Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations.
KRAS mutations are highly prevalent in non-small cell lung cancer (NSCLC), and tumors harboring these mutations tend to be aggressive and resistant to chemotherapy. We used next-generation sequencing technology to identify pathways that are specifically altered in lung tumors harboring a KRAS mutation. Paired-end RNA-sequencing of 15 primary lung adenocarcinoma tumors (8 harboring mutant KRAS and 7 with wild-type KRAS) were performed. Sequences were mapped to the human genome, and genomic features, including differentially expressed genes, alternate splicing isoforms and single nucleotide variants, were determined for tumors with and without KRAS mutation using a variety of computational methods. Network analysis was carried out on genes showing differential expression (374 genes), alternate splicing (259 genes), and SNV-related changes (65 genes) in NSCLC tumors harboring a KRAS mutation. Genes exhibiting two or more connections from the lung adenocarcinoma network were used to carry out integrated pathway analysis. The most significant signaling pathways identified through this analysis were the NFκB, ERK1/2, and AKT pathways. A 27 gene mutant KRAS-specific sub network was extracted based on gene-gene connections from the integrated network, and interrogated for druggable targets. Our results confirm previous evidence that mutant KRAS tumors exhibit activated NFκB, ERK1/2, and AKT pathways and may be preferentially sensitive to target therapeutics toward these pathways. In addition, our analysis indicates novel, previously unappreciated links between mutant KRAS and the TNFR and PPARγ signaling pathways, suggesting that targeted PPARγ antagonists and TNFR inhibitors may be useful therapeutic strategies for treatment of mutant KRAS lung tumors. Our study is the first to integrate genomic features from RNA-Seq data from NSCLC and to define a first draft genomic landscape model that is unique to tumors with oncogenic KRAS mutations.


Cone structure imaged with adaptive optics scanning laser ophthalmoscopy in eyes with nonneovascular age-related macular degeneration.
To evaluate cone spacing using adaptive optics scanning laser ophthalmoscopy (AOSLO) in eyes with nonneovascular AMD, and to correlate progression of AOSLO-derived cone measures with standard measures of macular structure. Adaptive optics scanning laser ophthalmoscopy images were obtained over 12 to 21 months from seven patients with AMD including four eyes with geographic atrophy (GA) and four eyes with drusen. Adaptive optics scanning laser ophthalmoscopy images were overlaid with color, infrared, and autofluorescence fundus photographs and spectral domain optical coherence tomography (SD-OCT) images to allow direct correlation of cone parameters with macular structure. Cone spacing was measured for each visit in selected regions including areas over drusen (n = 29), at GA margins (n = 14), and regions without drusen or GA (n = 13) and compared with normal, age-similar values. Adaptive optics scanning laser ophthalmoscopy imaging revealed continuous cone mosaics up to the GA edge and overlying drusen, although reduced cone reflectivity often resulted in hyporeflective AOSLO signals at these locations. Baseline cone spacing measures were normal in 13/13 unaffected regions, 26/28 drusen regions, and 12/14 GA margin regions. Although standard clinical measures showed progression of GA in all study eyes, cone spacing remained within normal ranges in most drusen regions and all GA margin regions. Adaptive optics scanning laser ophthalmoscopy provides adequate resolution for quantitative measurement of cone spacing at the margin of GA and over drusen in eyes with AMD. Although cone spacing was often normal at baseline and remained normal over time, these regions showed focal areas of decreased cone reflectivity. These findings may provide insight into the pathophysiology of AMD progression. (ClinicalTrials.gov number, NCT00254605).


Host-derived 5' ends and overlapping complementary 3' ends of the two mRNAs transcribed from the ambisense S segment of Uukuniemi virus.
Two mRNAs, coding for the N and NSS proteins, are transcribed from the small (S) Uukuniemi virus RNA segment by an ambisense strategy (J. F. Simons, U. Hellman, and R. F. Pettersson, J. Virol. 64:247-255, 1990). In this report, we describe the analysis of the 5' and 3' ends of the two mRNAs. Primer extension as well as cloning and sequencing of individual mRNAs showed that the 5' ends of both mRNAs contained nonviral sequences ranging from 7 to 25 residues in length (mean, 12 residues), indicating a cap-snatching mechanism similar to the one originally described for priming of influenza virus mRNA synthesis. In 35% of the cases, the first virion-specified nucleotide (an A residue) was substituted with a G residue. Between the translation termination codons of N and NSS, there is a 74-residue-long noncoding intergenic region (Simons et al., J. Virol. 64:247-255, 1990). Nuclease protection assays using both RNA and DNA hybridization probes showed that the 3' ends of the N and NSS mRNAs overlap each other by about 100 nucleotides. The 3' end of the NSS mRNA extends into the coding sequence of the N mRNA, whereas the N mRNA is terminated just prior to the stop codon of NSS. To our knowledge, this is the first example of overlapping complementary mRNAs in viruses with an ambisense coding strategy. No obvious transcription termination sequence was identified. However, because of a short palindromic sequence in the intergenic region, the 3' ends of both mRNAs (and consequently also the template RNAs) can be folded into an A/U-rich hairpin structure. It remains to be determined whether this structure plays any role in transcription termination.


Evolutionary history of wild barley (Hordeum vulgare subsp. spontaneum) analyzed using multilocus sequence data and paleodistribution modeling.
Studies of Hordeum vulgare subsp. spontaneum, the wild progenitor of cultivated barley, have mostly relied on materials collected decades ago and maintained since then ex situ in germplasm repositories. We analyzed spatial genetic variation in wild barley populations collected rather recently, exploring sequence variations at seven single-copy nuclear loci, and inferred the relationships among these populations and toward the genepool of the crop. The wild barley collection covers the whole natural distribution area from the Mediterranean to Middle Asia. In contrast to earlier studies, Bayesian assignment analyses revealed three population clusters, in the Levant, Turkey, and east of Turkey, respectively. Genetic diversity was exceptionally high in the Levant, while eastern populations were depleted of private alleles. Species distribution modeling based on climate parameters and extant occurrence points of the taxon inferred suitable habitat conditions during the ice-age, particularly in the Levant and Turkey. Together with the ecologically wide range of habitats, they might contribute to structured but long-term stable populations in this region and their high genetic diversity. For recently collected individuals, Bayesian assignment to geographic clusters was generally unambiguous, but materials from genebanks often showed accessions that were not placed according to their assumed geographic origin or showed traces of introgression from cultivated barley. We assign this to gene flow among accessions during ex situ maintenance. Evolutionary studies based on such materials might therefore result in wrong conclusions regarding the history of the species or the origin and mode of domestication of the crop, depending on the accessions included.


Cirrus cloud top temperatures retrieved from radiances in the National Polar-Orbiting Operational Environmental Satellite System--Visible Infrared Imager Radiometer Suite 8.55 and 12.0 microm bandpasses.
We describe what is believed to be a new approach developed for the National Polar-Orbiting Operational Environmental Satellite System (NPOESS) to retrieve pixel-level, cirrus cloud top temperatures (CTTs) from radiances observed in the 8.55 and 12.0 microm bandpasses. The methodology solves numerically a set of nonlinear algebraic equations derived from the theory of radiative transfer based upon the correlation between emissivities in these two bandpasses. This new approach has been demonstrated using NASA's Moderate Resolution Imaging Spectroradiometer (MODIS) as a proxy to Visible Infrared Imager Radiometer Suite (VIIRS) data. Many scenes have been analyzed covering a wide range of geophysical conditions, including single-layered and multilayered cirrus cloud situations along with diverse backgrounds and seasons. For single-layer clouds, the new approach compares very favorably with the MODIS 5 km resolution cloud products; the mean CTT for both methods are very close, while the standard deviation for the new approach is smaller. However, in multilayered cloud situations, the mean CTTs for the new approach appear to be colder than the CTTs from MODIS cloud products, which are acknowledged to be too warm. Finally, partly because the new approach is applied at the pixel level, CTTs do not increase toward cloud edges as is seen in the MODIS products. Based upon these initial results, the new approach to retrieve improved VIIRS cloud top properties has been incorporated into the ground-based data processing segment of the NPOESS system where prelaunch testing of all VIIRS algorithms continues.


A comparison of the availability and affordability of a market basket in two communities in the Chicago area.
The purpose of the present study was to characterise the food landscape of an inner city African American neighbourhood and its mixed-race suburban neighbour. Detailed analysis focuses on the relationship between community store mix and price, availability and produce quality. A market basket study was completed by members of the Chicago Food Systems Collaborative. The US Department of Agriculture's standard market basket survey and methodology were used. Additional items and analyses were added in consultation with community members. Austin is a lower-middle-class African American community of 117,500 on the western edge of Chicago. Oak Park, which borders Austin, is an upper-middle-income suburb of 52,500 with a mixed racial profile. A market basket survey of every retail food store in Austin and Oak Park was completed. A total of 134 were included. Results indicate that Austin has many grocery stores and few supermarkets. Many Austin groceries stores carry produce that is usually competitively priced, but often of unacceptable quality. Supermarkets had the best selection. Prices were lowest at discount supermarkets. Prices of packaged items were higher at independent stores than at chain supermarkets, but fresh items were cheaper. Food access is related more to store type than number. In this study, item availability and produce quality varied greatly between store types. Price differences were complicated and varied by store type and food category. This has consequences in terms of food purchasing decisions and dietary quality that public health professionals should acknowledge.


The role of hydrophobic active-site residues in substrate specificity and acyl transfer activity of penicillin acylase.
Penicillin acylase of Escherichia coli catalyses the hydrolysis and synthesis of beta-lactam antibiotics. To study the role of hydrophobic residues in these reactions, we have mutated three active-site phenylalanines. Mutation of alphaF146, betaF24 and betaF57 to Tyr, Trp, Ala or Leu yielded mutants that were still capable of hydrolysing the chromogenic substrate 2-nitro-5-[(phenylacetyl)amino]-benzoic acid. Mutations on positions alphaF146 and betaF24 influenced both the hydrolytic and acyl transfer activity. This caused changes in the transferase/hydrolase ratios, ranging from a 40-fold decrease for alphaF146Y and alphaF146W to a threefold increase for alphaF146L and betaF24A, using 6-aminopenicillanic acid as the nucleophile. Further analysis of the betaF24A mutant showed that it had specificity constants (kcat/Km) for p-hydroxyphenylglycine methyl ester and phenylglycine methyl ester that were similar to the wild-type values, whereas the specificity constants for p-hydroxyphenylglycine amide and phenylglycine amide had decreased 10-fold, due to a decreased kcat value. A low amidase activity was also observed for the semisynthetic penicillins amoxicillin and ampicillin and the cephalosporins cefadroxil and cephalexin, for which the kcat values were fivefold to 10-fold lower than the wild-type values. The reduced specificity for the product and the high initial transferase/hydrolase ratio of betaF24A resulted in high yields in acyl transfer reactions.


Enhanced phosphorylation of transcription factor sp1 in response to herpes simplex virus type 1 infection is dependent on the ataxia telangiectasia-mutated protein.
The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. In ATM-deficient cells or cells silenced for ATM expression by short hairpin RNA targeting, hyperphosphorylation of Sp1 was prevented even as HSV-1 infection progressed. Mutational analysis of putative ATM phosphorylation sites on Sp1 and immunoblot analysis with phosphopeptide-specific Sp1 antibodies clarified that at least Ser-56 and Ser-101 residues on Sp1 became phosphorylated upon HSV-1 infection. Serine-to-alanine mutations at both sites on Sp1 considerably abolished hyperphosphorylation of Sp1 upon infection. Although ATM phosphorylated Ser-101 but not Ser-56 on Sp1 in vitro, phosphorylation of Sp1 at both sites was not detected at all upon infection in ATM-deficient cells, suggesting that cellular kinase(s) activated by ATM could be involved in phosphorylation at Ser-56. Upon viral infection, Sp1-dependent transcription in ATM expression-silenced cells was almost the same as that in ATM-intact cells, suggesting that ATM-dependent phosphorylation of Sp1 might hardly affect its transcriptional activity during the HSV-1 infection. ATM-dependent Sp1 phosphorylation appears to be a global response to various DNA damage stress including viral DNA replication.


Pain and Self-Efficacy Among Patients With Systemic Sclerosis: A Scleroderma Patient-Centered Intervention Network Cohort Study.
Pain is one of the most common symptoms affecting patients with systemic sclerosis; however, little is known about the relationship between self-efficacy and pain and changes in pain over time. The purpose of this study was to describe the relationships between self-efficacy and pain in patients with systemic sclerosis, as well as determine whether changes in self-efficacy mediate changes in pain. A prospective longitudinal study was conducted using data from the Scleroderma Patient-Centered Intervention Network Cohort. The baseline sample included 1,903 adults, with a trajectory subsample of 427 who completed 3-month assessments across 3 years. Hierarchical (sequential) forward multivariable regression, covarying for participant characteristics, was conducted to determine the association between self-efficacy and patient characteristics on pain outcomes. Trajectory models, covarying for participant characteristics, were used to examine changes in self-efficacy and pain outcomes across time and whether self-efficacy mediated the pain trajectories. Mean time since diagnosis was 9.5 years, with 39.2% diagnosed with diffuse cutaneous systemic sclerosis. Greater self-efficacy was associated with less pain interference and intensity. Increasing age, female gender, finger ulcers, and small joint contractures were related to greater pain interference and intensity. Esophageal gastrointestinal symptoms were associated with more pain interference. Self-efficacy and pain trajectories remained stable across time, and self-efficacy did not mediate the pain trajectories. This study identified self-efficacy, age, gender, finger ulcers, small joint contractures, and esophageal gastrointestinal symptoms as important correlates associated with pain in patients with systemic sclerosis. In addition, this study found that self-efficacy and pain outcomes remained stable over time, providing important insights into the longitudinal pain experiences of patients with systemic sclerosis.


Visual motion detection circuits in flies: peripheral motion computation by identified small-field retinotopic neurons.
Giant motion-sensitive tangential neurons in the lobula plate are thought to be cardinal elements in the oculomotor pathways of flies. However, these large neurons do not themselves compute motion, and elementary motion detectors have been proposed only from theory. Here we identify the forms, projections, and responses of small-field retinotopic neurons that comprise a well known pathway from the retina to the lobula plate. Already at the level of the second and third synapses beneath the photoreceptor layer, certain of these small elements show responses that distinguish motion from flicker. At a level equivalent to the vertebrate inner plexiform layer (the fly's outer medulla) at least one retinotopic element is directionally selective. At the inner medulla, small retinotopic neurons with bushy dendrites extending through a few neighboring columns leave the inner medulla and supply inputs onto lobula plate tangentials. These medulla relays have directionally selective responses that are indistinguishable from those of large-field tangentials except for their amplitude and modulation with contrast frequency. Centrifugal neurons leading back from the inner medulla out to the lamina also show orientation-selective responses to motion. The results suggest that specific cell types between the lamina and inner medulla correspond to stages of the Hassenstein-Reichardt correlation model of motion detection.


Low dose prenatal ethanol exposure induces anxiety-like behaviour and alters dendritic morphology in the basolateral amygdala of rat offspring.
Prenatal exposure to high levels of alcohol is strongly associated with poor cognitive outcomes particularly in relation to learning and memory. It is also becoming more evident that anxiety disorders and anxiety-like behaviour can be associated with prenatal alcohol exposure. This study used a rat model to determine if prenatal exposure to a relatively small amount of alcohol would result in anxiety-like behaviour and to determine if this was associated with morphological changes in the basolateral amygdala. Pregnant Sprague Dawley rats were fed a liquid diet containing either no alcohol (Control) or 6% (vol/vol) ethanol (EtOH) throughout gestation. Male and Female offspring underwent behavioural testing at 8 months (Adult) or 15 months (Aged) of age. Rats were perfusion fixed and brains were collected at the end of behavioural testing for morphological analysis of pyramidal neuron number and dendritic morphology within the basolateral amygdala. EtOH exposed offspring displayed anxiety-like behaviour in the elevated plus maze, holeboard and emergence tests. Although sexually dimorphic behaviour was apparent, sex did not impact anxiety-like behaviour induced by prenatal alcohol exposure. This increase in anxiety - like behaviour could not be attributed to a change in pyramidal cell number within the BLA but rather was associated with an increase in dendritic spines along the apical dendrite which is indicative of an increase in synaptic connectivity and activity within these neurons. This study is the first to link increases in anxiety like behaviour to structural changes within the basolateral amygdala in a model of prenatal ethanol exposure. In addition, this study has shown that exposure to even a relatively small amount of alcohol during development leads to long term alterations in anxiety-like behaviour.


Trends in dental-related emergency department visits in the State of California from 2005 to 2011.
Objectives of this study were to provide trends in hospital-based emergency department (ED) visits involving dental conditions in California and to identify clinical and patient characteristics associated with these trends. We used 2005 to 2011 data from the California Emergency Department Database. We examined all ED visits related to dental conditions. During the study period (2005-2011), 402,077 ED visits were attributed to dental conditions. The number of ED visits that were dental-related increased from 44,516 (in 2005) to 70,385 (in 2011). Most of these visits were for dental caries (44.0%) and pulp/periapical lesions (48.6%) in 2011. Nearly one third of patients visiting the ED were uninsured, and the percentage of Medicaid patients increased from 30.3% in 2006 to 35.1% in 2011. The number and rate of visits to the ED for dental-related problems has increased substantially in recent years in California. A large proportion of these patients are uninsured and those covered by Medicaid.


MaxQuant.Live Enables Global Targeting of More Than 25,000 Peptides.
Mass spectrometry (MS)-based proteomics is often performed in a shotgun format, in which as many peptide precursors as possible are selected from full or MS1 scans so that their fragment spectra can be recorded in MS2 scans. Although achieving great proteome depths, shotgun proteomics cannot guarantee that each precursor will be fragmented in each run. In contrast, targeted proteomics aims to reproducibly and sensitively record a restricted number of precursor/fragment combinations in each run, based on prescheduled mass-to-charge and retention time windows. Here we set out to unify these two concepts by a global targeting approach in which an arbitrary number of precursors of interest are detected in real-time, followed by standard fragmentation or advanced peptide-specific analyses. We made use of a fast application programming interface to a quadrupole Orbitrap instrument and real-time recalibration in mass, retention time and intensity dimensions to predict precursor identity. MaxQuant.Live is freely available (www.maxquant.live) and has a graphical user interface to specify many predefined data acquisition strategies. Acquisition speed is as fast as with the vendor software and the power of our approach is demonstrated with the acquisition of breakdown curves for hundreds of precursors of interest. We also uncover precursors that are not even visible in MS1 scans, using elution time prediction based on the auto-adjusted retention time alone. Finally, we successfully recognized and targeted more than 25,000 peptides in single LC-MS runs. Global targeting combines the advantages of two classical approaches in MS-based proteomics, whereas greatly expanding the analytical toolbox.


Effects of compression on language evolution.
For many adaptive complex systems information about the environment is not simply recorded in a look-up table, but is rather encoded in a theory, schema, or model, which compresses information. The grammar of a language can be viewed as such a schema or theory. In a prior study [Teal et al., 1999] we proposed several conjectures about the learning and evolution of language that should follow from these observations: (C1) compression aids in generalization; (C2) compression occurs more easily in a "smooth," as opposed to a "rugged," problem space: and (C3) constraints from compression make it likely that natural languages evolve towards smooth string spaces. This previous work found general, if not complete support for these three conjectures. Here we build on that study to clarify the relationship between Minimum Description Length (MDL) and error in our model and examine evolution of certain languages in more detail. Our results suggest a fourth conjecture: that all else being equal, (C4) more complex languages change more rapidly during evolution.


Effects of cinnamic acid on complications of diabetes
Background/aim: Diabetes mellitus (DM) is a major health problem worldwide. Cinnamic acid (CA) and its derivatives are synthesized in plants and increasing attention has been given to them in recent years due to the high number of beneficial health properties attributed to their consumption. The aim of this study was to investigate the effects of CA on streptozotocin-induced diabetes in Wistar albino rats. Materials and methods: DNA damage was evaluated in the blood, liver, and kidney cells of rats by the alkaline comet assay. Oxidative stress parameters such as catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase activities and 8-hydroxy-2-deoxyguanosine, total glutathione, and malondialdehyde levels; biochemical parameters including insulin, total bilirubin, and BCA protein levels; hepatic enzyme levels such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase; and lipid profile parameters including high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglyceride levels were also evaluated. Results: DM caused genotoxic damage and alterations in lipid profiles, oxidative stress parameters, and hepatic enzymes levels. CA treatment ameliorated these effects. Conclusion: It seems that CA might have a role in the prevention of the complications of diabetes.


Double stranded sperm DNA breaks, measured by Comet assay, are associated with unexplained recurrent miscarriage in couples without a female factor.
It is known that sperm samples from recurrent pregnancy loss (RPL) couples have an increase in their sperm DNA fragmentation (SDF), but no studies have been performed in order to identify differences between single stranded SDF (ssSDF) and double stranded SDF (dsSDF) in these patients. This could be relevant because the type of DNA damage could have different effects. Semen samples were classified attending their clinical status: 25 fertile donors and 20 RPL patients with at least two unexplained first trimester miscarriages. SDF was analysed using alkaline and neutral Comet assay, SCD test and pulsed-field gel electrophoresis (PFGE), and ROC analysis including data from 105 more infertile patients (n = 150) was performed to establish predictive threshold values. SDF for alkaline and neutral Comet, and the SCD test was analysed in these categories of individuals. Data revealed the presence of two subgroups within fertile donors. The values obtained were 21.10±9.13, 23.35±10.45 and 12.31±4.31, respectively, for fertile donors with low values for both ssSDF and dsSDF; 27.86±12.64, 80.69±12.67 and 12.43±5.22, for fertile donors with low ssSDF and high dsSDF; and 33.61±15.50, 84.64±11.28 and 19.28±6.05, for unexplained RPL patients, also showing a low ssSDF and high dsSDF profile. This latter profile was seen in 85% of unexplained RPL and 33% of fertile donors, suggesting that it may be associated to a male risk factor for undergoing RPL. ROC analysis regarding recurrent miscarriage set the cut-off value at 77.50% of dsDNA SDF. PFGE for low ssSDF and high dsSDF profile samples and positive controls treated with DNase, to induce dsDNA breaks, showed a more intense band of about 48 kb, which fits the toroid model of DNA compaction in sperm, pointing out that some nuclease activity may be affecting their sperm DNA in RPL patients. This work identifies a very specific SDF profile related to the paternal risk of having RPL.


Microdiversity and temporal dynamics of marine bacterial dimethylsulfoniopropionate genes.
Dimethylsulfoniopropionate (DMSP) is an abundant organic sulfur metabolite produced by many phytoplankton species and degraded by bacteria via two distinct pathways with climate-relevant implications. We assessed the diversity and abundance of bacteria possessing these pathways in the context of phytoplankton community composition over a 3-week time period spanning September-October, 2014 in Monterey Bay, CA. The dmdA gene from the DMSP demethylation pathway dominated the DMSP gene pool and was harboured mostly by members of the alphaproteobacterial SAR11 clade and secondarily by the Roseobacter group, particularly during the second half of the study. Novel members of the DMSP-degrading community emerged from dmdA sequences recovered from metagenome assemblies and single-cell sequencing, including largely uncharacterized gammaproteobacteria and alphaproteobacteria taxa. In the DMSP cleavage pathway, the SAR11 gene dddK was the most abundant early in the study, but was supplanted by dddP over time. SAR11 members, especially those harbouring genes for both DMSP degradation pathways, had a strong positive relationship with the abundance of dinoflagellates, and DMSP-degrading gammaproteobacteria co-occurred with haptophytes. This in situ study of the drivers of DMSP fate in a coastal ecosystem demonstrates for the first time correlations between specific groups of bacterial DMSP degraders and phytoplankton taxa.


NOGOB receptor-mediated RAS signaling pathway is a target for suppressing proliferating hemangioma.
Infantile hemangioma is a vascular tumor characterized by the rapid growth of disorganized blood vessels followed by slow spontaneous involution. The underlying molecular mechanisms that regulate hemangioma proliferation and involution still are not well elucidated. Our previous studies reported that NOGOB receptor (NGBR), a transmembrane protein, is required for the translocation of prenylated RAS from the cytosol to the plasma membrane and promotes RAS activation. Here, we show that NGBR was highly expressed in the proliferating phase of infantile hemangioma, but its expression decreased in the involuting phase, suggesting that NGBR may have been involved in regulating the growth of proliferating hemangioma. Moreover, we demonstrate that NGBR knockdown in hemangioma stem cells (HemSCs) attenuated growth factor-stimulated RAS activation and diminished the migration and proliferation of HemSCs, which is consistent with the effects of RAS knockdown in HemSCs. In vivo differentiation assay further shows that NGBR knockdown inhibited blood vessel formation and adipocyte differentiation of HemSCs in immunodeficient mice. Our data suggest that NGBR served as a RAS modulator in controlling the growth and differentiation of HemSCs.


Signatures of spatially correlated noise and non-secular effects in two-dimensional electronic spectroscopy.
We investigate how correlated fluctuations affect oscillatory features in rephasing and non-rephasing two-dimensional (2D) electronic spectra of a model dimer system. Based on a beating map analysis, we show that non-secular environmental couplings induced by uncorrelated fluctuations lead to oscillations centered at both cross- and diagonal-peaks in rephasing spectra as well as in non-rephasing spectra. Using an analytical approach, we provide a quantitative description of the non-secular effects in terms of the Feynman diagrams and show that the environment-induced mixing of different inter-excitonic coherences leads to oscillations in the rephasing diagonal-peaks and non-rephasing cross-peaks. We demonstrate that as correlations in the noise increase, the lifetime of oscillatory 2D signals is enhanced at rephasing cross-peaks and non-rephasing diagonal-peaks, while the other non-secular oscillatory signals are suppressed. We discuss that the asymmetry of 2D lineshapes in the beating map provides information on the degree of correlations in environmental fluctuations. Finally we investigate how the oscillatory features in 2D spectra are affected by inhomogeneous broadening.


Dynamics of adhesive rupture between fibroblasts and fibronectin: microplate manipulations and deterministic model.
To characterize the dynamics of cell-substrate adhesive rupture, we used a novel micromanipulation technique, in which individual fibroblasts seized on a rigid microplate were placed into contact with a fibronectin-coated flexible microplate, then pulled away. The fibronectin density (0-3000 molecules/microm2) and the pulling rate (1-10 microm/s) were controlled. The extent of the contact zone decreased to zero at a time threshold corresponding to adhesive rupture. The uniaxial force at the interface, computed from the deflection of the microplate, increased linearly with time and reached a maximum before dropping to zero. A deterministic model, focusing on the mean number of bonds between fibronectin and its membrane receptor on the cell surface, shows rapid rupture when the force reaches a critical value, in agreement with experimental observations. Increasing the ligand density and the rate of load raises the maximal force (30 200 nN), in reasonably good agreement with the model predictions. Minimization of error between experimental and simulated forces allowed identification of two physicochemical properties of the bond, i.e. its association rate constant (k(2D)on = 3 x 10(-4) microm2/s) and structural length (d = 3 nm). These results may help understand better fibroblast locomotion and interaction with the extracellular matrix.


The scientific development of the physiology of plants in the American tropics.
This paper is a research and journalistic work that summarizes and synthesizes the scientific development of the physiology of plants in the American tropics, also known as the Neotropics. It contains the contributions of numerous biologists interested in the physiology of tropical plants. The fabulous structural and functional diversity of tropical forests is still the major driver of research in this field. Classical physiological work involving tropical plants, such as the discovery of C4 photosynthesis in sugarcane, is invoked to exemplify the historical and current importance of physiological research in the tropics, and its applications in agriculture, forestry and conservation. An historical background describing the early and more recent development of a tradition on the physiological study of tropical plants is followed by a summary of the research conducted on the physiology of tropical crops. Common areas of interest and influence between the fields of crop physiology and plant ecophysiology are identified and exemplified with problems on the environmental physiology of crops like coffee and cassava. The physiology of tropical forest plants is discussed in terms of its contributions to general plant physiological knowledge in areas such as photosynthetic metabolism and plant water relations. Despite the impressive technical advances achieved during the past decade, the importance of continuous development of appropriate instrumentation to study and measure the physiology of plants in situ is stressed. Although the basic metabolic processes that underlie the mechanisms of plant responses to the environment are probably highly conserved and qualitatively similar among tropical and temperate plants, it is also apparent that tropical plants exhibit metabolic peculiarities. These include aspects of photosynthetic metabolism, phloem transport physiology, sensitivity to low temperatures, reproduction, responses to climatic seasonality, and a large variety of biotic interactions. Old and new paradigms are examined in light of recent evidence and comparative studies, and the conceptual and technical advances needed to foster the development of tropical plant ecophysiology are identified.


Acute growth hormone effects on amino acid and lipid metabolism.
The anabolic actions of GH are well known, although specific tissue responses and the mechanism of nitrogen conservation are less well understood. This study was designed to examine the acute metabolic effects of GH on whole body and regional protein metabolism, using an experimental protocol which controlled for confounding perturbations in other hormones by a simultaneous infusion of somatostatin. Control subjects received replacement doses of insulin, glucagon, and GH for the entire 7-h study period, whereas GH subjects received an identical protocol, except for an increased dose of GH sufficient to increase serum concentrations into the high-physiological range (12-20 ng/mL) for the final 3.5 h of the study (P < 0.001). Thirteen young, healthy male subjects were studied in the postabsorptive period; five served as control subjects and eight as treatment (GH) subjects. Each received continuous iv infusions of somatostatin, L-[13-C]leucine, and L-[2H5]phenylalanine throughout the study. Femoral arterial and venous sampling allowed for simultaneous measurements across the leg and in the whole body. C-Peptide levels were suppressed throughout the infusion; insulin, glucagon, insulin-like growth factor I, cortisol, epinephrine, norepinephrine, and glucose concentrations were not different between groups. Glycerol concentrations increased 3-fold in GH subjects during the final 3.5-h period (P = 0.04). Concentrations of several amino acids declined through the study, but no differences were observed between treatment groups. Leucine oxidation was reduced in GH compared to control subjects (P = 0.04). No changes in CO2 production or whole body leucine or phenylalanine flux were observed, whereas nonoxidative disposal of leucine was marginally higher in GH compared to control subjects (P = 0.07). By contrast, rates of appearance and disappearance of both leucine and phenylalanine across the leg all were relatively lower in GH compared to control subjects; leucine balance across the leg was reduced by GH (P = 0.03), whereas phenylalanine balance was not influenced by GH. Our data thus demonstrate an acute stimulatory effect of GH on lipolysis, a decrease in leucine oxidation, and no stimulation of muscle protein synthesis in spite of enhanced protein synthesis in nonmuscle tissue.


Flexibility of Fluorinated Graphene-Based Materials.
The resistivity of different films and structures containing fluorinated graphene (FG) flakes and chemical vapor deposition (CVD)-grown graphene of various fluorination degrees under tensile and compressive strains due to bending deformations was studied. Graphene and multilayer graphene films grown by means of the chemical vapor deposition (CVD) method were transferred onto the flexible substrate by laminating and were subjected to fluorination. They demonstrated a weak fluorination degree (F/C lower 20%). Compressive strains led to a strong (one-two orders of magnitude) decrease in the resistivity in both cases, which was most likely connected with the formation of additional conductive paths through fluorinated graphene. Tensile strain up to 3% caused by the bending of both types of CVD-grown FG led to a constant value of the resistivity or to an irreversible increase in the resistivity under repeated strain cycles. FG films created from the suspension of the fluorinated graphene with a fluorination degree of 20-25%, after the exclusion of design details of the used structures, demonstrated a stable resistivity at least up to 2-3% of tensile and compressive strain. The scale of resistance changes R/R0 was found to be in the range of 14-28% with a different sign at the 10% tensile strain (bending radius 1 mm). In the case of the structures with the FG thin film printed on polyvinyl alcohol, a stable bipolar resistive switching was observed up to 6.5% of the tensile strain (bending radius was 2 mm). A further increase in strain (6.5-8%) leads to a decrease in ON/OFF current ratio from 5 down to 2 orders of magnitude. The current ratio decrease is connected with an increase under the tensile strain in distances between conductive agents (graphene islands and traps at the interface with polyvinyl alcohol) and thickness of fluorinated barriers within the active layer. The excellent performance of the crossbar memristor structures under tensile strain shows that the FG films and structures created from suspension are especially promising for flexible electronics.


Fast Transport of Water Droplets over a Thermo-Switchable Surface Using Rewritable Wettability Gradient.
In spite of the reported temperature dependent tunability in wettability of poly(N-isopropylacrylamide) (PNIPAAm) surfaces for below and above lower critical solution temperature (32 °C), the transport of water droplets is inhibited by the large contact angle hysteresis. Herein, for the first time, we report on-demand, fast, and reconfigurable droplet manipulation over a PNIPAAm grafted structured polymer surface using temperature-induced wettability gradient. Our study reveals that the PNIPAAm grafted on intrinsically superhydrophobic surfaces exhibit hydrophilic nature with high contact angle hysteresis below 30 °C and superhydrophobic nature with ultralow contact angle hysteresis above 36 °C. The transition region between 30 and 36 °C is characterized by a large change in water contact angle (∼100°) with a concomitant change in contact angle hysteresis. By utilizing this "transport zone" wherein driving forces overcome the frictional forces, we demonstrate macroscopic transport of water drops with a maximum transport velocity of approximately 40 cm/s. The theoretical calculations on the force measurements concur with dominating behavior of driving forces across the transport zone. The tunability in transport velocity by varying the temperature gradient along the surface or the inclination angle of the surface (maximum angle of 15° with a reduced velocity 0.4 mm/s) is also elucidated. In addition, as a practical application, coalescence of water droplets is demonstrated by using the temperature controlled wettability gradient. The presented results are expected to provide new insights on the design and fabrication of smart multifunctional surfaces for applications such as biochemical analysis, self-cleaning, and microfluidics.


Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.
Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear. To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum. Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium. Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests. Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05). Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.


Epidemiologic studies of Cyclospora cayetanensis in Guatemala.
In 1996 and 1997, cyclosporiasis outbreaks in North America were linked to eating Guatemalan raspberries. We conducted a study in health-care facilities and among raspberry farm workers, as well as a case-control study, to assess risk factors for the disease in Guatemala. From April 6, 1997, to March 19, 1998, 126 (2.3%) of 5, 552 surveillance specimens tested positive for Cyclospora; prevalence peaked in June (6.7%). Infection was most common among children 1.5 to 9 years old and among persons with gastroenteritis. Among 182 raspberry farm workers and family members monitored from April 6 to May 29, six had Cyclospora infection. In the case-control analysis, 62 (91%) of 68 persons with Cyclospora infection reported drinking untreated water in the 2 weeks before illness, compared with 88 (73%) of 120 controls (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.4, 10.8 by univariate analysis). Other risk factors included water source, type of sewage drainage, ownership of chickens or other fowl, and contact with soil (among children younger than 2 years).


Orexin A inhibits propofol-induced neurite retraction by a phospholipase D/protein kinase Cε-dependent mechanism in neurons.
The intravenous anaesthetic propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons. Orexin A (OA) is an endogenous neuropeptide regulating wakefulness and may counterbalance anaesthesia. We aim to investigate if OA interacts with anaesthetics by inhibition of the propofol-induced neurite retraction. In primary cortical cell cultures from newborn rats' brains, live cell light microscopy was used to measure neurite retraction after propofol (2 µM) treatment with or without OA (10 nM) application. The intracellular signalling involved was tested using a protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (PMA)] and inhibitors of Rho-kinase (HA-1077), phospholipase D (PLD) [5-fluoro-2-indolyl des-chlorohalopemide (FIPI)], PKC (staurosporine), and a PKCε translocation inhibitor peptide. Changes in PKCε Ser729 phosphorylation were detected with Western blot. The neurite retraction induced by propofol is blocked by Rho-kinase and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, staurosporine and PKCε translocation inhibitor peptide. OA increases via PLD and propofol decreases PKCε Ser729 phosphorylation, a crucial step in the activation of PKCε. Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC inhibits neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKCε-mediated pathway, and PKCε maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge.


Novel pancreatic beta cell-specific proteins: antibody-based proteomics for identification of new biomarker candidates.
Beta cell-specific surface targets are required for non-invasive monitoring of beta cell mass, which could be used for evaluation of new diabetes treatments as well as to help unravel pathogenic mechanisms underlying beta cell dysfunction. By antibody-based proteomics, we have identified and explored a set of islet cell-specific proteins. A search algorithm in the Human Protein Atlas was set up for identification of islet-specific proteins that yielded 27 hits, of which twelve showed a clear membranous expression pattern or had predicted transmembrane regions. The specificity of the identified proteins was investigated by immunohistochemical staining of pancreas sections from diabetic and non-diabetic subjects. No expression of these antigens could be detected in the exocrine pancreas. Colocalization with insulin and glucagon was further determined by confocal microscopy using isolated human islets. All antibodies specifically stained human islets and colocalization analysis revealed that four proteins were exclusively expressed in beta cells. Importantly, these antibodies were negative in sections from subjects with long-standing type 1 diabetes. In the present study, we present four proteins; DGCR2, GBF1, GPR44 and SerpinB10, the expression of which has not previously been described in beta cells.


Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) may recur after liver transplantation (LT), mainly in patients with multinodular and large tumors. However, factors predictive of outcome after LT in patients with small tumors remain ill defined. We investigated which factors were related to mortality or tumor recurrence among 47 liver transplant recipients with liver cirrhosis and HCC and compared them with 107 patients with liver cirrhosis without tumor who underwent LT in the same period. Patients with HCC were older (P <.001), more frequently had cirrhosis of a viral origin (P <.001), and had lower Child-Pugh scores (P <.001) than patients without tumor. Survival of patients with and without tumor was not significantly different (P =.20). Among patients with HCC, those with lower recurrence-free survival rates had liver cirrhosis of a viral origin, vascular invasion, bilobar disease, and tumor-node-metastasis (TNM) stage IV. At multivariate analysis, the only factor associated with mortality or recurrence was TNM stage IV (P =.02). Our results suggest that in patients with HCC and TNM stage IV, LT might be contraindicated.


Ear deformity due to neurofibromatosis type 1.
Neurofibromatosis is an autosomal dominant neurogenetic disorder. It is associated with significant morbidity and results in substantial loss of function as well as significant cosmetic problems. Elephantiasis neurofibromatosa is the most impressive manifestation of the disease because of its size. In this setting, the lesion leads to massive overgrowth of both the skin and the associated soft tissue, causing disturbing deformities. The reported patient had huge plexiform neurofibromas involving both the external right ear and neck regions. Deformed external ear and neck regions were restored surgically with satisfactory cosmetic results.


Serum diamine oxidase activity as a diagnostic test for histamine intolerance.
Histamine intolerance (HIT) is characterized by an imbalance between histamine intake and the capacity for histamine degradation. The main enzyme for metabolizing ingested histamine is diamine oxidase (DAO). Determining DAO activity in serum may be useful in diagnosing HIT. Over a period of 3.5 years we recruited 316 subjects with clinically suspected HIT and 55 healthy controls. Serum DAO activity was measured with a quantitative enzyme immunoassay. Twenty patients with highly reduced DAO activity went on a histamine-free diet for 6-12 months. Afterwards, their DAO activity was determined again. We found that DAO activity was significantly lower in patients than in healthy control subjects (P < 0.0001). Furthermore, 54 patients had highly reduced serum DAO activity (< 40 HDU/ml). Their main symptoms involved the skin, gastrointestinal tract, respiratory system, and eyes. In all the 20 patients with highly reduced DAO activity, the main clinical symptoms typical of histamine intolerance disappeared after they adopted a histamine-free diet. Furthermore, the serum DAO activity values measured increased significantly (P < 0.0001). Our results suggest that determining DAO activity in serum is a useful tool in diagnosing HIT. Furthermore, our results showed the benefit of a histamine-free diet because after the diet the majority of symptoms disappeared and the serum DAO activity significantly increased.


Evolutionary branching under slow directional evolution.
Evolutionary branching is the process by which ecological interactions induce evolutionary diversification. In asexual populations with sufficiently rare mutations, evolutionary branching occurs through trait-substitution sequences caused by the sequential invasion of successful mutants. A necessary and sufficient condition for evolutionary branching of univariate traits is the existence of a convergence stable trait value at which selection is locally disruptive. Real populations, however, undergo simultaneous evolution in multiple traits. Here we extend conditions for evolutionary branching to bivariate trait spaces in which the response to disruptive selection on one trait can be suppressed by directional selection on another trait. To obtain analytical results, we study trait-substitution sequences formed by invasions that possess maximum likelihood. By deriving a sufficient condition for evolutionary branching of bivariate traits along such maximum-likelihood-invasion paths (MLIPs), we demonstrate the existence of a threshold ratio specifying how much disruptive selection in one trait direction is needed to overcome the obstruction of evolutionary branching caused by directional selection in the other trait direction. Generalizing this finding, we show that evolutionary branching of bivariate traits can occur along evolutionary-branching lines on which residual directional selection is sufficiently weak. We then present numerical analyses showing that our generalized condition for evolutionary branching is a good indicator of branching likelihood even when trait-substitution sequences do not follow MLIPs and when mutations are not rare. Finally, we extend the derived conditions for evolutionary branching to multivariate trait spaces.


Building systemic capacity for nutrition: training towards a professionalised workforce for Africa.
The fundamental role played by good nutrition in enabling personal, social and economic development is now widely recognised as presenting a fundamental global challenge that has to be addressed if major national and international problems are to be resolved in the coming decades. The recent focus provided by the Millennium Development Goals and the Scaling-Up-Nutrition (SUN) movement has been towards reducing the extent of nutrition-related malnutrition in high-burden countries. This has served to emphasise that there is a problem of inadequate professional capacity in nutrition that is sufficiently widespread to severely limit all attempts at the effective delivery and sustainability of nutrition-related and nutrition-enabling interventions that have impact at scale. Many high-burden countries are in sub-Saharan Africa where there is a high dependency on external technical support to address nutrition-related problems. We have sought to explore the nature and magnitude of the capacity needs with a particular focus on achieving levels of competency within standardised professional pre-service training which is fit-for-purpose to meet the objectives within the SUN movement in Africa. We review our experience of engaging with stakeholders through workshops, a gap analysis of the extent of the problem to be addressed, and a review of current efforts in Africa to move the agenda forward. We conclude that there are high aspirations but severely limited human resource and capacity for training that is fit-for-purpose at all skill levels in nutrition-related subjects in Africa. There are no structured or collaborative plans within professional groups to address the wide gap between what is currently available, the ongoing needs and the future expectations for meeting local technical and professional capability. Programmatic initiatives encouraged by agencies and other external players, will need to be matched by improved local capabilities to address the serious efforts required to meet the needs for sustained improvements related to SUN in high-burden countries. Importantly, there are pockets of effort which need to be encouraged within a context in which experience can be shared and mutual support provided.


Characteristics of self-identified sexual addicts in a behavioral addiction outpatient clinic.
Background and aims Research on sexual addiction flourished during the last decade, promoted by the development of an increased number of online sexual activities. Despite the accumulation of studies, however, evidence collected in clinical samples of treatment-seeking people remains scarce. The aim of this study was to describe the characteristics (socio-demographics, sexual habits, and comorbidities) of self-identified "sexual addicts." Methods The sample was composed of 72 patients who consulted an outpatient treatment center regarding their sexual behaviors. Data were collected through a combination of structured interviewing and self-report measures. Results Most patients were males (94.4%) aged 20-76 years (mean 40.3 ± 10.9). Endorsement of sexual addiction diagnosis varied from 56.9% to 95.8% depending on the criteria used. The sexual behaviors reported to have the highest degree of functional impairment were having multiple sexual partners (56%), having unprotected sexual intercourse (51.9%), and using cybersex (43.6%). Ninety percent of patients endorsed a comorbid psychiatric diagnosis, and 60.6% presented at least one paraphilia. Conclusions Results showed highly different profiles in terms of sexual preferences and behaviors, as well as comorbidities involved. These findings highlight the need to develop tailored psychotherapeutic interventions by taking into account the complexity and heterogeneity of the disorder.


Genome sequencing and comparative genomics provides insights on the evolutionary dynamics and pathogenic potential of different H-serotypes of Shiga toxin-producing Escherichia coli O104.
Various H-serotypes of the Shiga toxin-producing Escherichia coli (STEC) O104, including H4, H7, H21, and H¯, have been associated with sporadic cases of illness and have caused food-borne outbreaks globally. In the U.S., STEC O104:H21 caused an outbreak associated with milk in 1994. However, there is little known on the evolutionary origins of STEC O104 strains, and how genotypic diversity contributes to pathogenic potential of various O104 H-antigen serotypes isolated from different ecological niches and/or geographical regions. Two STEC O104:H21 (milk outbreak strain) and O104:H7 (cattle isolate) strains were shot-gun sequenced, and the genomes were closed. The intimin (eae) gene, involved in the attaching-effacing phenotype of diarrheagenic E. coli, was not found in either strain. Examining various O104 genome sequences, we found that two "complete" left and right end portions of the locus of enterocyte effacement (LEE) pathogenicity island were present in 13 O104 strains; however, the central portion of LEE was missing, where the eae gene is located. In O104:H4 strains, the missing central portion of the LEE locus was replaced by a pathogenicity island carrying the aidA (adhesin involved in diffuse adherence) gene and antibiotic resistance genes commonly carried on plasmids. Enteroaggregative E. coli-specific virulence genes and European outbreak O104:H4-specific stx2-encoding Escherichia P13374 or Escherichia TL-2011c bacteriophages were missing in some of the O104:H4 genome sequences available from public databases. Most of the genomic variations in the strains examined were due to the presence of different mobile genetic elements, including prophages and genomic island regions. The presence of plasmids carrying virulence-associated genes may play a role in the pathogenic potential of O104 strains. The two strains sequenced in this study (O104:H21 and O104:H7) are genetically more similar to each other than to the O104:H4 strains that caused an outbreak in Germany in 2011 and strains found in Central Africa. A hypothesis on strain evolution and pathogenic potential of various H-serotypes of E. coli O104 strains is proposed.


Long-term seizure outcomes following resection of supratentorial cavernous malformations.
Symptomatic supratentorial cavernous malformations may present with seizure, headache, neurological deficit, or a combination thereof. Factors that contribute to treatment algorithms commonly include patient age, lesion size and location, lesion multiplicity, hemorrhage history, and the ability to control seizure activity with medication. A better appreciation of the impact of patient and lesion characteristics on post-operative seizure control may provide insight into management strategies. To determine long-term seizure outcomes following surgical resection of supratentorial cavernous malformations, the predictive value of characteristics including seizure duration and number, presence of generalized seizures, and lesion multiplicity and size on seizure control rate was evaluated. We performed a single institution retrospective review of consecutive patients with supratentorial cavernous malformations presenting with at least one seizure between 1995 and 2008. Univariate and multivariate analyses were used to determine the influence of patient and lesion characteristics on postoperative seizure control. Fifty-six patients met inclusion criteria. Mean follow-up duration was 87.9 months. At last follow-up there were 46 patients (82.1%) that were free from impairing seizures (Engel Class 1). Ten patients (17.9%) were classified as Engel Class 2-4. Univariate analysis demonstrated that only the presence of multiple cavernomas was associated with worse post-operative seizure outcome (p=0.006). Multivariate analysis demonstrated that multiple cavernomas remained a significant predictor for development of worse seizure outcome controlling for number and duration of seizures prior to operation, presence of generalized tonic-clonic seizures, and size (odds ratio, 0.17; 95% confidence interval, 0.03, 0.99). Resection of supratentorial cavernomas is associated with a high rate of postoperative seizure freedom. The presence of multiple cavernomas is predictive of seizure persistence following surgery.


Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy.
The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which regulates the activity of various enzymes including those that function to counteract oxidative stress within the cell. Trx can also scavenge reactive oxygen species (ROS) and directly inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). The oxidized form of Trx is reduced by thioredoxin reductase (TrxR). The cytoplasm and mitochondria contain equivalent Trx systems and inhibition of either system can lead to activation of apoptotic signaling pathways. There are a number of inhibitors with chemotherapy applications that target either Trx or TrxR to induce apoptosis in cancer cells. Suberoylanilide hydroxamic acid (SAHA) is effective against many cancer cells and functions by up-regulating an endogenous inhibitor of Trx. Other compounds target the selenocysteine-containing active site of TrxR. These include gold compounds, platinum compounds, arsenic trioxide, motexafin gadolinium, nitrous compounds, and various flavonoids. Inhibition of TrxR leads to an accumulation of oxidized Trx resulting in cellular conditions that promote apoptosis. In addition, some compounds also convert TrxR to a ROS generating enzyme. The role of Trx system inhibitors in cancer therapy is discussed in this review.


Using degrees of rate control to improve selective n-butane oxidation over model MOF-encapsulated catalysts: sterically-constrained Ag3Pd(111).
Metal nanoparticles encapsulated within metal organic frameworks (MOFs) offer steric restrictions near the catalytic metal that can improve selectivity, much like in enzymes. A microkinetic model is developed for the regio-selective oxidation of n-butane to 1-butanol with O2 over a model for MOF-encapsulated bimetallic nanoparticles. The model consists of a Ag3Pd(111) surface decorated with a 2-atom-thick ring of (immobile) helium atoms which creates an artificial pore of similar size to that in common MOFs, which sterically constrains the adsorbed reaction intermediates. The kinetic parameters are based on energies calculated using density functional theory (DFT). The microkinetic model was analysed at 423 K to determine the dominant pathways and which species (adsorbed intermediates and transition states in the reaction mechanism) have energies that most sensitively affect the reaction rates to the different products, using degree-of-rate-control (DRC) analysis. This analysis revealed that activation of the C-H bond is assisted by adsorbed oxygen atoms, O*. Unfortunately, O* also abstracts H from adsorbed 1-butanol and butoxy as well, leading to butanal as the only significant product. This suggested to (1) add water to produce more OH*, thus inhibiting these undesired steps which produce OH*, and (2) eliminate most of the O2 pressure to reduce the O* coverage, thus also inhibiting these steps. Combined with increasing butane pressure, this dramatically improved the 1-butanol selectivity (from 0 to 95%) and the rate (to 2 molecules per site per s). Moreover, 40% less O2 was consumed per oxygen atom in the products. Under these conditions, a terminal H in butane is directly eliminated to the Pd site, and the resulting adsorbed butyl combines with OH* to give the desired 1-butanol. These results demonstrate that DRC analysis provides a powerful approach for optimizing catalytic process conditions, and that highly selectivity oxidation can sometimes be achieved by using a mixture of O2 and H2O as the oxidant. This was further demonstrated by DRC analysis of a second microkinetic model based on a related but hypothetical catalyst, where the activation energies for two of the steps were modified.


Spatial-temporal dynamics of neotropical velvet ant (Hymenoptera: Mutillidae) communities along a forest-savanna gradient.
Understanding how and why biological communities are organized over space and time is a major challenge and can aid biodiversity conservation in times of global changes. Herein, spatial-temporal variation in the structure of velvet ant communities was examined along a forest-savanna gradient in the Brazilian Cerrado to assess the roles of environmental filters and interspecific interactions upon community assembly. Velvet ants were sampled using 25 arrays of Y-shaped pitfall traps with drift fences for one year along an environmental gradient from cerrado sensu stricto (open canopy, warmer, drier) to cerradão (closed canopy, cooler, moister). Dataloggers installed on each trap recorded microclimate parameters throughout the study period. The effects of spatial distances, microclimate parameters and shared ancestry on species abundances and turnover were assessed with canonical correspondence analysis, generalized dissimilarity modelling and variance components analysis. Velvet ant diversity and abundance were higher in the cerrado sensu stricto and early in the wet season. There was pronounced compositional turnover along the environmental gradient, and temporal variation in richness and abundance was stronger than spatial variation. The dry season blooming of woody plant species fosters host abundance and, subsequently, velvet ant captures. Species were taxonomically clustered along the gradient with Sphaeropthalmina (especially Traumatomutilla spp.) and Pseudomethocina more associated, respectively, with cerrado sensu stricto and cerradão. This suggests a predominant role of environmental filters on community assemble, with physiological tolerances and host preferences being shared among members of the same lineages. Induced environmental changes in Cerrado can impact communities of wasps and their hosts with unpredictable consequences upon ecosystem functioning and services.


The role of emergency ultrasound for evaluating acute pyelonephritis in the ED.
Controversy remains over the imaging method of choice for evaluating acute pyelonephritis (APN) in the emergency department (ED). The aim of the study was to determine the efficacy of ultrasound in the diagnosis and management of patients presented to the ED with APN. This was a retrospective study of prospectively collected data. A cohort of ED patients diagnosed as APN were prospectively registered, and their medical records were then retrospectively reviewed for the presence of complications (admitted >14 days, admission to intensive care unit, or received invasive procedures), significant abnormalities (hydronephrosis, polycystic kidney diseases, renal abscess, emphysematous pyelonephritis), and mild abnormalities (cysts, stones, swelling). The study included 243 patients. Most of the patients received one or more renal imaging studies (n = 206) and 39.5% of which were considered abnormal. The rates of significant abnormalities on different imaging methods were Kidney-ureter-bladder (KUB), 16.3%; emergency ultrasound (EUS), 39.6%; combination of KUB and EUS, 56.6%; and computed tomography, 58.8%. Factors contributed to complicated APN were elderly, male, a history of preexisting renal diseases, current use of catheters, previous renal calculi, and diabetes mellitus. Significant abnormalities can be identified by EUS in 61% of patients with complicated APN. In fact, the presence of significant sonographic abnormalities effectively diverted 34.3% of patients to receive surgical interventions (percutaneous nephrostomy, abscess aspiration, ureteroscopic stone manipulation, lithotripsy, or nephrectomy). Structural abnormalities are not uncommon in ED patients with APN. Early assessment of these patients with EUS is likely to have a great impact on their diagnosis and management.


Transport rates of radiolytic substances into Europa's ocean: implications for the potential origin and maintenance of life.
Abstract Bombardment of the surface of Europa produces oxidants and other biologically useful substances, but they can only contribute to the habitability of the ocean if they are delivered down through the icy crust. Previous estimates of the thickness of the oxygenated layer of ice assumed that impact gardening is the dominant factor and concluded that the ocean may be habitable if the oxidant delivery time, via undefined mechanisms, is sufficiently short. Consideration of the types of processes that continually resurface Europa suggests that the oxygenated layer is thicker than approximately 300 m, far greater than the few meters indicated by impact gardening alone, and possibly includes the entire ice crust. The estimated delivery rate to the ocean is such that the oxygen levels could now be high enough to support macrofauna; and, at approximately 3 x 10(11) mol/yr of oxygen, it could maintain 3 million tons of macrofauna, assuming respiration rates similar to terrestrial marine organisms. These values are independent of any additional contributions due to possible photosynthesis. Initial formation of life would be difficult with so much oxygen, but the start of oxidant delivery into the ocean would have been delayed by 1-2 billion years while the crust became loaded with oxidants. In the ocean, this delay would have allowed time for prebiotic assemblages and anaerobic biological development prior to the increasing oxidant concentration to otherwise toxic levels.


Triazolam improves sleep but fails to alter pain in TMD patients.
Patients with chronic orofacial pain often report disturbances in sleep, leading to the hypothesis that nocturnal motor hyperactivity of the muscles of mastication may contribute to the nociceptive process. This hypothesis was tested in a controlled study to evaluate the relationship between sleep stages, patient self-report of pain in the orofacial region, and nocturnal masticatory muscle activity. Twenty subjects participating in a two-period, within-subject, crossover study received triazolam or placebo for 4 nights. Sleep, pain, and mandibular range of motion were assessed at baseline, following the first period, and again following the second period; a 3-day washout period separated the two treatments. Subjective report of sleep quality was significantly improved following triazolam in comparison to placebo as measured by category scales for sleep quality, restfulness, and sleep compared to usual. The amount of time spent in stage-2 sleep was also significantly increased by triazolam. No improvement was seen in pain as measured by palpation with an algometer, in scales for sensory intensity and the affective component of pain, or in daily pain diaries. Mean facial muscle electromyographic activity for 30-second epochs averaged over the entire period of sleep did not reveal any differences in muscle activity across the three conditions. These data indicate that improvements in sleep quality and alterations in sleep architecture do not affect nocturnal facial muscle activity or subsequent pain report in temporomandibular patients, thereby failing to support the hypothesized relationship between sleep disturbances and chronic orofacial pain.


Goal-directed interaction of stimulus and task demand in the parahippocampal region.
The hippocampus and parahippocampal region are essential for representing episodic memories involving various spatial locations and objects, and for using those memories for future adaptive behavior. The "dual-stream model" was initially formulated based on anatomical characteristics of the medial temporal lobe, dividing the parahippocampal region into two streams that separately process and relay spatial and nonspatial information to the hippocampus. Despite its significance, the dual-stream model in its original form cannot explain recent experimental results, and many researchers have recognized the need for a modification of the model. Here, we argue that dividing the parahippocampal region into spatial and nonspatial streams a priori may be too simplistic, particularly in light of ambiguous situations in which a sensory cue alone (e.g., visual scene) may not allow such a definitive categorization. Upon reviewing evidence, including our own, that reveals the importance of goal-directed behavioral responses in determining the relative involvement of the parahippocampal processing streams, we propose the Goal-directed Interaction of Stimulus and Task-demand (GIST) model. In the GIST model, input stimuli such as visual scenes and objects are first processed by both the postrhinal and perirhinal cortices-the postrhinal cortex more heavily involved with visual scenes and perirhinal cortex with objects-with relatively little dependence on behavioral task demand. However, once perceptual ambiguities are resolved and the scenes and objects are identified and recognized, the information is then processed through the medial or lateral entorhinal cortex, depending on whether it is used to fulfill navigational or non-navigational goals, respectively. As complex sensory stimuli are utilized for both navigational and non-navigational purposes in an intermixed fashion in naturalistic settings, the hippocampus may be required to then put together these experiences into a coherent map to allow flexible cognitive operations for adaptive behavior to occur.


The effectiveness of the interview for predicting the presence of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS), a leading cause of female infertility, occurs in approximately 4% of women of reproductive age. Multifamily studies have established that PCOS has strong inherited traits. Although diagnosis of PCOS in the relatives of affected women can readily be made by clinical and biochemical evaluations, these methods are costly and laborious. The aim of this investigation was to determine whether clinically evident PCOS could be detected by a written questionnaire, which is a significantly less expensive means of detection than direct determination. A questionnaire about the history of possible androgenic symptoms of PCOS was presented to patients and their first-degree female relatives, who were also evaluated by physical and laboratory examinations. The sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) for the detection of PCOS by interview were calculated. The NPV of the proband interview was significantly lower for sisters than for mothers (82% vs. 100%, respectively; p < 0.05). When the family member completed the written questionnaire directly, the specificity and NPV of self-reporting were equally high (> 90%) for both mothers and sisters. Thus direct interviewing of PCOS patients or their mothers and sisters reliably predicts affected status, but patient interview alone will not predict PCOS in almost 50% of the affected sisters.


Guiding properties and dispersion control of kagome lattice hollow-core photonic crystal fibers.
Dispersion properties, loss and optimum design of kagome lattice hollow-core photonic crystal fibers filled with argon are studied for the purpose of possible applications in ultrafast nonlinear optics. As will be shown numerically and by using an approximate analytical formula these fibers exhibit anomalous dispersion for visible or UV wavelengths both for a 1-cell-core as well for a 3-ring-core which can be controlled by the gas pressure and do not suffer from high loss. It is shown that while the loss is mainly influenced by the strut thickness of the kagome lattice the group velocity dispersion is almost independently controlled by the core size. These results demonstrate that kagome lattice hollow fibers have a promising potential in ultrashort pulse delivering of high-energy pulses and in several interesting applications in ultrafast nonlinear optics.


Measurement of the human magnetic heart vector.
A unipositional lead system has been developed to record the human magnetic heart vector and to permit comparison with the electric heart vector recorded with a conventional Frank lead system. Recordings made in five normal subjects showed a remarkably consistent relation between the electric and magnetic heart vectors. However, the angle between electric heart vector R and T waves was markedly different from the magnetic heart vector R-T angle. In addition, recordings made in two patients with bundle branch block showed a different relation between the electric and magnetic heart vectors compared to normal subjects. These data support the hypothesis that magnetic measurements have a different sensitivity to some components of cardiac activation compared with body surface potential measurements.


Silencing RORγt in Human CD4+ T cells with CD30 aptamer-RORγt shRNA Chimera.
Targeting specific T cell subtypes and intervening in their function are emerging a critical strategy for treatment of autoimmune diseases. Here we report that an RNA CD30 aptamer was utilized to deliver short hairpin RNA (shRNA) to CD30+ T cells to target retinoic acid receptor-related orphan receptor gamma t (RORγt), leading to impaired expression of RORγt and suppression of IL-17A and IL-17F. A DNA template consisting of CD30 aptamer and RORγt shRNA sequences was synthesized and was transcribed CD30 aptamer-RORγt shRNA chimera (CD30-AshR-RORγt). Insertion of 2'-F-dCTP and 2'-FdUTP was incorporated during CD30-AshR-RORγt transcription to increase its resistance to RNase. CD30-AshR-RORγt was specifically up-taken by CD30+ Karpas 299 cells, but not by Jurkat cells which lack CD30. It was also up-taken by activated, CD30 expressing human CD4+T cells, but not by resting CD4+ T cells. The RORγt shRNA moiety of CD30-AshR-RORγt chimera was cleaved and released by Dicers. Then, CD30-AshR-RORγt suppressed RORγt gene expression in Karpas 299 cells and activated human CD4+ T cells. Consistently, silence of Th17 cell differentiation and IL-17A and IL-17F synthesis with CD30-AshR-RORγt was demonstrated in activated human CD4+ T cells from healthy donors and RA patients. CD30-AshR-negative control chimera and prostate specific membrane antigen (PSMA)-AshR-RORγt had no significant impact on the expression of RORγt or IL-17A and IL-17F. These data present a novel strategy for shRNA delivery using CD30 RNA aptamers to down-regulate CD30+ Th17 cells and can be developed as a targeted therapy for treating Th17 cell mediated conditions.


Escherichia coli thioredoxin stabilizes complexes of bacteriophage T7 DNA polymerase and primed templates.
The DNA polymerase activity induced after bacteriophage T7 infection of Escherichia coli is found in a complex of two proteins, the T7 gene 5 protein and a host protein, thioredoxin. Gene 5 protein is a DNA polymerase and a 3' to 5' exonuclease. Thioredoxin binds tightly to the gene 5 protein and increases the processivity of polymerization some 1000-fold. Gene 5 protein forms a short-lived complex with the primer-template, poly(dA).oligo(dT), in the absence of Mg2+ and nucleotides. Thioredoxin increases the half-life of the preformed primer-template-polymerase complex from less than a second to approximately 5 min. The dissociation is accelerated by excess single-stranded DNA in an apparent second order reaction, indicating direct transfer of polymerase between DNA fragments. Thioredoxin also reduces the equilibrium dissociation constant, Kd, of the gene 5 protein -poly(dA).oligo(dT) complex 20- to 80-fold. The salt dependence of Kd indicates that thioredoxin stabilizes the primer-template-polymerase complex mainly through additional charge-charge interactions, increasing the estimated number of interactions from 2 to 7. The affinity of gene 5 protein for single-stranded DNA is at least 1000-fold higher than for double-stranded DNA and is little affected by thioredoxin. Under conditions of steady state synthesis the effect of thioredoxin on the polymerization rate is determined by two competing factors, an increase in processivity and a decrease of the dissociation rate of polymerase and replicated template.


What we talk about when we talk about depression: doctor-patient conversations and treatment decision outcomes.
Efforts to address depression in primary care settings have focused on the introduction of care guidelines emphasising pharmacological treatment. To date, physician adherence remains low. Little is known of the types of information exchange or other negotiations in doctor-patient consultations about depression that influence physician decision making about treatment. The study sought to understand conversational influences on physician decision making about treatment for depression. A secondary analysis of consultation data collected in other studies. Using a maximum variation sampling strategy, 30 transcripts of primary care consultations about distress or depression were selected from datasets collected in three countries. Transcripts were analysed to discover factors associated with prescription of medication. The study employed two qualitative analysis strategies: a micro-analysis approach, which examines how conversation partners shape the dialogue towards pragmatic goals; and a narrative analysis approach of the problem presentation. Patients communicated their conceptual representations of distress at the outset of each consultation. Concepts of depression were communicated through the narrative form of the problem presentation. Three types of narratives were identified: those emphasising symptoms, those emphasising life situations, and mixed narratives. Physician decision making regarding medication treatment was strongly associated with the form of the patient's narrative. Physicians made few efforts to persuade patients to accept biomedical attributions or treatments. Results of the study provide insight into why adherence to depression guidelines remains low. Data indicate that patient agendas drive the 'action' in consultations about depression. Physicians appear to be guided by common-sense decision-making algorithms emphasising patients' views and preferences.


In vitro formation, disposition and toxicity of N-acetoxy-sulfamethoxazole, a potential mediator of sulfamethoxazole toxicity.
Variation in the formation and disposition of the hydroxylamine of (SMX-HA) is thought to play an important role in the pathogenesis of sulfamethoxazole (SMX)-induced idiosyncratic adverse drug reactions. We hypothesized that, in analogy to carcinogenic arylamines, SMX-HA might be further converted to an electrophilic N-acetoxy metabolite which could play a role in mediating SMX toxicity. Accordingly, we chemically synthesized N-acetoxy-SMX, and examined the characteristics of its formation, metabolism, cytotoxicity and mutagenicity in human and bacterial test systems. The human arylamine N-acetyl-transferases, (NAT)1 and NAT2, were capable of converting SMX-HA to N-acetoxy-SMX. NAT1 and NAT2 possessed similar affinities for SMX-HA (apparent Km values of 650 and 520 microM, respectively), but the apparent maximal velocity of the NAT1-mediated acetylation was higher than that of NAT2. (1332 vs. 37 nmol/min/U of immunoreactive NAT protein). Human peripheral blood mononuclear cells 12,000 x g supernatant fractions converted N-acetoxy-SMX mainly back to SMX-HA, and also to a lesser extent to SMX, at clinically relevant concentrations. Similar pathways were observed in human hepatic cytosolic fractions. In a cytotoxicity assay, N-acetoxy-SMX was significantly more toxic to human peripheral blood mononuclear cells than SMX-HA (16.6 vs. 11.5% dead cells at a concentration of 300 microM). N-acetoxy-SMX was weakly mutagenic to the Salmonella typhimurium TA100 strain in the Ames test. These data suggest that the N-acetoxy metabolites of sulfonamides could potentially play a role in mediating sulfonamide idiosyncratic adverse drug reactions.


Maternal mortality and distance to facility-based obstetric care in rural southern Tanzania: a secondary analysis of cross-sectional census data in 226 000 households.
Access to skilled obstetric delivery and emergency care is deemed crucial for reducing maternal mortality. We assessed pregnancy-related mortality by distance to health facilities and by cause of death in a disadvantaged rural area of southern Tanzania. We did a secondary analysis of cross-sectional georeferenced census data collected from June to October, 2007, in five rural districts of southern Tanzania. Heads of georeferenced households were asked about household deaths in the period June 1, 2004, to May 31, 2007, and women aged 13-49 years were interviewed about birth history in the same time period. Causes of death in women of reproductive age were ascertained by verbal autopsy. We also asked for sociodemographic information. Multilevel logistic regression was used to analyse the effects of distance to health facilities providing delivery care on pregnancy-related mortality (direct and indirect maternal and coincidental deaths). The study included 818 583 people living in 225 980 households. Pregnancy-related mortality was high at 712 deaths per 100 000 livebirths, with haemorrhage being the leading cause of death. Deaths due to direct causes of maternal mortality were strongly related to distance, with mortality increasing from 111 per 100 000 livebirths among women who lived within 5 km to 422 deaths per 100 000 livebirths among those who lived more than 35 km from a hospital (adjusted odds ratio 3·68; 95% CI 1·37-9·88). Neither pregnancy-related nor indirect maternal mortality was associated with distance to hospital. Among women who lived within 5 km of a hospital, pregnancy-related mortality was 664 deaths per 100 000 livebirths even though 72% gave birth in hospital and 8% had delivery by caesarean section. Large distances to hospital contribute to high levels of direct obstetric mortality. High pregnancy-related mortality in those living near to a hospital suggests deficiencies in quality of care. Bill & Melinda Gates Foundation.


Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot.
The purpose of this retrospective study was to evaluate outcomes of people with large diabetic foot wounds treated with subatmospheric pressure dressing therapy immediately following surgical wound debridement. Data were abstracted from the medical records of 31 consecutive patients with diabetes, 77.4% male (n = 24), aged 56.1 +/- 11.7 years, presenting for care at two large multidisciplinary wound care centers. All patients received surgical debridement for indolent diabetic foot wounds and were subsequently started on a regimen of subatmospheric pressure dressing therapy delivered using a vacuum-assisted closure device for a mean of 4.7 +/- 4.2 weeks (mode = 2 weeks) using a protocol that called for cessation of therapy when the wound bed approached 100% coverage with granulation tissue with no exposed tendon, joint capsule, or bone. Outcomes evaluated included time to complete wound closure, proportion of patients achieving wound healing at the level of initial debridement, and complications associated with use of the device. The mean duration of wounds before therapy was 25.4 +/- 23.8 weeks. In patients treated with subatmospheric pressure dressing therapy, 90.3% (n = 28) of wounds healed at the level of debridement without the need for further bony resection in a mean 8.1 +/- 5.5 weeks. The remaining 9.7% (n = 3) went on to higher level amputation (below knee amputation = 3.2%, [n = 1] and transmetatarsal amputation = 6.5% [n = 2]). Complications included periwound maceration (19.4% [n = 6]), periwound cellulitis (3.2% [n = 1]), and deep space infection (3.2% [n = 1]). The authors concluded that appropriate use of subatmospheric pressure dressing therapy to achieve a rapid granular bed in diabetic foot wounds may have promise in treatment of this population at high risk for amputation and that a large, randomized trial is now indicated.


Self-Presentation Strategies, Fear of Success and Anticipation of Future Success among University and High School Students.
The backlash avoidance model (BAM) suggests women insufficiently self-promote because they fear backlash for behavior which is incongruent with traditional gender roles. Avoiding self-promoting behavior is also potentially related to associating success with negative consequences. In two studies we tested whether self-promotion and fear of success will be predictors of lower salaries and anticipation of lower chances of success in an exam. In study 1, prior to the exam they were about to take, we asked 234 students about their predictions concerning exam results and their future earnings. They also filled scales measuring their associations with success (fear of success) and tendency for self-promotion. The tested model proved that in comparison to men, women expect lower salaries in the future, anticipate lower test performance and associate success with more negative consequences. Both tendency for self-promotion and fear of success are related to anticipation of success in test performance and expectations concerning future earnings. In study 2 we repeated the procedure on a sample of younger female and male high school pupils (N = 100) to verify whether associating success with negative consequences and differences in self-promotion strategies are observable in a younger demographic. Our results show that girls and boys in high school do not differ with regard to fear of success, self-promotion or agency levels. Girls and boys anticipated to obtain similar results in math exam results, but girls expected to have higher results in language exams. Nevertheless, school pupils also differed regarding their future earnings but only in the short term. Fear of success and agency self-ratings were significant predictors of expectations concerning future earnings, but only among high school boys and with regard to earnings expected just after graduation.


Four-year clinical follow-up of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions: the SPIRIT II trial.
This report describes the 4-year clinical outcomes of the SPIRIT II study, which randomized 300 patients to treatment with the XIENCE V everolimus-eluting stent (EES), or the TAXUS paclitaxel-eluting stent. At 4-year clinical follow-up, which was available in 256 (85.3%) patients, treatment with EES lead to a trend for lower rates of ischemia-driven major adverse cardiovascular events, a composite of cardiac death, myocardial infarction, and ischemia-driven target lesion revascularization (EES 7.7% vs. paclitaxel-eluting stent 16.4%, P = 0.056). Treatment with EES also resulted in a trend toward lower rates of cardiac death and numerically lower rates of myocardial infarction, ischemia-driven target lesion revascularization, and stent thrombosis. Overall, this study reports numerically fewer clinical events in patients treated with EES at 4-year follow-up, which is consistent with results from earlier follow-up.


Solar Cycle Prediction.
A review of solar cycle prediction methods and their performance is given, including forecasts for cycle 24. The review focuses on those aspects of the solar cycle prediction problem that have a bearing on dynamo theory. The scope of the review is further restricted to the issue of predicting the amplitude (and optionally the epoch) of an upcoming solar maximum no later than right after the start of the given cycle. Prediction methods form three main groups. Precursor methods rely on the value of some measure of solar activity or magnetism at a specified time to predict the amplitude of the following solar maximum. Their implicit assumption is that each numbered solar cycle is a consistent unit in itself, while solar activity seems to consist of a series of much less tightly intercorrelated individual cycles. Extrapolation methods, in contrast, are based on the premise that the physical process giving rise to the sunspot number record is statistically homogeneous, i.e., the mathematical regularities underlying its variations are the same at any point of time and, therefore, it lends itself to analysis and forecasting by time series methods. Finally, instead of an analysis of observational data alone, model based predictions use physically (more or less) consistent dynamo models in their attempts to predict solar activity. In their overall performance during the course of the last few solar cycles, precursor methods have clearly been superior to extrapolation methods. Nevertheless, most precursor methods overpredicted cycle 23, while some extrapolation methods may still be worth further study. Model based forecasts have not yet had a chance to prove their skills. One method that has yielded predictions consistently in the right range during the past few solar cycles is that of K. Schatten et al., whose approach is mainly based on the polar field precursor. The incipient cycle 24 will probably mark the end of the Modern Maximum, with the Sun switching to a state of less strong activity. It will therefore be an important testbed for cycle prediction methods and, by inference, for our understanding of the solar dynamo.


Self-propelled liquid metal motors steered by a magnetic or electrical field for drug delivery.
Self-propelled motors have inspired enormous potential in accomplishing various tasks when navigating in an aqueous environment due to their virtues of requiring no external energy source and autonomous locomotion. However, without reliable controllability, their potential value would be heavily reduced. Here, we demonstrate an innovative millimeter-scale self-propelled motor steered by an external magnetic or electric field, which successfully enables the motor to avoid out-of-control motion behavior encountered previously. A nickel cap is electroplated on a liquid metal droplet. The on-board fuel aluminum foil not only triggers the autonomous movement, but also enhances the adhesion between the nickel cap and the droplet. The current motor, composed of a nickel cap, aluminum and liquid metal, is capable of running with a velocity of 3 cm s-1 for hours without the use of an external energy source. In addition, the integration of the nickel cap renders a magnetic field exploitable to easily alter the performance of the motor remotely. Furthermore, an external electrical field offers a feasible way to accelerate the motor directionally in a reliable manner. More importantly, as a conceptual experiment, when loaded with soft alginate-based biomaterial containing aluminium nanoparticles as drugs, such a motor is still able to be self-propelled, exhibiting steerable motion for drug delivery. The remarkable features of the liquid metal motor, such as softness, controllable self-propelled movement and drug-delivery application, represent a critical step toward functional intelligent soft robots or machines.


Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.
Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.