Structured expert judgment to characterize uncertainty between PM2.5 exposure and mortality in Chile.
To further the understanding and implementation of expert elicitation methods in the evaluation of public policies related to air pollution, the present study's main goal was to explore the potential strengths and weaknesses of structured expert judgment (SEJ) methodology as a way to derive a C-R function for chronic PM(2.5) exposure and premature mortality in Chile. Local experts were classified in two groups according to background and experience: physicians (Group 1) and engineers (Group 2). Experts were required to provide an estimate of the true percent change in nonaccidental mortality resulting from a permanent 1 μg/m(3) reduction in PM2.5 annual average ambient concentration across the entire Chilean territory. Cooke's Classical Model was used to combine the individual experts' assessments. Experts' mortality estimations varied markedly across groups: while experts in Group 1 delivered higher estimations than those reported in major international cohort studies, estimations from Group 2 were, to varying degrees, anchored to previous studies. Accordingly, combined distributions for each group and all experts were significantly different, due to the high sensitivity of the weighted distribution to experts' performance in calibration variables. Results of this study suggest that, while the use of SEJ has great potential for estimating C-R functions for chronic exposure to PM2.5 and premature mortality and its major sources of uncertainty in countries where no studies are available, its successful implementation is conditioned by a number of factors, which are analyzed and discussed.


Exploration of the genetic organization of morphological modularity on the mouse mandible using a set of interspecific recombinant congenic strains between C57BL/6 and mice of the Mus spretus species.
Morphological integration and modularity within semi-autonomous modules are essential mechanisms for the evolution of morphological traits. However, the genetic makeup responsible for the control of variational modularity is still relatively unknown. In our study, we tested the hypothesis that the genetic variation for mandible shape clustered into two morphogenetic components: the alveolar group and the ascending ramus. We used the mouse as a model system to investigate genetics determinants of mandible shape. To do this, we used a combination of geometric morphometric tools and a set of 18 interspecific recombinant congenic strains (IRCS) derived from the distantly related species, Mus spretus SEG/Pas and Mus musculus C57BL/6. Quantitative trait loci (QTL) analysis comparing mandible morphometry between the C57BL/6 and the IRCSs identified 42 putative SEG/Pas segments responsible for the genetic variation. The magnitude of the QTL effects was dependent on the proportion of SEG/Pas genome inherited. Using a multivariate correlation coefficient adapted for modularity assessment and a two-block partial least squares analysis to explore the morphological integration, we found that these QTL clustered into two well-integrated morphogenetic groups, corresponding to the ascending ramus and the alveolar region. Together, these results provide evidence that the mouse mandible is subjected to genetic coordination in a modular manner.


Santosomes as natural and efficient carriers for the improvement of phycocyanin reepithelising ability in vitro and in vivo.
New biocarriers, named santosomes, were formulated using Santolina insularis essential oil and hydrogenated phosphatidylcholine. They were modified by adding propylene glycol, a hydrophylic penetration enhancer, and loaded with phycocyanin, a protein found in cyanobacteria, which possesses antioxidant and antiinflammatory properties. The essential oil was expected to modify the bilayer structure and improve the delivery and efficacy of the protein due to a synergistic effect of the phospholipid and S. insularis terpenes. Santosomes were small in size (∼118nm), unilamellar and with polyhedral shape. SAXS patterns showed that phycocyanin strongly interacted with the polar heads of the vesicle bilayer. Phycocyanin-loaded vesicles did not show any toxic effect in vitro: cell viability was ∼100% in endothelial cells and ∼120% in keratinocytes, at all the concentrations tested. In addition, phycocyanin-loaded vesicles protected the cells against free radical damage. In vivo studies were performed to evaluate the ability of santosomes to inhibit chemically-induced oedema and inflammation in mice. Results demonstrated that the application of phycocyanin-loaded santosomes produced an evident amelioration of the skin lesion, confirming their great potential for wound healing.


Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi.
Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.


Involvement of GANP in B cell activation in T cell-dependent antigen response.
Adaptive immunity is dependent on proliferation of antigen-driven B cells for clonal expansion in germinal centers (GCs) against T cell-dependent antigens (TD-Ag), accompanied with somatic hypermutation of variable-region gene and class switching of B cell antigen receptors. To study molecular mechanisms for B cell differentiation in GCs, we have identified and studied a 210kDa GANP protein expressed in GC-B cells. GANP has domains for MCM3-binding and RNA-primase activities and is selectively up-regulated in centrocytes surrounded with follicular dendritic cells (FDCs) upon immunization with TD-Ag in vivo and in B cells stimulated with anti-CD40 monoclonal antibody in vitro, which suggested that GANP plays a certain important role in the maturation of immunoglobulin or selection of B cells in GC during the immune response to TD-Ag. Since this up-regulation has not been detected in T cells in GCs and in Concanavalin A-stimulated T cells in vitro, selective function of GANP molecule on B cell proliferation and differentiation might exist.


Characterizing inflammatory breast cancer among Arab Americans in the California, Detroit and New Jersey Surveillance, Epidemiology and End Results (SEER) registries (1988-2008).
Inflammatory breast cancer (IBC) is characterized by an apparent geographical distribution in incidence, being more common in North Africa than other parts of the world. Despite the rapid growth of immigrants to the United States from Arab nations, little is known about disease patterns among Arab Americans because a racial category is rarely considered for this group. The aim of this study was to advance our understanding of the burden of IBC in Arab ethnic populations by describing the proportion of IBC among different racial groups, including Arab Americans from the Detroit, New Jersey and California Surveillance, Epidemiology and End Results (SEER) registries. We utilized a validated Arab surname algorithm to identify women of Arab descent from the SEER registries. Differences in the proportion of IBC out of all breast cancer and IBC characteristics by race and menopausal status were evaluated using chi-square tests for categorical variables, t-tests and ANOVA tests for continuous variables, and log-rank tests for survival data. We modeled the association between race and IBC among all women with breast cancer using hierarchical logistic regression models, adjusting for individual and census tract-level variables. Statistically significant differences in the proportion of IBC out of all breast cancers by race were evident. In a hierarchical model, adjusting for age, estrogen and progesterone receptor, human epidermal growth receptor 2, registry and census-tract level education, Arab-Americans (OR=1.5, 95% CI=1.2,1.9), Hispanics (OR=1.2, 95% CI=1.1,1.3), Non-Hispanic Blacks (OR=1.3, 95% CI=1.2, 1.4), and American Indians/Alaskans (OR=1.9, 95% CI=1.1, 3.4) had increased odds of IBC, while Asians (OR=0.6, 95% CI=0.6, 0.7) had decreased odds of IBC as compared to Non-Hispanic Whites. IBC may be more common among certain minority groups, including Arab American women. Understanding the descriptive epidemiology of IBC by race may generate hypotheses about risk factors for this aggressive disease. Future research should focus on etiologic factors that may explain these differences.


Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum.
The role of sodium-calcium exchange at the sarcolemma in the release of calcium from cardiac sarcoplasmic reticulum was investigated in voltage-clamped, isolated cardiac myocytes. In the absence of calcium entry through voltage-dependent calcium channels, membrane depolarization elicited release of calcium from ryanodine-sensitive internal stores. This process was dependent on sodium entry through tetrodotoxin-sensitive sodium channels. Calcium release under these conditions was also dependent on extracellular calcium concentration, suggesting a calcium-induced trigger release mechanism that involves calcium entry into the cell by sodium-calcium exchange. This sodium current-induced calcium release mechanism may explain, in part, the positive inotropic effects of cardiac glycosides and the negative inotropic effects of a variety of antiarrhythmic drugs that interact with cardiac sodium channels. In response to a transient rise of intracellular sodium, sodium-calcium exchange may promote calcium entry into cardiac cells and trigger sarcoplasmic calcium release during physiologic action potentials.


Our eclectic adventures in the slower eras of photosynthesis: from New England Down Under to biosphere 2 and beyond.
This is a tale of a career in plant physiological ecology that enjoyed the freedom to address photosynthetic physiology and biochemistry in leaves of plants from diverse environments. It was supported by block funding (now sadly a thing of the past) for research at the Australian National University, by grants during appointments in the United States and in Germany, and by Columbia University. It became a "career experiment" in which long-term, high-trust support for curiosity-driven plant biology in Australia, and at times in the United States, led to surprisingly innovative results. Although the rich diversity of short-term competitive grant opportunities in the United States sustained ongoing research, it proved difficult to mobilize support for more risky long-term projects. A decade after the closure of the Biosphere 2 Laboratory, this article highlights the achievements of colleagues in experimental climate change research from 1998 to 2003.


Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.
Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.


Role of the lateral prefrontal cortex in speech monitoring.
The role of lateral prefrontal cortex (LPFC) in speech monitoring has not been delineated. Recent work suggests that medial frontal cortex (MFC) is involved in overt speech monitoring initiated before auditory feedback. This mechanism is reflected in an event-related potential (ERP), the error negativity (Ne), peaking within 100 ms after vocal-onset. Critically, in healthy individuals the Ne is sensitive to the accuracy of the response; it is larger for error than correct trials. By contrast, patients with LPFC damage are impaired in non-verbal monitoring tasks showing no amplitude difference between the Ne measured in correct vs. error trials. Interactions between the LPFC and the MFC are assumed to play a necessary role for normal action monitoring. We investigated whether the LPFC was involved in speech monitoring to the same extent as in non-linguistic actions by comparing performance and EEG activity in patients with LPFC damage and in aged-matched controls performing linguistic (Picture Naming) and non-linguistic (Simon) tasks. Controls did not produce enough errors to allow the comparison of the Ne or other ERP in error vs. correct trials. PFC patients had worse performance than controls in both tasks, but their Ne was larger for error than correct trials only in Naming. This task-dependent pattern can be explained by LPFC-dependent working-memory requirements present in non-linguistic tasks used to study action monitoring but absent in picture naming. This suggests that LPFC may not be necessary for speech monitoring as assessed by simple picture naming. In addition, bilateral temporal cortex activity starting before and peaking around vocal-onset was observed in LPFC and control groups in both tasks but was larger for error than correct trials only in Naming, suggesting the temporal cortex is associated with on-line monitoring of speech specifically when access to lexical representations is necessary.


Fine-tuning of voltage sensitivity of the Kv1.2 potassium channel by interhelix loop dynamics.
Many proteins function by changing conformation in response to ligand binding or changes in other factors in their environment. Any change in the sequence of a protein, for example during evolution, which alters the relative free energies of the different functional conformations changes the conditions under which the protein will function. Voltage-gated ion channels are membrane proteins that open and close an ion-selective pore in response to changes in transmembrane voltage. The charged S4 transmembrane helix transduces changes in transmembrane voltage into a change in protein internal energy by interacting with the rest of the channel protein through a combination of non-covalent interactions between adjacent helices and covalent interactions along the peptide backbone. However, the structural basis for the wide variation in the V50 value between different voltage-gated potassium channels is not well defined. To test the role of the loop linking the S3 helix and the S4 helix in voltage sensitivity, we have constructed a set of mutants of the rat Kv1.2 channel that vary solely in the length and composition of the extracellular loop that connects S4 to S3. We evaluated the effect of these different loop substitutions on the voltage sensitivity of the channel and compared these experimental results with molecular dynamics simulations of the loop structures. Here, we show that this loop has a significant role in setting the precise V50 of activation in Kv1 family channels.


Gender differences in consulting a general practitioner for common symptoms of minor illness.
The aim of this paper is to examine whether, in response to the same symptoms of minor illness, women reported a greater propensity to consult a general practitioner than men. Respondents taking part in the West of Scotland Twenty-07 Study (853 aged 39 and 858 aged 58) were presented with a check-list of 33 symptoms during the course of a home interview conducted by nurses. They were asked whether they had experienced any of these symptoms in the last month, and if they had, whether they consulted a general practitioner about it. A summary indicator for reporting, or consulting for, at least one symptom was constructed, and statistical associations between gender, reporting and consulting for symptoms were examined using chi-square tests with Yates' correction. Women were more likely to have consulted a general practitioner for at least one of the 33 symptoms of minor illness reported in the previous month (34% of women, 27% of men aged 39, chi2 = 3.97, p < 0.05; 49% of women, 43% of men aged 58, chi2 = 3.21, (NS)). Women were significantly more likely to have consulted for five individual symptoms in the younger cohort, and for three symptoms in the older cohort, whilst men were significantly more likely to have consulted for only one symptom, in the younger cohort. However, when only those who had reported a symptom in the last month were included in analysis there were no gender differences in consulting for any of the 33 symptoms in the older cohort, and for just 3 symptoms in the younger cohort. These data do not support the most widely suggested explanation for gender differences in consulting, that once symptoms are perceived, women have a higher propensity to consult a general practitioner with the symptom than men.


Generation of a new adenovirus type 12-inducible fragile site by insertion of an artificial U2 locus in the human genome.
Infection with adenovirus type 12 (Ad12) induces four fragile sites in the human genome (H.F. Stich, G.L. van Hoosier, and J.J. Trentin, Exp. Cell Res. 34:400-403, 1964; H. zur Hausen, J. Virol. 1:1174-1185, 1967). The major site, at 17q21-22, contains the U2 gene cluster, which is specifically disrupted by infection in at least a percentage of the cells (D.M. Durnam, J.C. Menninger, S.H. Chandler, P.P. Smith, and J.K. McDougall, Mol. Cell. Biol. 8:1863-1867, 1988). For direct assessment of whether the U2 locus is the target of the Ad12 effect, an artificial locus, constructed in vitro and consisting of tandem arrays of the U2 6-kbp monomer, was transfected into human cells. We report that integration of this artificial locus on the p arm of chromosome 13 creates a new Ad12-inducible fragile site.


Effect of Sodium Hydroxide Treatments on the Tensile Strength and the Interphase Quality of Hemp Core Fiber-Reinforced Polypropylene Composites.
The formulation of greener composite materials by substituting glass fibers with natural fibers is a current field of research. If such natural fiber reinforcements come from industrial side streams, as hemp core fibers (HCFs) come from the extraction of hemp strands for the textile industry, an additional advantage can be identified. Nonetheless, such by-product fibers show some drawbacks, such as high lignin contents, which can make it difficult to obtain a good interphase between the fibers and the matrix and to obtain a good fiber individualization. A digestion treatment at different NaOH contents is proposed to eliminate soluble lignin and extractives from the surface of the fibers. At the same time, the use of a coupling agent solves incompatibilities between the fibers and the matrix. The composites were tensile tested and the impact of the proposed treatments is evaluated and discussed. Later, the Kelly-Tyson modified equation and a modified rule of mixtures-the micro-mechanic models-is used to study the impact of such treatments on the quality of the interphase between the polymer and the reinforcement. Both treatments showed a high impact on the tensile strength and the quality of the interphase, obtaining competitive composite materials reinforced with HCFs derived from a by-product.


Reduced Graphene Oxide-GelMA Hybrid Hydrogels as Scaffolds for Cardiac Tissue Engineering.
Biomaterials currently used in cardiac tissue engineering have certain limitations, such as lack of electrical conductivity and appropriate mechanical properties, which are two parameters playing a key role in regulating cardiac cell behavior. Here, the myocardial tissue constructs are engineered based on reduced graphene oxide (rGO)-incorporated gelatin methacryloyl (GelMA) hybrid hydrogels. The incorporation of rGO into the GelMA matrix significantly enhances the electrical conductivity and mechanical properties of the material. Moreover, cells cultured on composite rGO-GelMA scaffolds exhibit better biological activities such as cell viability, proliferation, and maturation compared to ones cultured on GelMA hydrogels. Cardiomyocytes show stronger contractility and faster spontaneous beating rate on rGO-GelMA hydrogel sheets compared to those on pristine GelMA hydrogels, as well as GO-GelMA hydrogel sheets with similar mechanical property and particle concentration. Our strategy of integrating rGO within a biocompatible hydrogel is expected to be broadly applicable for future biomaterial designs to improve tissue engineering outcomes. The engineered cardiac tissue constructs using rGO incorporated hybrid hydrogels can potentially provide high-fidelity tissue models for drug studies and the investigations of cardiac tissue development and/or disease processes in vitro.


LncRNA SNHG6 promotes proliferation, invasion and migration in colorectal cancer cells by activating TGF-β/Smad signaling pathway via targeting UPF1 and inducing EMT via regulation of ZEB1.
Background: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides in length. They drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, RNA and protein. Recent studies have identified numerous lncRNAs active in colorectal cancer (CRC). The lncRNA small nucleolar RNA host gene 6 (SNHG6) has been reported to have an oncogenic role in multiple cancers. However, the biological role and mechanism of SNHG6 in the tumorigenesis of CRC has not been reported in-deep. Methods: The Cancer Genome Atlas (TCGA) database and GEO database were used to identify SNHG6 expression in different human cancers and explore the relationship between SNHG6 expression and patient prognosis using Kaplan-Meier method analysis. SNHG6 expression in 77 pairs of clinical CRC tissues and different CRC cell lines were analyzed by quantitative real-time PCR (qRT-PCR). A CCK-8 assay was used to assess cell proliferation, transwell assay to detect the cell metastasis, and tumor growth was investigated with a nude mice model in vivo. Whether UPF1 and ZEB1 are downstream targets of SNHG6 was verified by bioinformatics target gene prediction, qRT-PCR and western blot. Results: TCGA data showed that SNHG6 was significantly upregulated in colorectal cancer samples in comparison with healthy data samples (P < 0.01). CRC patients with high levels of SNHG6 had a significantly shorter overall survival than those with low levels of SNHG6 (P = 0.0162). qRT-PCR confirmed that the expression of SNHG6 was significantly upregulated in CRC tissues and cell lines. Upregulation of SNHG6 expression induced RKO and HCT116 cell proliferation as well as RKO cell metastasis, while downregulation of SNHG6 expression supressed the proliferation and metastasis of RKO cells and tumor growth in vivo. UPF1 was upregulated and ZEB1 was decreased when SNHG6 knockdown, regulating the TGF-β/Smad pathway and inducing EMT respectively. Conclusions: SNHG6 may play an oncogenic role in CRC cells by activating TGF-β/Smad signaling pathway via targeting of UPF1 and inducing EMT via regulating ZEB1. This could be a prognostic biomarker and therapeutic target for CRC.


Registry-based outcome assessment in haemophilia: a scoping study to explore the available evidence.
Haemophilia is a congenital disorder with bleeding episodes as its primary symptom. These episodes can result in negative outcomes including joint damage, loss of active days due to hospitalization and reduced quality of life. Effective treatment, however, can improve the outcome. Registries have been used as a valuable source of information regarding the monitoring of treatment and outcome. The two main aims of this exploratory study were to establish which haemophilia registries publish peer-reviewed outcome assessment research and then to extract, classify and report the treatment outcomes and their extent of use in the retrieved registries. Using relevant keywords, we searched PubMed and Web of Science databases for publications during the period 1990-2015. Retrieved references were screened in a stepwise process. Eligible papers were original full articles on haemophilia outcomes that used data from a computerized patient database. Descriptive results were summarized. Of 2352 references reviewed, 25 full texts were eligible for inclusion in the study. These papers were published by 11 registries ranging from local to international in coverage. It is still relatively rare for registries to produce peer-reviewed publications about outcomes, and most that currently do produce such papers are located in Europe and North America. More information is available on traditional outcomes such as comorbidities and arthropathy than on health-related quality of life or the social and developmental impact of haemophilia on patients. Inhibitors, HIV and viral hepatitis are amongst the most commonly reported comorbidities. Research has focused more on factor consumption and less on hospitalization or time lost at school or work due to haemophilia. Haemophilia registries, especially those at the national level, are valuable resources for the delivery of effective health care to patients. Validated outcome measurement instruments are essential for the production of reliable and accurate evidence. Finally, such evidence should be communicated to physicians, patients, the public and health policymakers.


Virulence Characteristics and an Action Mode of Antibiotic Resistance in Multidrug-Resistant Pseudomonas aeruginosa.
Pseudomonas aeruginosa displays intrinsic resistance to many antibiotics and known to acquire actively genetic mutations for further resistance. In this study, we attempted to understand genomic and transcriptomic landscapes of P. aeruginosa clinical isolates that are highly resistant to multiple antibiotics. We also aimed to reveal a mode of antibiotic resistance by elucidating transcriptional response of genes conferring antibiotic resistance. To this end, we sequenced the whole genomes and profiled genome-wide RNA transcripts of three different multi-drug resistant (MDR) clinical isolates that are phylogenetically distant from one another. Multi-layered genome comparisons with genomes of antibiotic-susceptible P. aeruginosa strains and 70 other antibiotic-resistance strains revealed both well-characterized conserved gene mutations and distinct distribution of antibiotic-resistant genes (ARGs) among strains. Transcriptions of genes involved in quorum sensing and type VI secretion systems were invariably downregulated in the MDR strains. Virulence-associated phenotypes were further examined and results indicate that our MDR strains are clearly avirulent. Transcriptions of 64 genes, logically selected to be related with antibiotic resistance in MDR strains, were active under normal growth conditions and remained unchanged during antibiotic treatment. These results propose that antibiotic resistance is achieved by a "constitutive" response scheme, where ARGs are actively expressed even in the absence of antibiotic stress, rather than a "reactive" response. Bacterial responses explored at the transcriptomic level in conjunction with their genome repertoires provided novel insights into (i) the virulence-associated phenotypes and (ii) a mode of antibiotic resistance in MDR P. aeruginosa strains.


Activating Electroluminescence of Charged Naphthalene Diimide Complexes Directly Adsorbed on a Metal Substrate.
Electroluminescence from single molecules adsorbed on a conducting surface imposes conflicting demands for the molecule-electrode coupling. To conduct electrons, the molecular orbitals need to be hybridized with the electrodes. To emit light, they need to be decoupled from the electrodes to prevent fluorescence quenching. Here, we show that fully quenched 2,6-core-substituted naphthalene diimide derivative in a self-assembled monolayer directly deposited on a Au(111) surface can be activated with the tip of a scanning tunneling microscope to decouple the relevant frontier orbitals from the metallic substrate. In this way, individual molecules can be driven from a strongly hybridized state with quenched luminescence to a light-emitting state. The emission performance compares in terms of quantum efficiency, stability, and reproducibility to that of single molecules deposited on thin insulating layers. Quantum chemical calculations suggest that the emitted light originates from the singly charged cationic pair of the molecules.


Long-term diabetes alters the hepatobiliary clearance of acetaminophen, bilirubin and digoxin.
The effect of insulin-dependent diabetes on hepatobiliary clearance of acetaminophen, bilirubin and digoxin was determined using Sprague-Dawley rats that were treated with a 45 mg/kg dose of streptozotocin 28 days before experimentation. Urinary excretion of acetaminophen was increased 280%, whereas biliary excretion was decreased 65% and total clearance was unchanged. Both steady-state volume of distribution and elimination half-life of acetaminophen were decreased in diabetic rats by 23 and 25%, respectively. Biliary excretion of glucuronide and sulfate conjugates was decreased by 75 and 50%, respectively, whereas parent acetaminophen excretion was unchanged. The glutathione conjugate was only detected in normal and insulin-treated rats; however, comparable levels of a cysteine conjugate were detected in bile of diabetic rats. Administration of insulin reversed the hyperglycemia and the changes in volume of distribution, elimination half-life and glutathione excretion. Other diabetes-induced alterations were unchanged. In contrast, digoxin plasma disappearance, volume of distribution and total clearance were significantly increased in diabetic rats, whereas the elimination half-life was decreased. Administration of insulin reversed the changes in serum disappearance and partially reversed the increased biliary excretion of digoxin. No differences were observed for the serum disappearance, glucuronidation or biliary excretion of bilirubin in diabetic vs. normal rats. These data indicate that insulin deficiency for 1 month can alter hepatic excretory function and the pharmacokinetics of commonly used drugs.


Polymorphism analyses and protein modelling inform on functional specialization of Piwi clade genes in the arboviral vector Aedes albopictus.
Current knowledge of the piRNA pathway is based mainly on studies on Drosophila melanogaster where three proteins of the Piwi subclade of the Argonaute family interact with PIWI-interacting RNAs to silence transposable elements in gonadal tissues. In mosquito species that transmit epidemic arboviruses such as dengue and chikungunya viruses, Piwi clade genes underwent expansion, are also expressed in the soma and cross-talk with proteins of recognized antiviral function cannot be excluded for some Piwi proteins. These observations underscore the importance of expanding our knowledge of the piRNA pathway beyond the model organism D. melanogaster. Here we focus on the emerging arboviral vector Aedes albopictus and we couple traditional approaches of expression and adaptive evolution analyses with most current computational predictions of protein structure to study evolutionary divergence among Piwi clade proteins. Superposition of protein homology models indicate possible high structure similarity among all Piwi proteins, with high levels of amino acid conservation in the inner regions devoted to RNA binding. On the contrary, solvent-exposed surfaces showed low conservation, with several sites under positive selection. Analysis of the expression profiles of Piwi transcripts during mosquito development and following infection with dengue serotype 1 or chikungunya viruses showed a concerted elicitation of all Piwi transcripts during viral dissemination of dengue viruses while maintenance of infection relied on expression of primarily Piwi5. Opposite, establishment of persistent infection by chikungunya virus is accompanied by increased expression of all Piwi genes, particularly Piwi4 and, again, Piwi5. Overall these results are consistent with functional specialization and a general antiviral role for Piwi5. Experimental evidences of sites under positive selection in Piwi1/3, Piwi4 and Piwi6, that have complex expression profiles, provide useful knowledge to design tailored functional experiments.


Transcriptomic Profiling of Adipose Derived Stem Cells Undergoing Osteogenesis by RNA-Seq.
Adipose-derived stromal/stem cells (ASCs) are multipotent in nature that can be differentiated into various cells lineages such as adipogenic, osteogenic, and chondrogenic. The commitment of a cell to differentiate into a particular lineage is regulated by the interplay between various intracellular pathways and their resultant secretome. Similarly, the interactions of cells with the extracellular matrix (ECM) and the ECM bound growth factors instigate several signal transducing events that ultimately determine ASC differentiation. In this study, RNA-sequencing (RNA-Seq) was performed to identify the transcriptome profile of osteogenic induced ASCs to understand the associated genotype changes. Gene ontology (GO) functional annotations analysis using Database for Annotation Visualization and Integrated Discovery (DAVID) bioinformatics resources on the differentially expressed genes demonstrated the enrichment of pathways mainly associated with ECM organization and angiogenesis. We, therefore, studied the expression of genes coding for matrisome proteins (glycoproteins, collagens, proteoglycans, ECM-affiliated, regulators, and secreted factors) and ECM remodeling enzymes (MMPs, integrins, ADAMTSs) and the expression of angiogenic markers during the osteogenesis of ASCs. The upregulation of several pro-angiogenic ELR+ chemokines and other angiogenic inducers during osteogenesis indicates the potential role of the secretome from differentiating ASCs in the vascular development and its integration with the bone tissue. Furthermore, the increased expression of regulatory genes such as CTNNB1, TGBR2, JUN, FOS, GLI3, and MAPK3 involved in the WNT, TGF-β, JNK, HedgeHog and ERK1/2 pathways suggests the regulation of osteogenesis through interplay between these pathways. The RNA-Seq data was also validated by performing QPCR on selected up- and down-regulated genes (COL10A1, COL11A1, FBLN, FERMT1, FN1, FOXF1, LAMA3, LAMA4, LAMB1, IGF1, WNT10B, MMP1, MMP3, MMP16, ADAMTS6, and ADAMTS14).


Multisensory warning signals: when spatial correspondence matters.
We report a study designed to investigate the effectiveness of task-irrelevant unimodal and bimodal audiotactile stimuli in capturing a person's spatial attention away from a highly perceptually demanding central rapid serial visual presentation (RSVP) task. In "Experiment 1", participants made speeded elevation discrimination responses to peripheral visual targets following the presentation of auditory stimuli that were either presented alone or else were paired with centrally presented tactile stimuli. The results showed that the unimodal auditory stimuli only captured spatial attention when participants were not performing the RSVP task, while the bimodal audiotactile stimuli did not result in any performance change in any of the conditions. In "Experiment 2", spatial auditory stimuli were either presented alone or else were paired with a tactile stimulus presented from the same direction. In contrast to the results of "Experiment 1", the bimodal audiotactile stimuli were especially effective in capturing participants' spatial attention from the concurrent RSVP task. These results therefore provide support for the claim that auditory and tactile stimuli should be presented from the same direction if they are to capture attention effectively. Implications for multisensory warning signal design are discussed.


An automated homology-based approach for identifying transposable elements.
Transposable elements (TEs) are mobile sequences found in nearly all eukaryotic genomes. They have the ability to move and replicate within a genome, often influencing genome evolution and gene expression. The identification of TEs is an important part of every genome project. The number of sequenced genomes is rapidly rising, and the need to identify TEs within them is also growing. The ability to do this automatically and effectively in a manner similar to the methods used for genes is of increasing importance. There exist many difficulties in identifying TEs, including their tendency to degrade over time and that many do not adhere to a conserved structure. In this work, we describe a homology-based approach for the automatic identification of high-quality consensus TEs, aimed for use in the analysis of newly sequenced genomes. We describe a homology-based approach for the automatic identification of TEs in genomes. Our modular approach is dependent on a thorough and high-quality library of representative TEs. The implementation of the approach, named TESeeker, is BLAST-based, but also makes use of the CAP3 assembly program and the ClustalW2 multiple sequence alignment tool, as well as numerous BioPerl scripts. We apply our approach to newly sequenced genomes and successfully identify consensus TEs that are up to 99% identical to manually annotated TEs. While TEs are known to be a major force in the evolution of genomes, the automatic identification of TEs in genomes is far from mature. In particular, there is a lack of automated homology-based approaches that produce high-quality TEs. Our approach is able to generate high-quality consensus TE sequences automatically, requiring the user to only provide a few basic parameters. This approach is intentionally modular, allowing researchers to use components separately or iteratively. Our approach is most effective for TEs with intact reading frames. The implementation, TESeeker, is available for download as a virtual appliance, while the library of representative TEs is available as a separate download.


Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial.
Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain. To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects. Pragmatic, 12-month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized. Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function. Each intervention had its own prescribing strategy that included multiple medication options in 3 steps. In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response. The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale). For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient-reported checklist; range, 0-19). Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, -0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]). Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. clinicaltrials.gov Identifier: NCT01583985.


Prediction of prostate cancer for patients receiving finasteride: results from the Prostate Cancer Prevention Trial.
Using data from men in the finasteride group of the Prostate Cancer Prevention Trial (PCPT), we evaluated the impact of prostate-specific antigen (PSA) and other risk factors on the risk of prostate cancer. Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate biopsy, had at least one PSA and a digital rectal exam (DRE) during the year before biopsy, had at least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA evaluation. Logistic regression was conducted using the variables age, race, family history of prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy. Six hundred forty-nine (14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included high PSA value and a rising PSA (24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age. Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of prostate cancer and high-grade prostate cancer. Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age, race, family history, and history of a prior negative biopsy. With the exception of the approximate reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do not receive finasteride.


Online social networking and addiction--a review of the psychological literature.
Social Networking Sites (SNSs) are virtual communities where users can create individual public profiles, interact with real-life friends, and meet other people based on shared interests. They are seen as a 'global consumer phenomenon' with an exponential rise in usage within the last few years. Anecdotal case study evidence suggests that 'addiction' to social networks on the Internet may be a potential mental health problem for some users. However, the contemporary scientific literature addressing the addictive qualities of social networks on the Internet is scarce. Therefore, this literature review is intended to provide empirical and conceptual insight into the emerging phenomenon of addiction to SNSs by: (1) outlining SNS usage patterns, (2) examining motivations for SNS usage, (3) examining personalities of SNS users, (4) examining negative consequences of SNS usage, (5) exploring potential SNS addiction, and (6) exploring SNS addiction specificity and comorbidity. The findings indicate that SNSs are predominantly used for social purposes, mostly related to the maintenance of established offline networks. Moreover, extraverts appear to use social networking sites for social enhancement, whereas introverts use it for social compensation, each of which appears to be related to greater usage, as does low conscientiousness and high narcissism. Negative correlates of SNS usage include the decrease in real life social community participation and academic achievement, as well as relationship problems, each of which may be indicative of potential addiction.


Molecular structure of yeast RNA polymerase III: demonstration of the tripartite transcriptive system in lower eukaryotes.
Homogeneous RNA polymerase III (RNA nucleotidyltransferase III) has been obtained from yeast. The subunit composition of the enzyme was examined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The enzyme is composed of 12 putative subunits with molecular weights 160,000, 128,000, 82,000, 41,000, 40,500, 37,000, 34,000, 28,000, 24,000, 20,000, 14,500, and 11,000. The high-molecular-weight subunits and several of the smaller subunits of yeast RNA polymerase III are clearly different from those of enzymes I and II, indicating a distinct molecular structure. However, the molecular weights of some of the small subunits (41,000, 28,000, 24,000, and 14,500) appear to be identical to those of polymerases I and II. Thus, it is possible that the three classes of enzymes in yeast have some common subunits. As in other eukaryotes, yeast polymerase II is inhibited by relatively low concentrations of alpha-amanitin; however, contrary to what has been found in higher eukaryotes, yeast polymerase III is resistant (up to 2 mg/ml) to alpha-amanitin, while yeast polymerase I is sensitive to high concentrations of the drug (50% inhibition at 0.3 mg/ml). These results establish the existence of RNA polymerase III in yeast and provide a structural basis for the discrimination of the three functional polymerases in eukaryotes.


Detection and quantification of airborne norovirus during outbreaks in healthcare facilities.
Noroviruses are responsible for at least 50% of all gastroenteritis outbreaks worldwide. Noroviruses GII can infect humans via multiple routes including direct contact with an infected person, fecal matter, or vomitus, and contact with contaminated surfaces. Although norovirus is an intestinal pathogen, aerosols could, if inhaled, settle in the pharynx and later be swallowed. The aims of this study were to investigate the presence of norovirus GII bioaerosols during gastroenteritis outbreaks in healthcare facilities and to study the in vitro effects of aerosolization and air sampling on the noroviruses using murine norovirus as a surrogate. A total of 48 air samples were collected during norovirus outbreaks in 8 healthcare facilities. Samples were taken 1 m away from each patient, in front of the patient's room and at the nurses' station. The resistance to aerosolization stress of murine norovirus type 1 (MNV-1) bioaerosols was also tested in vitro using an aerosol chamber. Norovirus genomes were detected in 6 of 8 healthcare centers. The concentrations ranged from 1.35 × 10(1) to 2.35 × 10(3) genomes/m(3) in 47% of air samples. MNV-1 preserved its infectivity and integrity during in vitro aerosol studies. Norovirus genomes are frequently detected in the air of healthcare facilities during outbreaks, even outside patients' rooms. In addition, in vitro models suggest that this virus may withstand aerosolization.


Municipal solid waste management scenarios for Attica and their greenhouse gas emission impact.
Disposal of municipal solid waste in sanitary landfills is still the main waste management method in the Attica region, as in most regions of Greece. Nevertheless, diversion from landfilling is being promoted by regional plans, in which the perspectives of new waste treatment technologies are being evaluated. The present study aimed to assess the greenhouse gas (GHG) emissions impact of different municipal solid waste treatment technologies currently under assessment in the new regional plan for Attica. These technologies are mechanical-biological treatment, mass-burn incineration and mechanical treatment and have been assessed in the context of different scenarios. The present study utilized existing methodologies and emission factors for the quantification of GHG emissions from the waste management process and found that all technologies under assessment could provide GHG emission savings. However, the performance and ranking of these technologies is strongly dependent on the existence of end markets for the waste-derived fuels produced by the mechanical-biological treatment processes. In the absence of these markets the disposal of these fuels would be necessary and thus significant GHG savings would be lost.


Inhibition and avoidance of mRNA degradation by RNA viruses.
The cellular mRNA decay machinery plays a major role in regulating the quality and quantity of gene expression in cells. This machinery involves multiple enzymes and pathways that converge to promote the exonucleolytic decay of mRNAs. The transcripts made by RNA viruses are susceptible to degradation by this machinery and, in fact, can be actively targeted. Thus, to maintain gene expression and replication, RNA viruses have evolved a number of strategies to avoid and/or inactivate aspects of the cellular mRNA decay machinery. Recent work uncovering the mechanisms used by RNA viruses to maintain the stability of their transcripts is described below.


Clinico-hematological profile and natural history of childhood myelodysplastic syndromes.
The clinical and hematological characteristics of ten children with myelodysplastic syndromes diagnosed and followed up over a 3 year period are presented. All of them had anemia and a low platelet count whilst the white blood cell count was variable. Presentation with bilateral proptosis and acute febrile neutrophilic dermatosis (Sweet's syndrome) were unique features observed in one case each. None of these cases could afford specific therapy and thus serve to illustrate the natural history of the disease in pediatric practice.


Effect of eye trauma on mental health and quality of life in children and adolescents.
The purpose of this study is to evaluate the effects of eye traumas on mental health and quality of life of children, adolescents, and their parents. Medical records of 20 children and adolescents presented with blunt and open eye injuries between June 2009 and May 2014 were reviewed. Demographics of patients, timing and type of trauma, findings of initial examination, and medical and surgical interventions applied were recorded. To detect mental health, "Affect disorders and schizophrenia interview chart for school children, now and lifelong" (AFSIC-NL) and "Child Post-Traumatic Stress Reaction Index (CPTSD-RI)" were used. "Pediatric scale of quality of life" (PedsQL) was used to assess quality of life for both parents and children. According to AFSIC-NL, 9 patients were diagnosed with mental disorders including posttraumatic stress disorder (n = 3, 15 % patients), generalized anxiety disorder (n = 3, 15 % patients), and major depression (n = 3, 15 % patients). The PedsQL values of both children's and parents' were at their lowest in school and physical health domains for children and in physical health domain for parents. A reverse correlation was detected between the number of surgeries and PedsQL-child physical functionality, school functionality, psychosocial functionality, and total scale point. There was a statistically significant relationship between initial visual acuity or lens damage and PedsQL-parent emotional functionality scale. Regarding CPTSD-RI, the parents of these patients have a mild posttraumatic stress disorder. Eye injuries can lead development of psychopathology in children. Therefore, psychiatric support must be provided in follow-up period for these patients.


A 3D adult zebrafish brain atlas (AZBA) for the digital age.
Zebrafish have made significant contributions to our understanding of the vertebrate brain and the neural basis of behavior, earning a place as one of the most widely used model organisms in neuroscience. Their appeal arises from the marriage of low cost, early life transparency, and ease of genetic manipulation with a behavioral repertoire that becomes more sophisticated as animals transition from larvae to adults. To further enhance the use of adult zebrafish, we created the first fully segmented three-dimensional digital adult zebrafish brain atlas (AZBA). AZBA was built by combining tissue clearing, light-sheet fluorescence microscopy, and three-dimensional image registration of nuclear and antibody stains. These images were used to guide segmentation of the atlas into over 200 neuroanatomical regions comprising the entirety of the adult zebrafish brain. As an open source, online (azba.wayne.edu), updatable digital resource, AZBA will significantly enhance the use of adult zebrafish in furthering our understanding of vertebrate brain function in both health and disease.


Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors.
Identifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment. Twenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted "detected <12IU/ml" or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR. According to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively. HCV RNA "not detected" by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.


Oesophageal corrosive injuries in children: a forgotten social and health challenge in developing countries.
An unsafe environment is a risk factor for child injury and violence. Among those injuries that are caused by an unsafe environment, the accidental ingestion of corrosive substances is significant, especially in developing countries where it is generally underreported. To address this challenging, unmet medical need, we started a humanitarian programme in Sierra Leone. By reviewing the current literature from developing countries and our own experience in the field, we developed a flowchart for management of this clinical condition. This injury is underreported in developing countries. Data available are heavily skewed towards well-resourced centres and do not reflect the entire reality of the condition. Late oesophageal strictures are usually severe. Parent's lack of knowledge, crowded living conditions and availability of chemicals in and around houses account for most ingestions. The widespread lack of any preventive measures represents the strongest risk factor. Timely admission was observed in 19.5% of 148 patients studied. A gastrostomy was performed on 62.1% of patients, 42.8% had recurrent strictures and 19% are still on a continuous dilatation programme. Perforation and death rate were respectively 5.6% and 4%. The majority of oesophageal caustic strictures in children are observed late, when dilatation procedures are likely to be more difficult and carry a significantly higher recurrence rate. Gastrostomy is necessary to maintain adequate nutritional status but mothers need training in feeding techniques. Both improvement in nutritional status and sustained oesophageal patency should be the reference points to a successful dilatation.


Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor.
Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.


Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis.
Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn's disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model. The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm (2); delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4 (+) T cells, percentage of apoptotic CD4 (+) T cells, body weight, and systemic side effects were evaluated. LDPDT improved the MEIC ( P = 0.011) and the histological score ( P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 ( P = 0.042), interleukin-17 ( P = 0.029), and interferon-gamma ( P = 0.014), decreased the number of mucosal CD4 (+) T cells, and increased the percentage of apoptotic CD4 (+) T cells compared with the disease control group. No local or systemic side effects occurred. LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4 (+) T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.


Adaptive steered molecular dynamics: validation of the selection criterion and benchmarking energetics in vacuum.
The potential of mean force (PMF) for stretching decaalanine in vacuum was determined earlier by Park and Schulten [J. Chem. Phys. 120, 5946 (2004)] in a landmark article demonstrating the efficacy of combining steered molecular dynamics and Jarzynski's nonequilibrium relation. In this study, the recently developed adaptive steered molecular dynamics (ASMD) algorithm [G. Ozer, E. Valeev, S. Quirk, and R. Hernandez, J. Chem. Theory Comput. 6, 3026 (2010)] is used to reproduce the PMF of the unraveling of decaalanine in vacuum by averaging over fewer nonequilibrium trajectories. The efficiency and accuracy of the method are demonstrated through the agreement with the earlier work by Park and Schulten, a series of convergence checks compared to alternate SMD pulling strategies, and an analytical proof. The nonequilibrium trajectories obtained through ASMD have also been used to analyze the intrapeptide hydrogen bonds along the stretching coordinate. As the decaalanine helix is stretched, the initially stabilized i → i + 4 contacts (α-helix) is replaced by i → i + 3 contacts (3(10)-helix). No significant formation of i → i + 5 hydrogen bonds (π-helix) is observed.


Elastic guided waves in helical multi-wire armors.
In this paper, a numerical method is proposed to investigate the propagation of elastic guided waves in the armors protecting cylindrical structures, such as cables and pipes, and evaluate the feasibility of using these waves in the context of non-destructive evaluation and structural health monitoring. Armors usually consist of a large number of helical wires in contact with polymeric sheaths surrounding the structure. The numerical method combines a semi-analytical finite element method written in twisting coordinates, which accounts for the continuous screw symmetry of the problem along the structure axis, with rotational Bloch conditions in the cross-section in order to account for the high order of the discrete circular symmetry. The proposed formulation allows the initial three-dimensional problem to be reduced to a two-dimensional unit cell involving only one wire, well suited for fast computations of contact problems and dispersion curves. The existence of wave modes along the two directions (screw axis and circumferential direction) is justified from a theoretical point of view by considering the metric tensor of a mixed twisting-polar coordinate system. Numerical results are presented for a typical armor of power cable, focusing on longitudinal waves propagating predominantly inside the wires. The internal part of the cable is approximated as a homogenized medium to preserve the continuous screw symmetry of the problem. A comparison with experimental measurements is carried out. The results show that the modal velocity of longitudinal waves behaves as in a single free wire above a limit frequency identified by the model. This is not the case of modal attenuation, always greater in the armor due to mechanical contact with the viscoelastic sheaths. Two modes of potential interest for the non-destructive evaluation of armors are identified. The influence of mechanical contacts on wave propagation in armors is finally discussed, including interwire contact.


Microcomputed Assessment of Transportation, Centering Ratio, Canal Area, and Volume Increase after Single-file Rotary and Reciprocating Glide Path Instrumentation in Curved Root Canals: A Laboratory Study.
The aim of this study was to compare the transportation and centering abilities of the ProGlider (PG; Dentsply-Sirona, Ballaigues, Switzerland), WaveOne Gold Glider (WOGG; Dentsply-Sirona), and R-Pilot (RP; VDW, Munich, Germany) file systems and the changes in the structure model index (SMI), surface area, and root canal volume (after creating the glide path in the mandibular first molar teeth's mesial canals with moderate curvature) using the micro-computed tomographic (micro-CT) method. In the present study, 24 mandibular first molar teeth with 2 separate mesial canals and moderate (10°-20°) curvature were used. After scanning with micro-CT imaging before the procedure, the teeth were divided into 3 groups, PG, WOGG, and RP (n = 10/each group), followed by the glide path procedure. After the root canal preparation, changes in the root canals regarding the volume, surface area, SMI, transportation made by the files, and the change of their centering ability in the apical, middle, and coronal third were analyzed by micro-CT imaging. The data were statistically evaluated using 1-way analysis of variance and the Kruskal-Wallis test with a significance level set at 5% (P < .05). The WOGG and RP file systems showed better centering abilities at all thirds compared with the PG file system (P < .05). No significant difference was found in the apical third between the groups in terms of canal transportation degree (P > .05). However, in the WOGG and RP groups, less transportation was observed in the middle and coronal thirds compared with the PG group (P < .05). When the SMI changed, after the root canal preparation was compared, no significant differences were found between the groups (P > .05). Nevertheless, the changes in volume and surface area of the root canal in the WOGG and RP groups were significantly lower than in the PG group (P < .05). The WOGG and RP file systems caused similar levels of change in the root canal systems based on all parameters. Moreover, it was determined that the PG file system caused a significantly higher volume and surface area increase than the WOGG and RP file systems.


Seroprevalence of human immunodeficiency virus-1, hepatitis B virus, and hepatitis C virus in patients having major surgery.
To determine the proportion of major surgical procedures that involve patients having serologic evidence of infection with human immunodeficiency virus-1 (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) in a single center in Westchester County, New York. Blood samples sent for transfusion screening or cross-match were tested blindly for HIV antibody (anti-HIV), HBV core antibody, HBV surface antigen (HBsAg), and HCV antibody (anti-HCV). Demographic characteristics and operation category were correlated with serologic results by univariate and regression analyses. Of 1,062 operations evaluated, 71 (6.7%, 95% confidence interval [CI95], 5.2% to 8.4%) were performed on patients with either anti-HIV, HBsAg, or anti-HCV. In 17 (1.6%, CI95, .93% to 2.5%) of these operations, the patient evidenced anti-HIV; in 15 (1.4%; CI95, .79% to 2.3%), HBsAg; and in 55 (5.2%, CI95, 3.9% to 6.7%), anti-HCV. Anti-HCV was detected significantly more often than anti-HIV (5.2% versus 1.6%, P < .001) or HBsAg (5.2% versus 1.4%, P < .001). Operations involving women aged 25 to 44 years had the highest proportion with serologic evidence of at least one of the three viruses (17.2%); of anti-HCV (15.3%); and of anti-HIV (6.7%). Logistic regression analysis found that being in the 25- to 44-year age group was associated significantly with infection with any virus (P < .001) and with anti-HCV (P < .001). The strongest logistic predictors of anti-HIV seropositivity were having anti-HCV seropositivity (P < .001), being age 25 to 44 years (P < .001), and having a general surgery operation (P = .002). The prevalences of serologic evidence of at least one of the three viruses (16.7%), of anti-HCV (14.5%), and of anti-HIV (5.6%) are high in patients aged 25 to 44 years undergoing major surgery at a tertiary-care medical center located in Westchester County, New York. Anti-HCV is more prevalent than anti-HIV or HBsAg and is predictive of anti-HIV seropositivity. Testing for anti-HIV alone would have detected only 24% of patients infected with a bloodborne pathogen. These data strongly underscore the importance of universal precautions.


Multivariate Analysis of Two-Dimensional 1H, 13C Methyl NMR Spectra of Monoclonal Antibody Therapeutics To Facilitate Assessment of Higher Order Structure.
Two-dimensional (2D) 1H-13C methyl NMR provides a powerful tool to probe the higher order structure (HOS) of monoclonal antibodies (mAbs), since spectra can readily be acquired on intact mAbs at natural isotopic abundance, and small changes in chemical environment and structure give rise to observable changes in corresponding spectra, which can be interpreted at atomic resolution. This makes it possible to apply 2D NMR spectral fingerprinting approaches directly to drug products in order to systematically characterize structure and excipient effects. Systematic collections of NMR spectra are often analyzed in terms of the changes in specifically identified peak positions, as well as changes in peak height and line widths. A complementary approach is to apply principal component analysis (PCA) directly to the matrix of spectral data, correlating spectra according to similarities and differences in their overall shapes, rather than according to parameters of individually identified peaks. This is particularly well-suited for spectra of mAbs, where some of the individual peaks might not be well resolved. Here we demonstrate the performance of the PCA method for discriminating structural variation among systematic sets of 2D NMR fingerprint spectra using the NISTmAb and illustrate how spectral variability identified by PCA may be correlated to structure.


Long-term results after accessory renal artery coverage during endovascular aortic aneurysm repair.
Current information regarding coverage of accessory renal arteries (ARAs) during endovascular aneurysm repair (EVAR) is based on small case series with limited follow-up. This study evaluates the outcomes of ARA coverage in a large contemporary cohort. Consecutive EVAR data from January 2004 to August 2010 were collected in a prospective database at a University Hospital. Patient and aneurysm-related characteristics, imaging studies, and ARA coverage versus preservation were analyzed. Volumetric analysis of three-dimensional reconstruction computed tomography scans was used to assess renal infarction volume extent. Long-term renal function and overall technical success of aneurysm exclusion were compared. A cohort of 426 EVARs was identified. ARAs were present in 69 patients with a mean follow-up of 27 months (range, 1 to 60 months). Forty-five ARAs were covered in 40 patients; 29 patients had intentional ARA preservation. Patient and anatomic characteristics were similar between groups except that ARA coverage patients had shorter aneurysm necks (P = .03). Renal infarctions occurred in 84% of kidneys with covered ARAs. There was no significant deterioration in long-term glomerular filtration rate when compared with patients in the control group. No difference in the rate of endoleak, secondary procedures, or the requirement for antihypertensive medications was found. This study is the largest to date with the longest follow-up relating to ARA coverage. Contrary to previous reports, renal infarction after ARA coverage is common. Nevertheless, coverage is well tolerated based upon preservation of renal function without additional morbidity. These results support the long-term safety of ARA coverage for EVAR when necessary.


Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.
Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.


Five-year risks of CIN 2+ and CIN 3+ among women with HPV-positive and HPV-negative LSIL Pap results.
Low-grade squamous intraepithelial lesion (LSIL) Pap results do not typically lead to human papillomavirus (HPV) testing. HPV triage is not cost-effective because most cases are HPV-positive. However, under new national guidelines recommending cotesting for women aged 30 to 64 years, clinicians will increasingly receive the HPV test result with LSIL Pap results. Some authors have suggested that HPV triage might be effective at older ages, when the percentage of HPV positivity among women with LSIL declines. We estimated 5-year risks of CIN 2+ and CIN 3+ among 9,033 women aged 30 to 64 years who had both an HPV test and an LSIL Pap result. HPV positivity among women with LSIL decreased only slightly with age (30 to 34 vs 60 to 64 years, 88% vs 72%, p < .0001). The 5-year risks of CIN 2+ and CIN 3+ of women aged 30 to 64 years testing HPV-positive/LSIL were larger than those among women testing HPV-negative/LSIL (CIN 2+, 19% vs 5.1%, p < .0001; CIN 3+, 6.1% vs 2.0%, p<.0001). The 5-year risk of CIN 3+ in HPV-negative/LSIL women was similar to that for women with atypical squamous cells of undetermined significance (ASC-US) Pap test result without knowledge of HPV test results (2.0% vs 2.6%, p = .4). HPV-negative/LSIL posed lower risk than other Pap results that guidelines currently recommend for referral to immediate colposcopy. By the principle of "equal management of equal risks," women with HPV-negative/LSIL might reasonably be managed similarly to those with ASC-US Pap results without knowledge of HPV testing, that is, retesting at 6 to 12 months, rather than immediate colposcopy. Although the HPV test result for LSIL Pap results provides actionable information to clinicians who screen with cotesting, the high HPV positivity of LSIL at even the oldest ages suggests the lack of cost-effectiveness of HPV triage of LSIL for clinicians who do not use routine cotesting.


γ-Secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines.
This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angiogenesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression during CNV.


Fungal Rhinosinusitis: Microbiological and Histopathological Perspective.
On the basis of histopathology Fungal Rhinosinusitis (FRS) is categorized into non-invasive (allergic fungal rhinosinusitis, fungal ball) and invasive (acute invasive, chronic invasive and granulomatous invasive fungal sinusitis). This differentiation helps to decide the treatment. Role of latest molecular methods such as PCR and conventional methods such as KOH microscopy and culture also needs to be evaluated. Therefore, in this study we planned to categorise fungal rhinosinusitis on the basis of histopathology and compare it with other methods such as PCR, culture and KOH microscopy. To analyse fungal rhinosinusitis cases by both histopathologically and microbiologically. A total of 76 clinically suspected fungal rhinosinusitis cases were included in the study. The tissue of suspected cases were processed and examined by KOH microscopy, histopathologically, culture and PCR. Histopathological examination was done by PAS, GMS and H&E stain. FRS was diagnosed in 37 (48.68%) cases out of 76 clinically suspected cases of FRS. In which 17 (22.3%) cases were positive by direct microscopy, 21 (27.6%) by culture, 27 (35.5%) by PCR and 14 (18.42%) by histopathology. Approximately 14 cases of FRS were classified according to histopathology; 10 (71.3%) as non-invasive FRS. Out of these 10, 9 (64.2%) were classified as AFRS and 1 (7.14%) as fungal ball. Only 4 cases (28.5%) were diagnosed with invasive FRS. Out of these 4 cases, 2 (14.2%) were of chronic invasive fungal rhinosinusitis, 1 (7.14%) was of granulomatous invasive fungal rhinosinusitis and 1 (7.14%) was of acute fulminant invasive fungal rhinosinusitis. Allergic Fungal Rhinosinusitis (AFRS) is the most common type of FRS. Aspergillus flavus was found to be the most common fungi causing FRS. Diagnosis should not be based on the single method. It should be done by both histopathological and microbiological methods, especially for those cases which are difficult to diagnose.


Reconstructed structures of nanosized co islands on Ag/Ge(111) mean square root of 3 x mean square root of 3 surfaces.
Structural evolution of Co/Ag/Ge(111) at high temperatures was studied by using scanning tunneling microscopy and low energy electron diffraction. The mean square root of 3 x mean square root of 3-Ag layer between the substrate Ge( 11) and Co adatoms can avoid the formation of Co-Ge compounds below 800 K. The Co atoms nucleate to form islands where mean square root of 13 x mean square root of 13 or 2 x 2 reconstructions were observed after annealing between 373 K and 737 K. The mean square root of 13 x mean square root of 13 structure with mirror symmetry relative to [-211], [11-2], and [1-21] axes was observed for 1-2 layer Co islands. Co islands with over 2 layers appear 2 x 2 structure. All reconstruction structures of the nano-sized Co islands and substrate Ag/Ge(111) mean square root of 3 x mean square root of 3 surface were analyzed using the atomic hard sphere model. The bright protrusions of these reconstructions all sit in the centers of Ag or Ge trimers, which were predicted to have maximum binding energy.


Shortening the 'short-course' therapy- insights into host immunity may contribute to new treatment strategies for tuberculosis.
Achieving global control of tuberculosis (TB) is a great challenge considering the current increase in multidrug resistance and mortality rate. Considerable efforts are therefore being made to develop new effective vaccines, more effective and rapid diagnostic tools as well as new drugs. Shortening the duration of TB treatment with revised regimens and modes of delivery of existing drugs, as well as development of new antimicrobial agents and optimization of the host response with adjuvant immunotherapy could have a profound impact on TB cure rates. Recent data show that chronic worm infection and deficiencies in micronutrients such as vitamin D and arginine are potential areas of intervention to optimize host immunity. Nutritional supplementation to enhance nitric oxide production and vitamin D-mediated effector functions as well as the treatment of worm infection to reduce immunosuppressive effects of regulatory T (Treg) lymphocytes may be more suitable and accessible strategies for highly endemic areas than adjuvant cytokine therapy. In this review, we focus mainly on immune control of human TB, and discuss how current treatment strategies, including immunotherapy and nutritional supplementation, could be optimized to enhance the host response leading to more effective treatment.


Green fluorescent protein chromophore derivative suppresses ultraviolet A-induced JNK-signalling and apoptosis in keratinocytes and adverse effects in zebrafish embryos.
Solar ultraviolet (UV) light has been recognized as the important environmental hazard and contributes to diverse skin damage such as cell death, photoageing and even carcinogenesis. Revelation of harmful responses attributed to UVA radiation has promoted the development of photoprotective agents against UVA-induced skin damage. In the present study, we tried to evaluate the potential protective effects of a synthetic green fluorescent protein (GFP) chromophore derivative, 4-chlorobenzyldene-1, 2-dimethylimidazolinone (Cl-BDI, called TC-22) on UVA- and UVB- induced stress responses in skin. The HaCaT keratinocytes were used to evaluate the cellular effects. Zebrafish (Danio rerio), which is regarded as a useful and cost-effective alternative to some mammalian models, was applied as the in vivo animal model. In HaCaT keratinocytes, TC-22 was able to obviously decrease UVA-induced cell death. Dissection of the UVA-induced signalling pathways revealed that TC-22 could suppress the activation of JNK and caspase 3, but not of ERK and p38. Reduction of UVA-induced cleavage of caspase 3 and sub-G1 phase accumulation by pretreatment of TC-22 was also observed. In zebrafish, we showed that UVA irradiation could decrease the survival and hatching rate, suppress heart beats of embryos and enhance the pigmentation of larvae. Pretreatment of TC-22 could significantly reverse UVA-induced the suppression in hatching of eggs and heart beating of embryos and also lowered the UVA-induced pigmentation in zebrafish. Collectively, we demonstrate that TC-22, a GFP chromophore derivative, can ameliorate the UVA-induced stress responses in both epidermal keratinocytes and zebrafish, suggesting the potential use of TC-22 in photoprotection in the future.


Changes in vestibular and cochlear function following platinum-based chemotherapy: A preliminary report.
This study investigated the changes in vestibular and cochlear function in patients receiving platinum-based chemotherapy. A longitudinal study of 32 participants (10-70 years) receiving chemotherapy participated in the study. Baseline and exit vestibular and hearing assessments that included video head impulse (VHIT) testing, cervical and ocular vestibular evoked myogenic potentials (VEMP), dynamic visual acuity (DVA) and pure-tone audiometry were performed at the patient's treatment venue. Half (50%) of the participants showed cochleotoxicity from baseline to exit testing, with left ears significantly more affected than right ears. There was no consistent relationship between hearing loss and vestibular dysfunction. DVA yielded normal results at baseline and exit testing in all participants. VEMP responses were absent in 28.1% of participants at baseline, reflecting the challenges of using VEMP for monitoring. VEMP and VHIT results showed a statistically significant (p < 0.05) decline in results from baseline to exit testing; however, participants did not report symptoms related to vestibular dysfunction. VHIT also showed left ears significantly (p < 0.05) more affected than right ears. VHIT proved to be a valuable measure of changes in vestibular function secondary to ototoxicity. Future investigations should determine vestibulotoxicity criteria and optimal protocols for vestibulotoxicity monitoring at the patient's treatment venue.


The Nutrition and Enjoyable Activity for Teen Girls (NEAT girls) randomized controlled trial for adolescent girls from disadvantaged secondary schools: rationale, study protocol, and baseline results.
Child and adolescent obesity predisposes individuals to an increased risk of morbidity and mortality from a range of lifestyle diseases. Although there is some evidence to suggest that rates of pediatric obesity have leveled off in recent years, this has not been the case among youth from low socioeconomic backgrounds. The purpose of this paper is to report the rationale, study design and baseline findings of a school-based obesity prevention program for low-active adolescent girls from disadvantaged secondary schools. The Nutrition and Enjoyable Activity for Teen Girls (NEAT Girls) intervention will be evaluated using a group randomized controlled trial. NEAT Girls is a 12-month multi-component school-based intervention developed in reference to Social Cognitive Theory and includes enhanced school sport sessions, interactive seminars, nutrition workshops, lunch-time physical activity (PA) sessions, PA and nutrition handbooks, parent newsletters, pedometers for self-monitoring and text messaging for social support. The following variables were assessed at baseline and will be completed again at 12- and 24-months: adiposity, objectively measured PA, muscular fitness, time spent in sedentary behaviors, dietary intake, PA and nutrition social-cognitive mediators, physical self-perception and global self-esteem. Statistical analyses will follow intention-to-treat principles and hypothesized mediators of PA and nutrition behavior change will be explored. NEAT Girls is an innovative intervention targeting low-active girls using evidence-based behavior change strategies and nutrition and PA messages and has the potential to prevent unhealthy weight gain and reduce the decline in physical activity and poor dietary habits associated with low socio-economic status. Few studies have reported the long-term effects of school-based obesity prevention programs and the current study has the potential to make an important contribution to the field. Australian New Zealand Clinical Trials Registry No: ACTRN12610000330044.


Holographic near-eye display with continuously expanded eyebox using two-dimensional replication and angular spectrum wrapping.
Holographic near-eye displays present true three-dimensional images with full monocular depth cues. In this paper, we propose a technique to expand the eyebox of the holographic near-eye displays. The base eyebox of the holographic near-eye displays is determined by the space bandwidth product of a spatial light modulator. The proposed technique replicates and stitches the base eyebox by the combined use of a holographic optical element and high order diffractions of the spatial light modulator, achieving horizontally and vertically expanded eyebox. An angular spectrum wrapping technique is also applied to alleviate image distortions observed at the boundaries between the replicated base eyeboxes.


Six months supplementation with conjugated linoleic acid induces regional-specific fat mass decreases in overweight and obese.
Long-term supplementation with conjugated linoleic acid (CLA) reduces body fat mass (BFM) and increases or maintains lean body mass (LBM). However, the regional effect of CLA was not studied. The study aimed to evaluate the effect of CLA per region and safety in healthy, overweight and obese adults. A total of 118 subjects (BMI: 28-32 kg/m2) were included in a double blind, placebo-controlled trial. Subjects were randomised into two groups supplemented with either 3 x 4 g/d CLA or placebo for 6 months. CLA significantly decreased BFM at month 3 (Delta=- 0 x 9 %, P=0 x 016) and at month 6 (Delta=- 3 x 4 %, P=0 x 043) compared with placebo. The reduction in fat mass was located mostly in the legs (Delta=- 0 x 8 kg, P<0 x 001), and in women (Delta=-1 x 3 kg, P=0 x 046) with BMI >30 kg/m2 (Delta=-1 x 9 kg, P=0 x 011), compared with placebo. The waist-hip ratio decreased significantly (P=0 x 043) compared with placebo. LBM increased (Delta=+0 x 5 kg, P=0 x 049) within the CLA group. Bone mineral content was not affected (P=0 x 70). All changes were independent of diet and physical exercise. Safety parameters including blood lipids, inflammatory and diabetogenic markers remained within the normal range. Adverse events did not differ between the groups. It is concluded that supplementation with CLA in healthy, overweight and obese adults decreases BFM in specific regions and is well tolerated.


Anxiety After Stroke: The Importance of Subtyping.
Anxiety after stroke is common and disabling. Stroke trialists have treated anxiety as a homogenous condition, and intervention studies have followed suit, neglecting the different treatment approaches for phobic and generalized anxiety. Using diagnostic psychiatric interviews, we aimed to report the frequency of phobic and generalized anxiety, phobic avoidance, predictors of anxiety, and patient outcomes at 3 months poststroke/transient ischemic attack. We followed prospectively a cohort of new diagnosis of stroke/transient ischemic attack at 3 months with a telephone semistructured psychiatric interview, Fear Questionnaire, modified Rankin Scale, EuroQol-5D5L, and Work and Social Adjustment Scale. Anxiety disorder was common (any anxiety disorder, 38 of 175 [22%]). Phobic disorder was the predominant anxiety subtype: phobic disorder only, 18 of 175 (10%); phobic and generalized anxiety disorder, 13 of 175 (7%); and generalized anxiety disorder only, 7 of 175 (4%). Participants with anxiety disorder reported higher level of phobic avoidance across all situations on the Fear Questionnaire. Younger age (per decade increase in odds ratio, 0.64; 95% confidence interval, 0.45-0.91) and having previous anxiety/depression (odds ratio, 4.38; 95% confidence interval, 1.94-9.89) were predictors for anxiety poststroke/transient ischemic attack. Participants with anxiety disorder were more dependent (modified Rankin Scale score 3-5, [anxiety] 55% versus [no anxiety] 29%; P<0.0005), had poorer quality of life on EQ-5D5L, and restricted participation (Work and Social Adjustment Scale: median, interquartile range, [anxiety] 19.5, 10-27 versus [no anxiety] 0, 0-5; P<0.001). Anxiety after stroke/transient ischemic attack is predominantly phobic and is associated with poorer patient outcomes. Trials of anxiety intervention in stroke should consider the different treatment approaches needed for phobic and generalized anxiety.


Membrane cholesterol affects stimulus-activity coupling in type 1, but not type 2, CCK receptors: use of cell lines with elevated cholesterol.
The lipid microenvironment of membrane proteins can affect their structure, function, and regulation. We recently described differential effects of acute modification of membrane cholesterol on the function of type 1 and 2 cholecystokinin (CCK) receptors. We now explore the regulatory impact of chronic cholesterol modification on these receptors using novel receptor-bearing cell lines with elevated membrane cholesterol. Stable CCK1R and CCK2R expression was established in clonal lines of 25RA cells having gain-of-function in SCAP [sterol regulatory element binding protein (SREBP) cleavage-activating protein] and SRD15 cells having deficiencies in Insig-1 and Insig-2 enzymes affecting HMG CoA reductase and SREBP. Increased cholesterol in the plasma membrane of these cells was directly demonstrated, and receptor binding and signaling characteristics were shown to reflect predicted effects on receptor function. In both environments, both types of CCK receptors were internalized and recycled normally in response to agonist occupation. No differences in receptor distribution within the membrane were appreciated at the light microscopic level in these CHO-derived cell lines. Fluorescence anisotropy was studied for these receptors occupied by fluorescent agonist and antagonist, as well as when tagged with YFP. These studies demonstrated increased anisotropy of the agonist ligand occupying the active state of the CCK1R in a cholesterol-enriched environment, mimicking fluorescence of the uncoupled, inactive state of this receptor, while there was no effect of increasing cholesterol on fluorescence at the CCK2R. These cell lines should be quite useful for examining the functional characteristics of potential drugs that might be used in an abnormal lipid environment.


Extract of Helicobacter pylori Ameliorates Parameters of Airway Inflammation and Goblet Cell Hyperplasia following Repeated Allergen Exposure.
An inverse relation between Helicobacter pylori infection and asthma has been shown in epidemiological studies. Infection with H. pylori, or application of an extract of it before or after sensitization, inhibits allergic airway disease in mice. The aim of this study was to investigate the effect of an extract of H. pylori on allergic airway disease induced by repeated allergen exposure in mice that were sensitized and challenged prior to extract application. C57BL/6 mice were intranasally (i.n.) sensitized and challenged with house dust mite (HDM). After a minimum of 4 weeks, mice received the H. pylori extract intraperitoneally and were rechallenged i.n. with HDM. Allergen-specific antibodies were measured by ELISA. Cells present in the bronchoalveolar lavage fluid and dendritic cell (DC) subsets in the lung tissue were analyzed by flow cytometry. Tissue inflammation and goblet cell hyperplasia were assessed by histology. Cells of the mediastinal lymph node (mLN) were isolated and in vitro restimulated with HDM or H. pylori extract. Treatment with H. pylori extract before rechallenge reduced allergen-specific IgE, the DC numbers in the tissue, and goblet cell hyperplasia. Cells isolated from mLN of mice treated with the extract produced significantly more IL-10 and IL-17 after in vitro restimulation with HDM. mLN cells of H. pylori-treated mice that were re-exposed to the H. pylori extract produced significantly more interferon gamma. An extract of H. pylori is effective in reducing mucus production and various features of inflammation in HDM rechallenged mice.


Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols.
In order to expedite the rapid and efficient discovery and isolation of novel specialized metabolites, while minimizing the waste of resources on rediscovery of known compounds, it is crucial to develop efficient approaches for strain prioritization, rapid dereplication, and the assessment of favored cultivation and extraction conditions. Herein we interrogated bacterial strains by systematically evaluating cultivation and extraction parameters with LC-MS/MS analysis and subsequent dereplication through the Global Natural Product Social Molecular Networking (GNPS) platform. The developed method is fast, requiring minimal time and sample material, and is compatible with high-throughput extract analysis, thereby streamlining strain prioritization and evaluation of culturing parameters. With this approach, we analyzed 146 marine Salinispora and Streptomyces strains that were grown and extracted using multiple different protocols. In total, 603 samples were analyzed, generating approximately 1.8 million mass spectra. We constructed a comprehensive molecular network and identified 15 molecular families of diverse natural products and their analogues. The size and breadth of this network shows statistically supported trends in molecular diversity when comparing growth and extraction conditions. The network provides an extensive survey of the biosynthetic capacity of the strain collection and a method to compare strains based on the variety and novelty of their metabolites. This approach allows us to quickly identify patterns in metabolite production that can be linked to taxonomy, culture conditions, and extraction methods, as well as informing the most valuable growth and extraction conditions.