Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts. Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure (ICP). This syndrome is considered the most mission-critical medical problem identified in the past decade of manned spaceflight. We recruited five men and three women who had an Ommaya reservoir inserted for the delivery of prophylactic CNS chemotherapy, but were free of their malignant disease for at least 1 year. ICP was assessed by placing a fluid-filled 25 gauge butterfly needle into the Ommaya reservoir. Subjects were studied in the upright and supine position, during acute zero gravity (parabolic flight) and prolonged simulated microgravity (6 deg head-down tilt bedrest). ICP was lower when seated in the 90 deg upright posture compared to lying supine (seated, 4 ± 1 vs. supine, 15 ± 2 mmHg). Whilst lying in the supine posture, central venous pressure (supine, 7 ± 3 vs. microgravity, 4 ± 2 mmHg) and ICP (supine, 17 ± 2 vs. microgravity, 13 ± 2 mmHg) were reduced in acute zero gravity, although not to the levels observed in the 90 deg seated upright posture on Earth. Prolonged periods of simulated microgravity did not cause progressive elevations in ICP (supine, 15 ± 2 vs. 24 h head-down tilt, 15 ± 4 mmHg). Complete removal of gravity does not pathologically elevate ICP but does prevent the normal lowering of ICP when upright. These findings suggest the human brain is protected by the daily circadian cycles in regional ICPs, without which pathology may occur.


Implementation and Operational Research: Feasibility of Using Tuberculin Skin Test Screening for Initiation of 36-Month Isoniazid Preventive Therapy in HIV-Infected Patients in Resource-Constrained Settings.
The tuberculin skin test (TST) can be used to identify HIV-infected people who would benefit the most from long-term isoniazid preventive therapy (IPT). However, in resource-constrained settings, implementation of the TST can be challenging. The objectives of this study were to assess the feasibility of implementing the TST for IPT initiation and to estimate the proportion of TST-positive incidence among HIV-positive patients in 2 high tuberculosis and HIV burden settings. Two prospective observational cohort studies were conducted under programmatic conditions in Mathare, an urban slum of Nairobi, Kenya, and in rural Shiselweni, Swaziland. HIV-positive adults with negative tuberculosis symptomatic screening underwent the TST. Those testing positive were started on 36-month IPT. Of 897 and 1021 patients screened in Mathare and Shiselweni, 550 and 696, respectively, were included. Median age was 38 years, 67.7% were female, and 86.8% were on antiretroviral therapy. Among TST-eligible participants, 88.0% (491/558) and 81.8% (694/848) accepted TST and 74.2% (414/558) and 77.1% (654/858) returned for test reading in Mathare and Shiselweni, respectively. The TST was positive in 49.8% (95% confidence interval: 44.9 to 54.6) in Mathare and 33.2% (95% confidence interval: 29.6 to 36.8) in Shiselweni. The 36-month IPT was accepted by 96.1% (198/206) patients in Mathare and 99.5% (216/217) in Shiselweni. IPT implementation at the clinics was managed with no additional staff or extra space. Implementing the TST for IPT initiation was feasible and acceptable in both urban and rural resource-constrained settings. This strategy allows patients who can benefit the most to receive long-term IPT and avoids unnecessarily treating a significant number of patients who do not stand to benefit.


Self-related consequences of death fear and death denial.
This study explores self-related outcomes (e.g., esteem, self-concept clarity, existential well-being) as a function of the interaction between self-reported levels of death fear and death denial. Consistent with the idea that positive existential growth can come from individuals facing, rather than denying, their mortality (Cozzolino, 2006 ), the authors observed that not fearing and denying death can bolster important positive components of the self. That is, individuals low in death denial and death fear evidenced an enhanced self that is valued, clearly conceived, efficacious, and that has meaning and purpose.


Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction.
Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.


Warren K. Sinclair keynote address: contemporary issues in risk-informed decision making on the disposition of radioactive waste.
A consistent and transparent risk-informed approach to managing nuclear waste is plagued with different regulators, different rules and regulations for different waste types, different compliance requirements, and indecisions about probabilistic vs. deterministic models. Low-activity waste management is particularly void of a path forward with respect to being risk-informed. Risk assessment is not referenced in the statutes on low-activity waste even though both the U.S. Environmental Protection Agency and U.S. Nuclear Regulatory Commission (U.S. NRC) have policies to apply consistent risk management approaches to all of their programs. The U.S. NRC has developed guidance on the preparation of probabilistic performance assessments for low-activity waste facilities, but there have been no serious takers and a lack of initiative on the part of licensees. Thus, little to no experience exists on risk-informing low-activity waste. The missed opportunities include establishing a risk basis that would allow for simpler, safer, and much less costly alternatives for low-activity waste disposal while enabling society to have the full benefit of radiation technologies. There is hope that congressional action or regulatory rule making will address some of these issues with the result being the adoption of a more general and unified approach to risk-informed regulation of all types of waste. Just as much of the initiative for risk-informed nuclear power came from industry, it must also be the case for nuclear waste. A start would be the adoption of a basic framework of risk assessment in waste management applicable to all types of waste--radioactive and nonradioactive. The "set of triplets" risk assessment framework that is applicable to any kind of risk is an established alternative. It is believed that such a framework with the support of a regulatory structure made compatible through appropriate rulemaking or congressional action, and the experience of the probabilistic performance assessments for the Waste Isolation Pilot Plant and the proposed Yucca Mountain high-level waste repository, could result in the right path forward for the regulation and management of low-activity waste.


Distribution of Response Time, Cortical, and Cardiac Correlates during Emotional Interference in Persons with Subclinical Psychotic Symptoms.
A psychosis phenotype can be observed below the threshold of clinical detection. The study aimed to investigate whether subclinical psychotic symptoms are associated with deficits in controlling emotional interference, and whether cortical brain and cardiac correlates of these deficits can be detected using functional near-infrared spectroscopy (fNIRS). A data set derived from a community sample was obtained from the Zurich Program for Sustainable Development of Mental Health Services. 174 subjects (mean age 29.67 ± 6.41, 91 females) were assigned to four groups ranging from low to high levels of subclinical psychotic symptoms (derived from the Symptom Checklist-90-R). Emotional interference was assessed using the emotional Stroop task comprising neutral, positive, and negative conditions. Statistical distributional methods based on delta plots [behavioral response time (RT) data] and quantile analysis (fNIRS data) were applied to evaluate the emotional interference effects. Results showed that both interference effects and disorder-specific (i.e., group-specific) effects could be detected, based on behavioral RTs, cortical hemodynamic signals (brain correlates), and heart rate variability (cardiac correlates). Subjects with high compared to low subclinical psychotic symptoms revealed significantly reduced amplitudes in dorsolateral prefrontal cortices (interference effect, p < 0.001) and middle temporal gyrus (disorder-specific group effect, p < 0.001), supported by behavioral and heart rate results. The present findings indicate that distributional analyses methods can support the detection of emotional interference effects in the emotional Stroop. The results suggested that subjects with high subclinical psychosis exhibit enhanced emotional interference effects. Based on these observations, subclinical psychosis may therefore prove to represent a valid extension of the clinical psychosis phenotype.


Routing light with ultrathin nanostructures beyond the diffraction limit.
An open nanostructure consisting of a periodic chain of subwavelength-nanoparticles for compressing and routing light beyond the diffraction limit is proposed. The open nanostructure is ultrathin and compact, with a size much smaller than the wavelength of light. We demonstrate that our ultrathin open nanostructure provides functions that can route and manipulate light at the subwavelength scale and can also sharply bend and split light beams below the diffraction limit while exhibiting broadband, incident-angle-tolerant, and robust against disorder. A physical picture based on all-angle self-collimation is presented to understand the manipulation of light using the ultrathin open nanostructure. Experimental and numerical observations validate our findings. This approach provides great flexibility in the design of nanophotonic devices for routing and manipulating light beyond the diffraction limit.


Minimum redundancy maximum relevance feature selection approach for temporal gene expression data.
Feature selection, aiming to identify a subset of features among a possibly large set of features that are relevant for predicting a response, is an important preprocessing step in machine learning. In gene expression studies this is not a trivial task for several reasons, including potential temporal character of data. However, most feature selection approaches developed for microarray data cannot handle multivariate temporal data without previous data flattening, which results in loss of temporal information. We propose a temporal minimum redundancy - maximum relevance (TMRMR) feature selection approach, which is able to handle multivariate temporal data without previous data flattening. In the proposed approach we compute relevance of a gene by averaging F-statistic values calculated across individual time steps, and we compute redundancy between genes by using a dynamical time warping approach. The proposed method is evaluated on three temporal gene expression datasets from human viral challenge studies. Obtained results show that the proposed method outperforms alternatives widely used in gene expression studies. In particular, the proposed method achieved improvement in accuracy in 34 out of 54 experiments, while the other methods outperformed it in no more than 4 experiments. We developed a filter-based feature selection method for temporal gene expression data based on maximum relevance and minimum redundancy criteria. The proposed method incorporates temporal information by combining relevance, which is calculated as an average F-statistic value across different time steps, with redundancy, which is calculated by employing dynamical time warping approach. As evident in our experiments, incorporating the temporal information into the feature selection process leads to selection of more discriminative features.


Effects of the winter of 1976-1977 on the northwestern sargasso sea.
A survey was conducted in the northwestern Sargasso Sea during the spring to assess the effect and extent of the winter cooling of 1976 to 1977 on the ocean. Newly formed, well-mixed layers of 18 degrees C water as deep as 550 meters were observed. The main thermocline south of the Gulf Stream was 100 to 150 meters deeper than it is on the average, which implies significant changes in the baroclinic transports.