A nuclear receptor-like pathway regulating multidrug resistance in fungi.
Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.


Continuation of Nesterov's Smoothing for Regression With Structured Sparsity in High-Dimensional Neuroimaging.
Predictive models can be used on high-dimensional brain images to decode cognitive states or diagnosis/prognosis of a clinical condition/evolution. Spatial regularization through structured sparsity offers new perspectives in this context and reduces the risk of overfitting the model while providing interpretable neuroimaging signatures by forcing the solution to adhere to domain-specific constraints. Total variation (TV) is a promising candidate for structured penalization: it enforces spatial smoothness of the solution while segmenting predictive regions from the background. We consider the problem of minimizing the sum of a smooth convex loss, a non-smooth convex penalty (whose proximal operator is known) and a wide range of possible complex, non-smooth convex structured penalties such as TV or overlapping group Lasso. Existing solvers are either limited in the functions they can minimize or in their practical capacity to scale to high-dimensional imaging data. Nesterov's smoothing technique can be used to minimize a large number of non-smooth convex structured penalties. However, reasonable precision requires a small smoothing parameter, which slows down the convergence speed to unacceptable levels. To benefit from the versatility of Nesterov's smoothing technique, we propose a first order continuation algorithm, CONESTA, which automatically generates a sequence of decreasing smoothing parameters. The generated sequence maintains the optimal convergence speed toward any globally desired precision. Our main contributions are: gap to probe the current distance to the global optimum in order to adapt the smoothing parameter and the To propose an expression of the duality convergence speed. This expression is applicable to many penalties and can be used with other solvers than CONESTA. We also propose an expression for the particular smoothing parameter that minimizes the number of iterations required to reach a given precision. Furthermore, we provide a convergence proof and its rate, which is an improvement over classical proximal gradient smoothing methods. We demonstrate on both simulated and high-dimensional structural neuroimaging data that CONESTA significantly outperforms many state-of-the-art solvers in regard to convergence speed and precision.


Conformational epitopes of myelin oligodendrocyte glycoprotein are targets of potentially pathogenic antibody responses in multiple sclerosis.
Myelin/oligodendrocyte glycoprotein (MOG) is a putative autoantigen in multiple sclerosis (MS). Establishing the pathological relevance and validity of anti-MOG antibodies as biomarkers has yielded conflicting reports mainly due to different MOG isoforms used in different studies. Because epitope specificity may be a key factor determining anti-MOG reactivity we aimed at identifying a priori immunodominant MOG epitopes by monoclonal antibodies (mAbs) and at assessing clinical relevance of these epitopes in MS. Sera of 325 MS patients, 69 patients with clinically isolated syndrome and 164 healthy controls were assayed by quantitative, high-throughput ELISA for reactivity to 3 different MOG isoforms, and quantitative titers correlated with clinical characteristics. mAbs defined unique immunodominant epitopes distinct to each of the isoforms. In the majority of human samples anti-MOG levels were skewed towards low titers. However, in 8.2% of samples high-titer anti-MOG antibodies were identified. In contrast to anti-MOG reactivity observed in a mouse model of MS, in patients with MS these never reacted with ubiquitously exposed epitopes. Moreover, in patients with relapsing-remitting MS high-titer anti-MOG IgG correlated with disability (EDSS; Spearman r = 0.574; p = 0.025). Thus high-titer reactivity likely represents high-affinity antibodies against pathologically relevant MOG epitopes, that are only present in a small proportion of patients with MS. Our study provides valuable information about requirements of anti-MOG reactivity for being regarded as a prognostic biomarker in a subtype of MS.


Involvement of the SnRK1 subunit KIN10 in sucrose-induced hypocotyl elongation.
A mechanism participating in energy sensing and signalling in plants involves the regulation of sucrose non-fermenting1 (Snf1)-related protein kinase 1 (SnRK1) activity in response to sugar availability. SnRK1 is thought to regulate the activity of both metabolic enzymes and transcription factors in response to changes in energy availability, with trehalose-6-phospate functioning as a signalling sugar that suppresses SnRK1 activity under sugar-replete conditions. Sucrose supplementation increases the elongation of hypocotyls of developing Arabidopsis seedlings, and this response to sucrose involves both the SnRK1 subunit KIN10 and also TREHALOSE-6-PHOSPHATE SYNTHASE1 (TPS1). Here, we measured sucrose-induced hypocotyl elongation in two insertional mutants of KIN10 (akin10 and akin10-2). Under short photoperiods, sucrose supplementation caused great proportional hypocotyl elongation in these KIN10 mutants compared with the wild type, and these mutants had shorter hypocotyls than the wild type in the absence of sucrose supplementation. One interpretation is that SnRK1 activity might suppress hypocotyl elongation in the presence of sucrose, because KIN10 overexpression inhibits sucrose-induced hypocotyl elongation and akin10 mutants enhance sucrose-induced hypocotyl elongation.


Physician satisfaction in a cancer prevention program for low-income women in Nevada.
Physicians and health care organizations that provide services to low-income patients are valuable partners in improving health care access for the uninsured and medically underserved. In this pilot study, we explored physicians' needs and factors for satisfaction in the Women's Health Connection (WHC), a breast and cervical cancer-screening program for low-income women in Nevada. Of the 126 physicians in the WHC program, 50 physicians completed a needs-and-satisfaction questionnaire. Survey data were subjected to factor analysis using Varimax rotation. The results yielded three components, which accounted for 65% of the variance. The three components or dimensions for physician satisfaction were: (1) appropriate administrative support and documentation, (2) availability of support for medical management, and (3) timeliness of diagnostic reports. Amount of reimbursement was not a significant factor. The respondents serving in this cancer prevention program for low-income women were satisfied in their involvement in the program. Further attention should be given on the identified issues for satisfaction among physicians, which could lead to quality improvement and serve as a model for other programs that serve low-income patients in cancer prevention.


A focus of human infection by Haplorchis taichui (Trematoda: Heterophyidae) in the southern Philippines.
We report an exceptionally high rate of infection by Haplorchis taichui (Nishigori, 1924) in human populations on Mindanao Island, southern Philippines. This intestinal fluke is seldom encountered, and this is the first report of high prevalence of infection (36%) in humans by H. taichui in the Philippines. The likely source of haplorchine infection has been linked to consumption of raw or undercooked freshwater fish containing infective metacercariae. The most common clinical symptoms appeared as upper abdominal discomfort or pain and borborygmi. Praziquantel (75 mg/kg divided in 3 doses in 1 day) was a well-tolerated and effective treatment for infection by H. taichui.


Thermo-reversible gelation of rod-coil and coil-rod-coil molecules based on poly(dimethyl siloxane) and perylene imides and self-sorting of the homologous pair.
Organogels with perylene derivatives and phthalocyanines reported in the literature so far involve self-assembly promoted by hydrogen bonds, in addition to aromatic and van der Waals interactions. Although the self assembly of these types of molecules without a hydrogen bonding group in the structure occurs in solution or during crystallization, the gelation studies reported so far incorporated a hydrogen bonding pair of the type N-H···O=C in the structure of the molecule. We present a case of thermo-reversible gelation without a hydrogen bonding group in the structure of (1) a coil-rod-coil molecule based on perylenetetracarboxylic diimide (PTCDI) and poly(dimethyl siloxane) (PDMS) and (2) a rod-coil molecule with perylene dicarboxylic imide (PDI) and PDMS. However IR spectroscopy shows the presence of multiple types of hydrogen bonding between the solvents and the gelator molecules. In addition, publications so far on gelation of perylene diimide based molecules involve groups attached to both imide nitrogens and with or without substitution in the bay position. We discuss here the gelation with a Mono-substituted perylene imide. The PDMS segment was attached to one side of PDI (Mono-PDMS) or to both imide nitrogens of PTCDI (Di-PDMS). The Mono-PDMS is an inverse macromolecular surfactant applicable to non-aqueous systems, and the Di-PDMS is a Gemini surfactant. The PDMS segment that we attached to PTCDI here is longer than most substituents used by other authors. These molecules gel propylamine, as well as mixed solvents of hexane-water and diisopropylamine-water. Both hexane and diisopropylamine dissolve Mono-PDMS and Di-PDMS at room temperature and addition of water results in precipitation. However, heating the solution to about 70 °C, adding water (5-15 wt%) and slowly cooling the solution, lead to gelation. The Di-PDMS forms fibers which are not flat but curved as an eaves trough. The Mono-PDMS forms hollow spheres. Although the Mono-PDMS and Di-PDMS are a homologous pair, blends of these do not show molecular intercalation during gelation, but self-sort. The fibers of Di-PDMS based gels encapsulate the spheres of the Mono-PDMS based gels.


Preventing collapse in early osteonecrosis of the femoral head. A randomised clinical trial of core decompression.
We performed a randomised trial on 37 hips (33 patients) with early-stage osteonecrosis (ON). After the initial clinical evaluation, including plain radiography and MRI, 18 hips were randomly assigned to a core-decompression group and 19 to a conservatively-treated group. All the patients were regularly followed up by clinical evaluation, plain radiography and MRI at intervals of three months. Hip pain was relieved in nine out of ten initially symptomatic hips in the core-decompression group but persisted in three out of four initially painful hips in the conservatively-treated group at the second assessment (p < 0.05). At a minimum follow-up of 24 months, 14 of the 18 core-decompressed hips (78%) and 15 of the 19 non-operated hips (79%) developed collapse of the femoral head. By survival analysis, there was no significant difference in the time to collapse between the two groups (log-rank test p = 0.79). Core decompression may be effective tin symptomatic relief, but is of no greater value than conservative management in preventing collapse in early osteonecrosis of the femoral head.


A practical guide for combining data to model species distributions.
Understanding and accurately modeling species distributions lies at the heart of many problems in ecology, evolution, and conservation. Multiple sources of data are increasingly available for modeling species distributions, such as data from citizen science programs, atlases, museums, and planned surveys. Yet reliably combining data sources can be challenging because data sources can vary considerably in their design, gradients covered, and potential sampling biases. We review, synthesize, and illustrate recent developments in combining multiple sources of data for species distribution modeling. We identify five ways in which multiple sources of data are typically combined for modeling species distributions. These approaches vary in their ability to accommodate sampling design, bias, and uncertainty when quantifying environmental relationships in species distribution models. Many of the challenges for combining data are solved through the prudent use of integrated species distribution models: models that simultaneously combine different data sources on species locations to quantify environmental relationships for explaining species distribution. We illustrate these approaches using planned survey data on 24 species of birds coupled with opportunistically collected eBird data in the southeastern United States. This example illustrates some of the benefits of data integration, such as increased precision in environmental relationships, greater predictive accuracy, and accounting for sample bias. Yet it also illustrates challenges of combining data sources with vastly different sampling methodologies and amounts of data. We provide one solution to this challenge through the use of weighted joint likelihoods. Weighted joint likelihoods provide a means to emphasize data sources based on different criteria (e.g., sample size), and we find that weighting improves predictions for all species considered. We conclude by providing practical guidance on combining multiple sources of data for modeling species distributions.


Everything Matters: The ReproNim Perspective on Reproducible Neuroimaging.
There has been a recent major upsurge in the concerns about reproducibility in many areas of science. Within the neuroimaging domain, one approach is to promote reproducibility is to target the re-executability of the publication. The information supporting such re-executability can enable the detailed examination of how an initial finding generalizes across changes in the processing approach, and sampled population, in a controlled scientific fashion. ReproNim: A Center for Reproducible Neuroimaging Computation is a recently funded initiative that seeks to facilitate the "last mile" implementations of core re-executability tools in order to reduce the accessibility barrier and increase adoption of standards and best practices at the neuroimaging research laboratory level. In this report, we summarize the overall approach and tools we have developed in this domain.


NMR-Based screening with competition water-ligand observed via gradient spectroscopy experiments: detection of high-affinity ligands.
Water-ligand observed via gradient spectroscopy (WaterLOGSY) represents a powerful method for primary NMR screening in the identification of compounds interacting with macromolecules, including proteins and DNA or RNA fragments. The method is useful for the detection of compounds binding to a receptor with binding affinity in the micromolar range. The Achille's heel of the method, as with all the techniques that detect the ligand resonances, is its inability to identify strong ligands with slow dissociation rates. We show here that the use of a reference compound with a known K(D) in the micromolar range together with properly designed competition binding experiments (c-WaterLOGSY) permits the detection of strong binders. A derived mathematical expression is used for the selection of the appropriate setup NMR experimental conditions and for an approximate determination of the binding constant. The experiment requires low ligand concentration, therefore allowing its application in the identification of potential strong inhibitors that are only marginally soluble. The technique is particularly suitable for rapid screening of chemical mixtures and plant or fungi extracts.


Virtual Environments for Visualizing Structural Health Monitoring Sensor Networks, Data, and Metadata.
Visualization of sensor networks, data, and metadata is becoming one of the most pivotal aspects of the structural health monitoring (SHM) process. Without the ability to communicate efficiently and effectively between disparate groups working on a project, an SHM system can be underused, misunderstood, or even abandoned. For this reason, this work seeks to evaluate visualization techniques in the field, identify flaws in current practices, and devise a new method for visualizing and accessing SHM data and metadata in 3D. More precisely, the work presented here reflects a method and digital workflow for integrating SHM sensor networks, data, and metadata into a virtual reality environment by combining spherical imaging and informational modeling. Both intuitive and interactive, this method fosters communication on a project enabling diverse practitioners of SHM to efficiently consult and use the sensor networks, data, and metadata. The method is presented through its implementation on a case study, Streicker Bridge at Princeton University campus. To illustrate the efficiency of the new method, the time and data file size were compared to other potential methods used for visualizing and accessing SHM sensor networks, data, and metadata in 3D. Additionally, feedback from civil engineering students familiar with SHM is used for validation. Recommendations on how different groups working together on an SHM project can create SHM virtual environment and convey data to proper audiences, are also included.


Weekly Crime Concentration.
Examine and visualise the temporal concentration of different crime types and detect if their intensity varies through distinct moments of the week. The "heartbeat of the crime signal" is constructed by overlapping the weekly time they were suffered. This study is based on more than 220,000 crimes reported to the Mexico City Police Department between January 2016 and March 2020 to capture the day and time of crimes and detect moments of the week in which the intensity exceeds the average frequency. A new metric for the temporal concentration of crime is constructed for different types of crime and regions of the city based on the corresponding heartbeats. The temporal concentration of crime is a stable signature of different types of crime. The intensity of robberies and theft is more homogeneous from Monday to Sunday, but robberies of a bank user are highly concentrated in a week, meaning that few hours of the week capture most of the burning moments. The concentration is not homogeneously distributed in the city, with some regions experiencing a much higher temporal concentration of crime. Crime is highly concentrated when observed in its weekly patterns, but different types of crime and regions exhibit substantially distinct concentration levels. The temporal trace indicates specific moments for the burning times of different types of crime, which is a critical element of a policing strategy.


The role of non-governmental organizations in global health diplomacy: negotiating the Framework Convention on Tobacco Control.
The Framework Convention on Tobacco Control (FCTC) is an exemplar result of global health diplomacy, based on its global reach (binding on all World Health Organization member nations) and its negotiation process. The FCTC negotiations are one of the first examples of various states and non-state entities coming together to create a legally binding tool to govern global health. They have demonstrated that diplomacy, once consigned to interactions among state officials, has witnessed the dilution of its state-centric origins with the inclusion of non-governmental organizations (NGOs) in the diplomacy process. To engage in the discourse of global health diplomacy, NGO diplomats are immediately presented with two challenges: to convey the interests of larger publics and to contribute to inter-state negotiations in a predominantly state-centric system of governance that are often diluted by pressures from private interests or mercantilist self-interest on the part of the state itself. How do NGOs manage these challenges within the process of global health diplomacy itself? What roles do, and can, they play in achieving new forms of global health diplomacy? This paper addresses these questions through presentation of findings from a study of the roles assumed by one group of non-governmental actors (the Canadian NGOs) in the FCTC negotiations. The findings presented are drawn from a larger grounded theory study. Qualitative data were collected from 34 public documents and 18 in-depth interviews with participants from the Canadian government and Canadian NGOs. This analysis yielded five key activities or roles of the Canadian NGOs during the negotiation of the FCTC: monitoring, lobbying, brokering knowledge, offering technical expertise and fostering inclusion. This discussion begins to address one of the key goals of global health diplomacy, namely 'the challenges facing health diplomacy and how they have been addressed by different groups and at different levels of governance' (Kickbusch et al. 2007a: 972).


Sampling natural biofilms: a new route to build efficient microbial anodes.
Electrochemically active biofilms were constructed on graphite anodes under constant polarization at -0.1V vs saturated calomel reference (SCE) with 10 mM acetate as substrate. The reactors were inoculated with three different microbial samples that were drawn from exactly the same place in a French Atlantic coastal port (i) by scraping the biofilm that had formed naturally on the surface of a floating bridge, (ii) by taking marine sediments just under the floating bridge, and (iii) by taking nearby beach sand. Current densities of 2.0 A/m2 were reached using the biofilm sample as inoculum while only 0.4 A/m2 and 0.8 A/m2 were obtained using the underlying sediments and the beach sand, respectively. The structure of bacterial communities forming biofilms was characterized by denaturing gradient gel electrophoresis (DGGE) analysis, and revealed differences between samples with the increase in relative intensities of some bands and the appearance of others. Bacteria close related to Bacteroidetes, Halomonas, and Marinobacterium were retrieved only from the efficient EA-biofilms formed from natural biofilms, whereas, bacteria close related to Mesoflavibacter were predominant on biofilm formed from sediments. The marine biofilm was selected as the inoculum to further optimize the microbial anode. Epifluorescence microscopy and SEM confirmed that maintaining the electrode under constant polarization promoted rapid settlement of the electrode surface by a bacterial monolayer film. The microbial anode was progressively adapted to the consumption of acetate by three serial additions of substrate, thus improving the Coulombic efficiency of acetate consumption from 31 to 89%. The possible oxidation of sulfide played only a very small part in the current production and the biofilm was not able to oxidize hydrogen. Graphite proved to be more efficient than dimensionally stable anode (DSA) or stainless steel butthis result might be due to differences in the surface roughness rather than the intrinsic features of the materials. Finally, a maximal current density of 7.9 A/m2 was reached with 10 mM acetate after only 8 days of biofilm formation at -0.1 V/SCE. These results are among the best performance values reported in the literature. Using natural biofilms as inoculum should, consequently, be a new, very promising wayto rapidly build more efficient microbial electrodes than those produced when the inoculum is drawn from bulk environments.


Uncertainty analysis of least-cost modeling for designing wildlife linkages.
Least-cost models for focal species are widely used to design wildlife corridors. To evaluate the least-cost modeling approach used to develop 15 linkage designs in southern California, USA, we assessed robustness of the largest and least constrained linkage. Species experts parameterized models for eight species with weights for four habitat factors (land cover, topographic position, elevation, road density) and resistance values for each class within a factor (e.g., each class of land cover). Each model produced a proposed corridor for that species. We examined the extent to which uncertainty in factor weights and class resistance values affected two key conservation-relevant outputs, namely, the location and modeled resistance to movement of each proposed corridor. To do so, we compared the proposed corridor to 13 alternative corridors created with parameter sets that spanned the plausible ranges of biological uncertainty in these parameters. Models for five species were highly robust (mean overlap 88%, little or no increase in resistance). Although the proposed corridors for the other three focal species overlapped as little as 0% (mean 58%) of the alternative corridors, resistance in the proposed corridors for these three species was rarely higher than resistance in the alternative corridors (mean difference was 0.025 on a scale of 1 10; worst difference was 0.39). As long as the model had the correct rank order of resistance values and factor weights, our results suggest that the predicted corridor is robust to uncertainty. The three carnivore focal species, alone or in combination, were not effective umbrellas for the other focal species. The carnivore corridors failed to overlap the predicted corridors of most other focal species and provided relatively high resistance for the other focal species (mean increase of 2.7 resistance units). Least-cost modelers should conduct uncertainty analysis so that decision-makers can appreciate the potential impact of model uncertainty on conservation decisions. Our approach to uncertainty analysis (which can be called a worst-case scenario approach) is appropriate for complex models in which distribution of the input parameters cannot be specified.


Cationic ionene as an n-dopant agent of poly(3,4-ethylenedioxythiophene).
We report the reduction of poly(3,4-ethylenedioxythiophene) (PEDOT) films with a cationic 1,4-diazabicyclo[2.2.2]octane-based ionene bearing N,N'-(meta-phenylene)dibenzamide linkages (mPI). Our main goal is to obtain n-doped PEDOT using a polymeric dopant agent rather than small conventional tetramethylammonium (TMA), as is usual. This has been achieved using a three-step process, which has been individually optimized: (1) preparation of p-doped (oxidized) PEDOT at a constant potential of +1.40 V in acetonitrile with LiClO4 as the electrolyte; (2) dedoping of oxidized PEDOT using a fixed potential of -1.30 V in water; and (3) redoping of dedoped PEDOT applying a reduction potential of -1.10 V in water with mPI. The resulting films display the globular appearance typically observed for PEDOT, with mPI being structured in separated phases forming nanospheres or ultrathin sheets. This organization, which has been supported by atomistic molecular dynamics simulations, resembles the nanosegregated phase distribution observed for PEDOT p-doped with poly(styrenesulfonate). Furthermore, the doping level achieved using mPI as the doping agent is comparable to that achieved using TMA, even though ionene provides distinctive properties to the conducting polymer. For example, films redoped with mPI exhibit much more hydrophilicity than the oxidized ones, whereas films redoped with TMA are hydrophobic. Similarly, films redoped with mPI exhibit the highest thermal stability, while those redoped with TMA show thermal stability that is intermediate between those of the latter and the dedoped PEDOT. Overall, the incorporation of an mPI polycation as the n-dopant into PEDOT has important advantages for modulating the properties of this emblematic conducting polymer.


Multiscale analysis of the laser-induced damage threshold in optical coatings.
We have investigated the influence of laser beam size on laser-induced damage threshold (LIDT) in the case of single- and multiple-shot irradiation. The study was performed on hafnia thin films deposited with various technologies (evaporation, sputtering, with or without ion assistance). LIDT measurements were carried out at 1064 nm and 12 ns with a spot size ranging from a few tens to a few hundreds of micrometers, in 1-on-1 and R-on-1 modes. These measurements were compared with simulations obtained with the statistical theory of laser-induced damage caused by initiating inclusions. We show how to obtain information on the initiating defect properties and the related physical damage mechanisms with a multiscale study. Under certain conditions, it is possible with this method to discriminate different defects, estimate their densities, and follow the evolution of the defects under multiple irradiation. The different metrology implications of our approach, particularly for obtaining a functional LIDT of optical components are discussed.


Correlation of GREB1 mRNA with protein expression in breast cancer: validation of a novel GREB1 monoclonal antibody.
Studies of gene regulated by estrogen in breast cancer 1 (GREB1) have focused on mRNA levels with limited evidence about GREB1 protein expression in normal and breast cancer cells. A monoclonal antibody that recognizes GREB1 protein in breast tissues could be applied to correlate protein expression with established mRNA expression data. A hybridoma expressing a murine monoclonal antibody targeting a 119 amino acid peptide specific to human GREB1 was generated. The novel monoclonal GREB1 antibody (GREB1ab) was validated for use in Western blotting as well as immunohistochemical (IHC) applications. GREB1ab detects a 216 kDa protein corresponding to GREB1 in estrogen receptor alpha (ERalpha+) breast cancer cells as well as ERalpha- breast cancer cells transduced with a GREB1 expression vector. GREB1ab specificity was verified using an ERalpha antagonist to prevent GREB1 induction as well as a silencing siRNA targeting GREB1 mRNA. GREB1ab was further validated for detection of GREB1 by IHC in breast cancer cell lines and breast tissue microarrays (TMA). ERalpha+ cell lines were observed to express GREB1 while ERalpha- cell lines did not express detectable levels of the protein. Using breast cancer tissue whole sections, IHC with the GREB1ab identified protein expression in ERalpha+ breast cancer tissue as well as normal breast tissue, with little GREB1 expression in ERalpha- breast cancer tissue. Furthermore, these data indicate that GREB1 mRNA expression correlates well with protein expression. The novel monoclonal GREB1ab is specific for GREB1 protein. This antibody will serve as a tool for investigations focused on the expression, distribution, and function of GREB1 in normal breast and breast cancer tissues.


Casein kinase activity in rat mammary gland Golgi vesicles. Demonstration of latency and requirement for a transmembrane ATP carrier.
A Golgi vesicle-enriched preparation from mammary tissue of lactating rats has been used to investigate the phosphorylation of caseins in vitro. Casein kinase, together with its casein substrates, is enclosed within the lumen of Golgi membrane vesicles and has a requirement for Ca2+ and ATP. The permeability characteristics of the Golgi membrane to ATP and Ca2+ therefore have a possible regulatory influence on casein kinase activity. This influence has been investigated by alteration of the permeability characteristics by using several agents having differing degrees of selectivity. The ionophore A23187, which permits loss of Ca2+ from the vesicles, caused a decrease in casein phosphorylation which could be reversed by externally supplied Ca2+. Alamethicin, an ionophore that creates larger transmembrane channels, caused an increase in casein phosphorylation. This increase showed a requirement for divalent metal ions which could be satisfied by either Ca2+ or Mn2+. Under the same conditions, La3+ was inhibitory. Triton X-100 caused loss of intravesicular Ca2+, yet this was accompanied by an increase in phosphate incorporation into the caseins. We conclude from these results that the binding site on casein kinase for ATP is within the Golgi membrane barrier and that they imply the presence of a transmembrane ATP-transport mechanism. Inhibition of casein phosphorylation by atractyloside and carboxyatractyloside lends support to this concept.


Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood.
Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.


Ontology patterns-based transformation of clinical information.
The semantic interoperability of clinical information requires methods able to transform heterogeneous data sources from both technological and structural perspectives, into representations that facilitate the sharing of meaning. The SemanticHealthNet (SHN) project proposes using semantic content patterns for representing clinical information based on a model of meaning, preventing users from a deep knowledge on ontology and description logics formalism. In this work we propose a flexible transformation method that uses semantic content patterns to guide the mapping between the source data and a target domain ontology. As use case we show how one of the semantic content patterns proposed in SHN can be used to transform heterogeneous data about medication administration.


Hyperinsulinaemia causes a preferential increase in hepatic P4501A2 activity.
Male NEDH (New England Deaconess Hospital) rats were transplanted with a radiation-induced tumour from a donor male rat and were killed 18 days following transplantation. At the time of killing the insulinoma-bearing animals were severely hypoglycaemic but plasma ketone levels were normal. Insulinoma-bearing animals exhibited higher hepatic O-deethylation of ethoxyresorufin and N-demethylation of ethylmorphine activities when compared to control animals. Similarly, hepatic microsomal preparations from insulinoma-bearing rats were more efficient than control animals in converting the promutagen 2-amino-6-methyldipyrido[1,2-a:3',2']imidazole (Glu-P-1) to mutagenic intermediates in the Ames test. Immunoblot analysis employing polyclonal antibodies against the P4501A and P453A families revealed that insulinoma-bearing rats had higher hepatic P4501A2 apoprotein levels. No major differences in P4503A1 apoprotein levels between insulinoma-bearing and control rats were noted. Subcutaneous administration of insulin to male Wistar rats gave rise to a modest increase in ethoxyresorufin O-deethylase activity and in the ability to activate Glu-P-1 to mutagens in the Ames test. Immunoblot analysis revealed an increase in hepatic P4501A2 apoprotein levels following the treatment with insulin. It is concluded that insulinoma-bearing rats display high P4501A2 activity and the hyperinsulinaemia that characterize this condition is responsible for the effect. Moreover, administration of insulin to other strains of rat, such as Wistar, also enhances P4501A2 activity, presumably as a result of hyperinsulinaemia.


Individual characteristics associated with changes in the contribution of plant foods to dietary intake in a French prospective cohort.
Rebalancing the contribution of animal- and plant-based foods is needed to achieve sustainable diet. However, little is known concerning individual characteristics that may influence intake of plant-based foods and their changes over time. We aimed to assess changes in the contribution of plant-based foods to dietary intake over time and their association with individual characteristics. The contribution of plant-based foods was assessed by percent energy intake provided by plant proteins in diet (PEIPP) and a score of adherence to a pro-vegetarian diet, using repeated 24-h records in 15,615 French adults participating in the NutriNet-Santé cohort study. Associations between baseline individual characteristics and changes in the two indicators over a 4-6-year follow-up were assessed using a linear mixed model. At baseline, PEIPP and pro-vegetarian score were positively associated with age [β65+ = 0.80, 95% CI = (0.71, 0.88), β65+ = 3.30, 95% CI = (2.97, 3.64), respectively] and education [βpostgraduate = 0.23, 95% CI = (0.12, 0.34), βpostgraduate = 1.19, 95% CI = (0.75, 1.62)], while they were inversely associated with BMI class [βobesity = - 0.48, 95% CI = (0.56, 0.41), βobesity = - 2.31, 95% CI = (- 2.63, - 1.98)]. Men had higher PEIPP than women [β = 0.06, 95% CI = (0.01, 0.11)]. Pro-vegetarian score significantly increased over time [β = 0.23, 95% CI = (0.08, 0.37)]. The older the individual at baseline, the greater the decrease in the two indicators during follow-up. Pro-vegetarian score increased during follow-up for obese participants at baseline. The contribution of plant-based foods was associated with several socio-demographic and economic characteristics at baseline, whereas change over time was related to age and weight status. Further analysis of individual obstacles and lever to consume plant-based foods is needed.


Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.
The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn, substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as β-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.


Personality disorder: the patients psychiatrists dislike.
A sample of psychiatrists was asked to read a case vignette and indicate likely management and attitudes to the patient on a number of semantic-differential scales. Patients given a previous diagnosis of personality disorder (PD) were seen as more difficult and less deserving of care compared with control subjects who were not. The PD cases were regarded as manipulative, attention-seeking, annoying, and in control of their suicidal urges and debts. PD therefore appears to be an enduring pejorative judgement rather than a clinical diagnosis. It is proposed that the concept be abandoned.


Treatment of KIT-mutated metastatic mucosal melanoma.
Mucosal melanoma is a rare, aggressive histologic subtype of malignant melanoma, and prognosis for patients with metastatic mucosal melanoma is very poor. In general, conventional cytotoxic agents alone or in combination with immunologic drugs have limited clinical benefit. Advances in molecular analytic techniques have helped researchers discover genetic aberrations in KIT, a receptor tyrosine kinase, in nearly 40% of patients with mucosal melanoma. Preclinical studies have demonstrated that hot-spot mutations, mostly substitutions in exons 11 and 13, result in constitutive activation of KIT and its downstream signal transduction pathways, such as the MEK/ERK, PI3K/AKT and JAK/STAT pathways. KIT inhibitors, most notably imatinib, have shown promising clinical activity in KIT-mutant advanced melanoma, including mucosal melanoma, with clinical response rates exceeding 35% in patients with hot-spot mutations in exon 11 or 13 and/or a high mutant/wild-type allelic ratio. However, the duration of disease control is rather short in general, and treatment with KIT inhibitors as single agents is not optimal. Well-designed mechanistic studies aimed at assessing molecular differences between various KIT mutations or other aberrations and mechanisms of resistance are urgently needed to improve KIT-targeting therapy for melanoma. In addition, with availability of checkpoint inhibitors, such as anti-CTLA4 and/or anti-PD-1 antibodies, immunotherapies using those inhibitors alone or in combinations of such immunotherapies with KIT inhibitors may lead to more effective therapeutic regimens. This review discusses the rationale for KIT inhibitor therapy in patients with metastatic mucosal melanoma and the findings of preclinical and clinical studies of KIT inhibitors in this patient population.


Photoluminescence of planar and 3D InGaN/GaN LED structures excited with femtosecond laser pulses close to the damage threshold.
We study the photoluminescence emission from planar and 3D InGaN/GaN LED structures, excited using a femtosecond laser with fluences close to sample's damage threshold. For a typical laser system consisting of a titanium-sapphire regenerative amplifier, which is pumping an optical parametric amplifier delivering output pulses of a few tens of MW pulse power with ∼100 fs pulse duration, 1 kHz repetition rate and a wavelength of 325 nm, we determine the damage threshold of the InGaN/GaN LEDs to be about 0.05 J/cm2. We find that the relative intensity of the GaN photoluminescence (PL) and InGaN PL changes significantly close to the damage threshold. The changes are irreversible once the damage threshold is exceeded. As the damage threshold is approached, the InGaN luminescence band blue-shifts by several tens of meV, which is attributed to band filling effects. The PL decay time reduces substantially, by about 30%, when the excitation energy density is increased by approximately two orders of magnitude. The results are comparable for 2D and 3D LED structures, where in the latter case m-plane QWs exhibit different recombination dynamics because of the absence of the quantum confined Stark effect.


Vaccines Against Antimicrobial Resistance.
In the last century, life expectancy has increased considerably, thanks to the introduction of antibiotics, hygiene and vaccines that have contributed to the cure and prevention of many infectious diseases. The era of antimicrobial therapy started in the nineteenth century with the identification of chemical compounds with antimicrobial properties. However, immediately after the introduction of these novel drugs, microorganisms started to become resistant through different strategies. Although resistance mechanisms were already present before antibiotic introduction, their large-scale use and mis-use have increased the number of resistant microorganisms. Rapid spreading of mobile elements by horizontal gene transfer such as plasmids and integrative conjugative elements (ICE) carrying multiple resistance genes has dramatically increased the worldwide prevalence of relevant multi drug-resistant human pathogens such as Staphylococcus aureus, Neisseria gonorrhoeae, and Enterobacteriaceae. Today, antimicrobial resistance (AMR) remains one of the major global concerns to be addressed and only global efforts could help in finding a solution. In terms of magnitude the economic impact of AMR is estimated to be comparable to that of climate global change in 2030. Although antibiotics continue to be essential to treat such infections, non-antibiotic therapies will play an important role in limiting the increase of antibiotic resistant microorganisms. Among non-antibiotic strategies, vaccines and therapeutic monoclonal antibodies (mAbs) play a strategic role. In this review, we will summarize the evolution and the mechanisms of antibiotic resistance, and the impact of AMR on life expectancy and economics.


Crystallographic data collection using a 0.22% bandwidth multilayer.
To bridge the gap between traditional multilayer and crystal optics a high-resolution multilayer monochromator with a bandwidth of 0.22% has been designed and installed on a bending-magnet beamline (F3) at the Cornell High Energy Synchrotron Source (CHESS) to provide an unfocused monochromatic X-ray beam for protein crystallography experiments. Crystallographic data of excellent quality from a medium-sized protein, Concanavalin A, were collected and processed using standard crystallographic programs. The data were successfully used for a structure solution and refinement. The flux from the multilayer monochromator is enhanced, relative to that from a flat Si(111) monochromator, by a factor of 5; consequently, data collection is faster and/or smaller samples may be used. At the same time, the bandwidth is narrow enough to avoid streaked spots. This experiment suggests that multilayer optics may play a valuable role in satisfying the demands of the structural biology community for rapid X-ray data collection, particularly at under-utilized bending-magnet beamlines.


Gestational Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal Birth Weight.
Medical nutrition therapy is a mainstay of gestational diabetes mellitus (GDM) treatment. However, data are limited regarding the optimal diet for achieving euglycemia and improved perinatal outcomes. This study aims to investigate whether modified dietary interventions are associated with improved glycemia and/or improved birth weight outcomes in women with GDM when compared with control dietary interventions. Data from published randomized controlled trials that reported on dietary components, maternal glycemia, and birth weight were gathered from 12 databases. Data were extracted in duplicate using prespecified forms. From 2,269 records screened, 18 randomized controlled trials involving 1,151 women were included. Pooled analysis demonstrated that for modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (-4.07 mg/dL [95% CI -7.58, -0.57]; P = 0.02 and -7.78 mg/dL [95% CI -12.27, -3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (-170.62 g [95% CI -333.64, -7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02). The quality of evidence for these outcomes was low to very low. Baseline differences between groups in postprandial glucose may have influenced glucose-related outcomes. As well, relatively small numbers of study participants limit between-diet comparison. Modified dietary interventions favorably influenced outcomes related to maternal glycemia and birth weight. This indicates that there is room for improvement in usual dietary advice for women with GDM.


Vertical distribution of fungal communities in tallgrass prairie soil.
We used 454 sequencing of the internal transcribed spacer region to characterize fungal communities in tallgrass prairie soils subdivided into strata 0-10, 10-20, 30-40 and 50-60 cm deep. The dataset included more than 14000 fungal sequences distributed across Basidiomycota, Ascomycota, basal fungal lineages and Glomeromycota in order of decreasing frequency. As expected the community richness and diversity estimators tended to decrease with increasing depth. Although species richness was significantly reduced for samples from the deeper profiles, even the deepest stratum sampled contained richness of more than a third of that in the topmost stratum. More importantly, nonparametric multidimensional scaling (NMS) ordination analyses indicated that the fungal communities differed across vertical profiles, although only the topmost and deepest strata were significantly different when the NMS axis scores were compared by ANOVA. These results emphasize the importance of considering the fungal communities across the vertical strata because the deeper soil horizons might maintain a distinct community composition and thus contribute greatly to overall richness. The majority of operational taxonomic units (OTUs) declined in frequency with increasing depth, although a linear regression analysis indicated that some increased with increasing depth. The OTUs and BLAST-assigned taxa that showed increasing frequencies were mainly unculturable fungi, but some showed likely affinities to families Nectriaceae and Venturiaceae or to genus Pachnocybe. Although the ecological roles of the fungi in the deeper strata remain uncertain, we hypothesize that the fungi with preferences for deeper soil have adequate access to substrates and possess environmental tolerances that enable their persistence in those environments.


Prepare the patient for future challenges when facing hemodialysis: nurses' experiences.
Chronic kidney disease is a major health problem due to the significant financial burden for the healthcare system and likewise for the patient who needs the treatment. The patient's whole life situation is turned upside down with chronic kidney disease when they are confronted with the forced change to start treatment with hemodialysis. Patients with chronic kidney disease experience a lack of adequate emotional support from nurses during the transition to hemodialysis. The purpose of this study was to explore nurses' experiences of giving support to patients during the transition to hospital-bound hemodialysis. The study had a qualitative descriptive design with a content analysis approach; eight nurses from four hospitals in the south of Sweden participated. The results showed that the nurses gave threshold support with an openness and awareness of the patient's individual needs during the transition, except that there seemed to be a lack of knowledge and ability to provide emotional support. Patient support during the transition could therefore be absent. Education, at local and national levels, is needed for the nurse to be able to give professional emotional support. Further research is also desired in order to provide nurses with the tools they need to give emotional support, which is of utmost importance.


Requirement for HLA-DR+ accessory cells in natural killing of cytomegalovirus-infected fibroblasts.
The role of HLA-DR+ cells in NK activity against CMV-infected FS4 foreskin fibroblasts and K562 erythroleukemia cells was examined. When nonadherent PBMC were depleted of either HLA-DR+ or Leu-11b+ cells by treatment with mAbs plus C, NK activity against CMV-FS4 target cells was markedly reduced. In contrast, depletion of HLA-DR+ cells had no effect on NK activity against K562 target cells. When HLA-DR-depleted cells were added to Leu-11b-depleted cells, NK activity against CMV-FS4 was restored. Negative selection experiments indicated that the HLA-DR+ cells contributing to NK activity against CMV-FS4 are not B or T cells, while negative and positive selection experiments excluded a role for monocytes. Experiments in which HLA-DR- and Leu-11b- cells were mixed in varying proportions indicated that NK(CMV-FS4) is mediated by Leu-11b+ cells, while HLA-DR+ cells provide an accessory function. Irradiation (50 GY) abolished the NK effector function of Leu-11b+ cells, but not the accessory function of HLA-DR+ cells. The NK activity against CMV-FS4 of HLA-DR- cells was restored by the addition of rIFN-alpha or of cell-free supernatants generated by coculturing PBMC or Leu-11b- cells with CMV-FS4. The ability of these supernatants to restore NK activity of HLA-DR- cells was completely abrogated by the addition of neutralizing amounts of antibody to IFN-alpha. In related experiments, neutralization of IFN-alpha in NK assays had little or no effect on NK activity against CMV-FS4, suggesting that the accessory function of HLA-DR+ cells might be mediated by alternative mechanisms in addition to the secretion of extracellular IFN-alpha.


NMDA receptor genotypes associated with the vulnerability to develop dyskinesia.
Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl-D-aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism.


A computational study on the amine-oxidation mechanism of monoamine oxidase: insight into the polar nucleophilic mechanism.
The proposed polar nucleophilic mechanism of MAO was investigated using quantum chemical calculations employing the semi-empirical PM3 method. In order to mimic the reaction at the enzyme's active site, the reactions between the flavin and the p-substituted benzylamine substrate analogs were modeled. Activation energies and rate constants of all the reactions were calculated and compared with the published experimental data. The results showed that electron-withdrawing groups at the para position of benzylamine increase the reaction rate. A good correlation between the log of the calculated rate constants and the electronic parameter (sigma) of the substituent was obtained. These results agree with the previous kinetic experiments on the effect of p-substituents on the reduction of MAO-A by benzylamine analogs. In addition, the calculated rate constants showed a correlation with the rate of reduction of the flavin in MAO-A. In order to verify the results obtained from the PM3 method single-point B3LYP/6-31G*//PM3 calculations were performed. These results demonstrated a strong reduction in the activation energy for the reaction of benzylamine derivatives having electron-withdrawing substituents, which is in agreement with the PM3 calculations and the previous experimental QSAR study. PM3 and B3LYP/6-31G* energy surfaces were obtained for the overall reaction of benzylamine with flavin. Results suggest that PM3 is a reasonable method for studying this kind of reaction. These theoretical findings support the proposed polar nucleophilic mechanism for MAO-A.


Concussion Reporting and Safeguarding Policy Development in British American Football: An Essential Agenda.
The objective of this study was to examine concussion reporting and safeguarding policy in British American Football (BAF). Data were collected via an online survey tool. The data presented are part of a broader study that examined injury profiles, concussion reporting behaviors, and medical provision in BAF. Concussion-like symptoms were found in over half (58.8%) of the participants. Of those, 36.4% reported they had previously been formally diagnosed with a concussion while playing BAF. Just under half of the participants (44.7%) had suspected they had had a concussion, although it was not formally diagnosed, and 23.5% of the participants had previously hidden concussion symptoms. Fifty-eight percent of the teams reported they did not have a regular game-day medic, with a range of hired medical personnel who attended the games. Prominent barriers to hiring a medic included budget, institutional support shortfall, and lack of medic reliability and game knowledge. BAF is a developing sport with a clear vision for growth of participation. Yet, the current concussion and medical provision policies do not address the sport's welfare needs. Through discussion of these policies in the context of this study's findings, we highlight vital areas of concern in policy and practice that the British American Football Association needs to address in their medical and concussion policies.


Time Trends and Educational Inequalities in Out-of-Hospital Coronary Deaths in Norway 1995-2009: A Cardiovascular Disease in Norway (CVDNOR) Project.
Recent time trends and educational gradients characterizing out-of-hospital coronary deaths (OHCD) are poorly described. We identified all deaths from coronary heart disease occurring outside the hospital in Norway during 1995 to 2009. Time trends were explored using Poisson regression analysis with year as the independent, continuous variable. Information on the highest achieved education was obtained from The National Education Database and classified as primary (up to 10 years of compulsory education), secondary (high school or vocational school), or tertiary (college/university). Educational gradients in OHCD were explored using Poisson regression, stratified by sex and age (<70 and ≥70 years), and results were expressed as incidence rate ratios (IRRs) and 95%CIs. Of 100 783 coronary heart disease deaths, 58.8% were OHCDs. From 1995 to 2009, age-adjusted OHCD rates declined across all education categories (primary, secondary, and tertiary) in younger men (IRR=0.35; 95%CI 0.32-0.38; IRR=0.38; 95%CI 0.35-0.42; IRR=0.33; 95%CI 0.28-0.40), younger women (IRR=0.47; 95% CI 0.40-0.56; IRR=0.55; 95%CI 0.45-0.67; IRR=0.28; 95% CI 0.16-0.47), older men (IRR=0.20; 95%CI 0.19-0.22; IRR=0.20; 95%CI 0.18-0.22; IRR=0.20; 95%CI 0.17-0.23), and older women (IRR=0.26; 95%CI 0.24-0.28; IRR=0.25; 95%CI 0.23-0.28; IRR=0.28; 95%CI 0.22-0.34). Tertiary education was associated with lower risk of OHCD compared to primary education (IRR=0.37; 95%CI 0.35-0.40 in younger men, IRR=0.26; 95%CI 0.22-0.30 in younger women, IRR=0.52; 95%CI 0.49-0.55 in older men, and IRR=0.61; 95%CI 0.57-0.66 in older women). These gradients did not change over time (P interaction=0.25). Although OHCD rates declined substantially during 1995 to 2009, they displayed educational gradients that remained constant over time.


Alterations in the Urinary Microbiota Are Associated With Cesarean Delivery.
Similar to the gut, the bladder contains urinary microbiota, and its bacterial composition and structure are determined by the individual's health status. Cesarean section is a traumatic event for women and it is correlated with postpartum complications. To better understand the urinary microbiota alterations caused by cesarean section, 16S rDNA sequencing was used to assess urine specimens collected by transurethral catheterization from 30 healthy women undergoing cesarean section pre-delivery (PreD) and post-delivery (PostD). A significant increase in bacterial diversity and more detectable bacteria at the phylum, family, and genus levels was observed in the PostD group compared to the PreD group, indicating that cesarean delivery (a process that includes surgery and delivery) altered the bacterial community. Specifically, the phylum Firmicutes and its affiliated family Lactobacillaceae and genus Lactobacillus dramatically decreased in the PostD group, suggesting that beneficial bacteria decreased after cesarean section, and clinicians should be aware that this might increase the risk of complications. Concurrently, the phylum Proteobacteria and its affiliated bacteria Pseudomonadaceae and Pseudomonas increased in the PostD group compared to the PreD group. This indicates that pathogen growth increases after cesarean section, making it important for clinicians to combat these changes to protect women from infectious diseases. Interestingly, several metabolic pathways, such as metabolism of energy, cofactors and vitamins were strengthened in the PostD group, whereas membrane transport was lessened in this group. This suggests that women's metabolic disorders might be cured by balancing urinary microbiota. In conclusion, the altered urinary microbiota between the PreD and PostD periods appears to provide insight into how to prevent postpartum metabolic disorders.


Conceptualized Use of Self-Expanding Foam to Rescue Special Operators From Abdominal Exsanguination: Percutaneous Damage Control for the Forward Deployed.
Noncompressible hemorrhage is the leading cause of potentially survivable death on the battlefield. In Special Operations Forces (SOF), 50% of potentially survivable deaths have been related to noncompressible hemorrhage. Currently, there are no widely available presurgical interventions that can slow abdominal bleeding. Consequently, many of the preventable deaths occur en route to definitive care as a failure to rescue from exsanguination. A self-expanding polyurethane foam has been developed as a percutaneous damage control intervention to rescue casualties who would otherwise die of noncompressible hemorrhage, and allow them to survive long enough to reach surgical intervention. The purpose of this paper is to summarize the existing preclinical data, describe the role of SOF personnel in foam delivery-system development, and to integrate these together to conceptualize how foam could be incorporated into SOF medical care. All existing publications on self-expanding foam are reviewed. Additionally, eight SOF medical providers with combat experience provided end-user input to delivery-device design through an interactive human-factors testing process. Ten preclinical publications described efficacy, safety, dose translation, and risk-benefit analysis of exsanguination rescue with percutaneous-foam damage control. SOF medical providers guided weight, cubic, operational requirements, and limits for the foam delivery device. Presurgical exsanguination rescue with percutaneous foam damage control is safe and effective with a favorable risk-benefit profile in preclinical studies. Battlefield, presurgical use by SOF medical providers is conceptually possible. Adoption of the technology on the battlefield should proceed with SOF medical provider input.


Effect of intracanal medicaments used in endodontic regeneration on the push-out bond strength of a calcium-phosphate-silicate-based cement to dentin.
To evaluate the effects of various endodontic regeneration agents on the push-out bond strength of Endosequence Root Repair Material (ERRM) to root-canal dentin. Fifty single-rooted human teeth were selected and instrumented to obtain a standard internal diameter of 1.5 mm. Specimens were randomly divided into four experimental groups and treated with an intracanal medicament [calcium hydroxide (CH), double antibiotic paste (DAP), triple antibiotic paste (TAP), TAP with amoxicillin (mTAP)] and a non-treated control group. Medicaments were removed after three weeks, and ERRM was applied to all specimens. The coronal portion of each root was then sliced into 2-mm-thick parallel transverse sections (2 slices per tooth, n=20 slices per group), and a push-out test was used to measure the bond strength of ERRM to dentin. Data were analyzed using Bonferroni-corrected Mann-Whitney tests, with the level of significance set at p<0.05. The push-out bond strength of the CH group was significantly higher than that of the TAP, DAP and mTAP groups (p< 0.005). Furthermore, the bond strength of the control group was higher than the bond strength of both the DAP and mTAP groups. The use of CH in clinical practice may help improve the adhesion of ERRM to dentin.


Chronic time abuse.
Anyone who has ever managed people who abuse time--whether they are chronic procrastinators or individuals who work obsessively to meet deadlines weeks in advance--knows how disruptive they can be to a business's morale and operating efficiency. But lessons in time management will have no impact on these employees. That's because real time abuse results from psychological conflict that neither a workshop nor a manager's cajoling can cure. Indeed, the time abuser's quarrel isn't even with time but rather with a brittle self-esteem and an unconscious fear of being evaluated and found wanting. This article describes four types of time abusers typically encountered in the workplace: Perfectionists are almost physically afraid of receiving feedback. Their work has to be "perfect," so they can increase their likelihood of earning a positive evaluation or at least avoid getting a negative one. Preemptives try to be in control by handing in work far earlier than they need to, making themselves unpopular and unavailable in the process. People pleasers commit to far too much work because they find it impossible to say no. Procrastinators make constant (and often reasonable-sounding) excuses to mask a fear of being found inadequate in their jobs. Managing these four types of people can be challenging, since time abusers respond differently from most other employees to criticism and approval. Praising a procrastinator when he is on time, for instance, will only exacerbate the problem, because he will fear that your expectations are even higher than before. In fact, some time abusers, like the perfectionist, may need professional treatment. This article will give you insight into why they are the way they are--and what can be done to help them manage their problems.


The evolution of primary progressive apraxia of speech.
Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49-76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.


In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B.
NF-kappa B is a major inducible transcription factor in many immune and inflammatory reactions. Its activation involves the dissociation of the inhibitory subunit I kappa B from cytoplasmic NF-kappa B/Rel complexes, following which the Rel proteins are translocated to the nucleus, where they bind to DNA and activate transcription. Phosphorylation of I kappa B in cell-free experiments results in its inactivation and release from the Rel complex, but in vivo NF-kappa B activation is associated with I kappa B degradation. In vivo phosphorylation of I kappa B alpha was demonstrated in several recent studies, but its role is unknown. Our study shows that the T-cell activation results in rapid phosphorylation of I kappa B alpha and that this event is a physiological one, dependent on appropriate lymphocyte costimulation. Inducible I kappa B alpha phosphorylation was abolished by several distinct NF-kappa B blocking reagents, suggesting that it plays an essential role in the activation process. However, the in vivo induction of I kappa B alpha phosphorylation did not cause the inhibitory subunit to dissociate from the Rel complex. We identified several protease inhibitors which allow phosphorylation of I kappa B alpha but prevent its degradation upon cell stimulation, presumably through inhibition of the cytoplasmic proteasome. In the presence of these inhibitors, phosphorylated I kappa B alpha remained bound to the Rel complex in the cytoplasm for an extended period of time, whereas NF-kappa B activation was abolished. It appears that activation of NF-kappa B requires degradation of I kappa B alpha while it is a part of the Rel cytoplasmic complex, with inducible phosphorylation of the inhibitory subunit influencing the rate of degradation.


Taurine transporter is expressed in osteoblasts.
Taurine influences bone metabolism and is taken up by cells via a specific transport system, the taurine transporter (TAUT). We report a link between taurine and bone homeostasis by demonstrating transcription and translation of TAUT in bone-forming cells. TAUT was expressed in human primary osteoblasts, the human osteosarcoma osteoblast-like cell line MG63, and the mouse osteoblastic cell line MC3T3-E1. Immunostaining with polyclonal antibodies also demonstrated the presence of TAUT in both human and murine osteoblasts. TAUT mRNA expression and [(3)H]taurine uptake increased during differentiation of MG63 cells in culture. Supplementation of culture medium with taurine enhanced alkaline phosphatase activity and osteocalcin secretion. The regulation and detailed function of taurine and TAUT in bone remain unclear, but our findings suggest a functional role for them in bone homeostasis.


Processing of the Müller-Lyer illusion by a Grey parrot (Psittacus erithacus).
Alex, a Grey parrot (Psittacus erithacus) who identifies the bigger or smaller of two objects by reporting its color or matter using a vocal English label and who states "none" if they do not differ in size, was presented with two-dimensional Müller-Lyer figures (Brentano form) in which the central lines were of contrasting colors. His responses to "What color bigger/ smaller?" demonstrated that he saw the standard length illusion in the Müller-Lyer figures in 32 of 50 tests where human observers would also see the illusion and reported the reverse direction only twice. He did not report the illusion when (a) arrows on the shafts were perpendicular to the shafts or closely approached perpendicularity, (b) shafts were 6 times thicker than the arrows, or (c) after being tested with multiple exposures conditions that also lessen or eliminate the illusion for human observers. These data suggest that parrot and human visual systems process the Müller-Lyer figure in analogous ways despite a 175-fold difference in the respective sizes of their brain volumes. The similarity in results also indicates that parrots with vocal abilities like Alex's can be reliably tested on visual illusions with paradigms similar to those used on human subjects.


Tuning of a basic coordination pattern constructs straight-ahead and curved walking in humans.
We tested the hypothesis that common principles govern the production of the locomotor patterns for both straight-ahead and curved walking. Whole body movement recordings showed that continuous curved walking implies substantial, limb-specific changes in numerous gait descriptors. Principal component analysis (PCA) was used to uncover the spatiotemporal structure of coordination among lower limb segments. PCA revealed that the same kinematic law accounted for the coordination among lower limb segments during both straight-ahead and curved walking, in both the frontal and sagittal planes: turn-related changes in the complex behavior of the inner and outer limbs were captured in limb-specific adaptive tuning of coordination patterns. PCA was also performed on a data set including all elevation angles of limb segments and trunk, thus encompassing 13 degrees of freedom. The results showed that both straight-ahead and curved walking were low dimensional, given that 3 principal components accounted for more than 90% of data variance. Furthermore, the time course of the principal components was unchanged by curved walking, thereby indicating invariant coordination patterns among all body segments during straight-ahead and curved walking. Nevertheless, limb- and turn-dependent tuning of the coordination patterns encoded the adaptations of the limb kinematics to the actual direction of the walking body. Absence of vision had no significant effect on the intersegmental coordination during either straight-ahead or curved walking. Our findings indicate that kinematic laws, probably emerging from the interaction of spinal neural networks and mechanical oscillators, subserve the production of both straight-ahead and curved walking. During locomotion, the descending command tunes basic spinal networks so as to produce the changes in amplitude and phase relationships of the spinal output, sufficient to achieve the body turn.


Risk factors for colorectal cancer in Taiwan: a hospital-based case-control study.
There have been few studies of the risk factors associated with colorectal cancer in Taiwan, a country of low incidence of the disease. This study investigated whether dietary and lifestyle factors correlate with colorectal cancer risks in Taiwan. A total of 352 patients with colon cancer and 375 patients with rectal cancer histologically confirmed between 1995 to 1999 at a medical center in northern Taiwan were included in the study. They were age- and gender-matched with 736 healthy controls who were recruited from the health examination clinic at the same hospital. Dietary intake and lifestyle variables were ascertained using a standardized questionnaire. Unconditional multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The risk of colon cancer and of rectal cancer was inversely associated with vegetable/fruit consumption in both men and women. The adjusted ORs based on the highest versus the lowest tertile consumption were 0.36 (95% CI, 0.21 to 0.61) and 0.44 (95% CI, 0.27 to 0.72) for men, respectively. The corresponding ORs for women were 0.32 (95% CI, 0.19 to 0.56) and 0.39 (95% CI, 0.23 to 0.69), respectively. However, the highest versus the lowest tertile meat consumption was associated with significantly elevated risk in both men and women for both colon cancer (ORs, 1.85 and 2.29, respectively) and rectal cancer (ORs, 2.32 and 2.42, respectively). Risk also increased with less exercise, low or moderate coffee consumption, cigarette smoking and alcohol intake, and decreased with the frequency of fish/shrimp consumption among men. Consistent with the findings of previous studies in Western populations, this study found that vegetable and fruit consumption, less meat consumption, and exercise were associated with a reduced incidence of colorectal cancer in Taiwanese.


Overcoming the challenges associated with symptom management in palliative care.
End of life (EOL) care is a topic that many families have difficulty discussing. A number of families are uncomfortable with accepting the fact that death is a part of every human's reality. Ideas and thoughts of death are interpreted differently across various cultures, and lacking to discuss disease trajectory and what to expect down the road with a physician, brings forward conflict during EOL care. Let us consider the complexities of treating Mr. X who is an 80-year-old male of Italian background with a history of advanced lung cancer with metastasis to the brain. He was recently diagnosed and his health began to rapidly decline at home. Mr. X is used in this case study to explore the challenges in providing care in a palliative care unit (PCU), and the ways in which we can overcome them.


Television habits in relation to overweight, diet and taste preferences in European children: the IDEFICS study.
Early television exposure has been associated with various health outcomes including childhood obesity. This paper describes associations between patterns of television viewing, on one hand, and diet, taste preference and weight status, on the other, in European preschoolers and schoolchildren. The IDEFICS baseline survey was conducted at examination centers in Italy, Estonia, Cyprus, Belgium, Sweden, Germany, Hungary, and Spain. 15,144 children aged 2-9 completed the basic protocol, including anthropometry and parental questionnaires on their diets and television habits. A subsample of 1,696 schoolchildren underwent further sensory testing for fat and sweet taste preferences. Three dichotomous indicators described: children's habitual television exposure time; television viewing during meals; and having televisions in their bedrooms. Based on these variables we investigated television habits in relation to overweight (IOTF) and usual consumption of foods high in fat and sugar. A possible role of taste preference in the latter association was tested in the sensory subgroup. All television indicators were significantly associated with increased risk of overweight, with odds ratios ranging from 1.21 to 1.30, in fully adjusted models. Children's propensities to consume high-fat and high-sugar foods were positively and, in most analyses, monotonically associated with high-risk television behaviors. The associations between television and diet propensities were not explained by preference for added fat or sugar in test foods. To summarize, in addition to being more overweight, children with high-risk television behaviors may, independent of objectively measured taste preferences for fat and sugar, passively overconsume higher-fat and particularly higher-sugar diets.


Chloride extrusion enhancers as novel therapeutics for neurological diseases.
The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.


Comparative assessment of the safety and effectiveness of radiofrequency ablation among elderly medicare beneficiaries with hepatocellular carcinoma.
Radiofrequency ablation (RFA) use among patients with hepatocellular carcinoma (HCC) has increased dramatically over the last decade, but assessments outside specialized centers are lacking. This population-based study was intended to evaluate the safety and effectiveness of RFA when used to treat HCC. A cohort study of HCC patients (diagnosed 2002-2005) was performed using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Early (≤90-day) mortality and readmission as well as survival among patients undergoing RFA, resection, or no treatment were compared using multivariate and propensity score adjusted Poisson and Cox regression models. Of 2631 patients (mean age 76.1±6.1 years, 65.9% male), 16% underwent RFA (49.6%) or resection (50.4%). Early mortality (13.6 vs. 18.7%, P=.16) and readmission (34.5 vs. 32.1%, P=.60) rates were similar among RFA and resection patients. The 1-year survival after RFA and resection was similar (72.2 vs. 79.7%, P=.18), but beyond 3 years there was a survival benefit among patients undergoing resection (39.2 vs. 58.0%, P<.001). Patients treated with RFA as a sole therapeutic intervention in the 1st year had a similar hazard of death compared with untreated patients (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.54-1.33). In the general community, patients treated with RFA have a similar risk of early adverse events compared with those treated with resection with no clear survival benefit when used as a sole intervention. Although RFA has been described as a safe and effective treatment for HCC at specialized centers, this experience may not extrapolate to the general community and requires further evaluation.


Statin use and lung cancer risk in chronic obstructive pulmonary disease patients: a population-based cohort study.
Patients living with chronic obstructive pulmonary disease (COPD) are at an increased risk of lung cancer. A common comorbidity of COPD is cardiovascular disease; as such, COPD patients often receive statins. This study sought to understand the association between statin exposure and lung cancer risk in a population-based cohort of COPD patients. We identified a population-based cohort of COPD patients based on having filled at least three prescriptions for an anticholinergic or short-acting beta-agonist (SABA). We used an array of methods of defining medication exposure including three conventional methods (ever statin exposure, cumulative duration of use, and cumulative dose) and two novel methods (recency-weighted cumulative duration of use and recency-weighted cumulative dose). To assess residual confounding, a negative control exposure was used to test the validity of our results. All exposure variables were time-dependent. The population-based cohort of COPD had 39,879 patients with mean age of 70.6 (SD: 11.2) years and, of which, 53.5% were female. There were 12,469 patients who received at least one statin prescription. Results from the reference case multivariable analysis indicated a reduced risk from statin exposure (HR: 0.85 (95% CI: 0.73-1.00) in COPD patients, but this result not statistically significant. Using the two recency-weighted modelling approaches, statin exposure was associated with a statistically significant reduction in lung cancer risk (recency-weighted cumulative dose, HR: 0.85 (95% CI: 0.77-0.93) and recency-weighted cumulative duration of use, HR: 0.97 (95% CI: 0.96-0.99). Multivariable analysis incorporating the negative control exposure was not statistically significant (HR: 0.89 (95% CI: 0.75-1.10). The results of this population-based analysis indicate that statin use in COPD patients may reduce the risk of lung cancer. While the effect was not statistically significantly across all exposure definitions, the overall results support the hypothesis that COPD patients might benefit from statin therapy.


Rotator cuff repair with biological graft augmentation causes adverse tissue outcomes.
Background and purpose - Biological patches can be used to augment rotator cuff tendon repair in an attempt to improve healing and reduce rates of re-rupture. However, little is known about the in vivo tissue response to these patches. We assessed native rotator cuff tissue response after surgical repair and augmentation with 2 commercially available extracellular matrix (ECM) patches. Patients and methods - Patients underwent a rotator cuff repair augmented with either GraftJacket (Wright Medical), Permacol (Zimmer Biomet), or no patch (Control), applied using an onlay technique. A sample of supraspinatus tendon was collected intraoperatively and 4 weeks post-surgery, using ultrasound-guided biopsy. Histology and immunohistochemistry were performed on all samples. Results - The Permacol group (n = 3) and GraftJacket group (n = 4) demonstrated some changes in native tendon ECM compared with the control group (n = 3). Significant disruption of the extracellular matrix of the repaired native supraspinatus, underlying both patches, was observed. The patches did not generally increase cellularity, foreign body giant cell count, or vascularity compared to the control group. 1 patient in the Permacol group had an adverse tissue immune response characterized by extensive infiltration of IRF5+, CD68+, and CD206+ cells, suggesting involvement of macrophages with a pro-inflammatory phenotype. No significant differences in protein expression of CD4, CD45, CD68, CD206, BMP7, IRF5, TGFß, and PDPN were observed among the groups. Interpretation - Histological and immunohistochemical analysis of native tendon tissue after patch augmentation in rotator cuff repair raises some concerns about a lack of benefit and potential for harm from these materials.


Antioxidant activity and nutritional assessment of under-utilized medicinal plants.
The present study investigates the nutritive and anti-nutritive composition of six species (Allium porrum, Amaranthus spinosis, Apium graveolens, Caralluma edulis, Chenopodium album, Urtica dioica). The studied species contained considerable amount of crude protein (4.53-11.41%), crude fat (1.25-3.74%), vitamin C (7.85-28.09mg 100-1 g) and β-Carotene (18.29-169.33mg 100-1g). The mineral profile of Chenopodium album is considered as potential source of Zn (14.51±1.14mg 100-1g), Mn (67.71±0.85mg 100-1g), Se (8.45±0.49mg 100-1g) and Fe (182.08±1.52mg 100-1g) and Caralluma edulis as potential source of Fe (7.28± 0.03mg 100-1g). Ca and P content ranged 63-306mg 100-1 g and 12-392mg 100-1 g in all studied plants with exceptionally high level was found in Chenopodium album (1084mg 100-1g) and (3924mg 100-1g), respectively. Similarly, total phenol, tannin and phytic acid were found in the range of 105-354, 5-90 and 10-85mg 100-1g, respectively. Total oxalates and soluble oxalates contents were below 200mg 100-1g in five examined plants with the exception of Chenopodium album (413mg 100-1g). Antioxidant activity of Caralluma edulis was found maximum while the rest of the examined plants had moderate levels.


The newt ribozyme is part of a riboprotein complex.
Strand-specific transcripts of a satellite DNA of the newts, Notophthalmus and Triturus, are present in cells in monomeric and multimeric sizes. These transcripts undergo self-catalyzed, site-specific cleavage in vitro: the reaction requires Mg2+ and is mediated by a "hammerhead" domain. Transcription of the newt ribozyme appears to be performed by RNA polymerase II under the control of a proximal sequence element and a distal sequence element. In vitro, the newt ribozyme can cleave in trans an RNA substrate, suggesting that in vivo it might be involved in RNA processing events, perhaps as a riboprotein complex. Here we show that the newt ribozyme is in fact present as a riboprotein particle of about 12 S in the oocytes of Triturus. In addition, reconstitution experiments and gel-shift analyses show that a complex is assembled in vitro on the monomeric ribozyme molecules. UV cross-linking studies identify a few polypeptide species, ranging from 31 to 65 kDa, associated to the newt ribozyme with different affinities. Finally, we find that an appropriate oligoribonucleotide substrate is specifically cleaved by the riboproteic activity in S-100 ovary extracts.


FAK signaling in human cancer as a target for therapeutics.
Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.


Relationship Between Hallux Valgus Interphalangeus Deformity and the Recurrence of Ingrown Toenail in Children.
An abnormal hallux interphalangeal angle may be an important risk factor for the recurrence of ingrown toenails. In this study, sixty pediatric patients who underwent surgery for an ingrown toenail were evaluated retrospectively in terms of recurrence. The patients were divided into two groups. Group 1 included 30 patients (22 male, 8 female) with hallux valgus interphalangeal deformity. Group 2 included 30 patients (20 male, 10 female) without toe deformity. The mean age was 12.8±1.42 years and 12.5±1.45 years for patients in Group 1 and in Group 2 respectively. There was no statistically significant difference between the patient and control group in terms of age and gender (p>0.05). The mean follow-up time was 40 months. We observed recurrence in six patients (20%) in Group 1 and in 2 patients (6.6%) in Group 2. We concluded that the recurrence of an ingrown toenail may be associated with increased hallux interphalangeal angle in pediatric patients. Factors related to the hallux interphalangeal angle abnormality, which increases the risk of ingrown toenails, also increase the recurrence rate in these patients. Therefore, it is surmised that hallux valgus interphalangeal deformity should be evaluated before surgery, and patients and their families should be informed about the risk of increased recurrence.


On reverse engineering of gene interaction networks using time course data with repeated measurements.
Gene expression measurements are the most common data source for reverse engineering gene interaction networks. When dealing with destructive sampling in time course experiments, it is common to average any available measurements for each time point and to treat this as the actual time series data for fitting the network, neglecting the variability contained in the repeated measurements. Proceeding in such a way can affect the retrieved network topology. We propose a fully Bayesian method for reverse engineering a gene interaction network, based on time course data with repeated measurements. The observations are treated as surrogate measurements of the underlying gene expression. As these measurements often contain outliers, we use a non-Gaussian specification for dealing with measurement error. The network interactions are assumed linear and an autoregressive model is specified, augmented with indicator variables that allow inference on the topology of the network. We analyse two in silico and one in vivo experiments, the latter dealing with the circadian clock in Arabidopsis thaliana. A systematic attenuation of the estimated regulation strengths and a concomitant overestimation of their precision is demonstrated when measurement error is disregarded. Thus, a clear improvement in the inferred topology for the synthetic datasets is demonstrated when this is included. Also, the influence of outliers in the retrieved network is demonstrated when using the in vivo data. Matlab code and data used in the article are available from http://go.warwick.ac.uk/majuarez/home/materials.


A dose-effect network meta-analysis model with application in antidepressants using restricted cubic splines.
Network meta-analysis has been used to answer a range of clinical questions about the preferred intervention for a given condition. Although the effectiveness and safety of pharmacological agents depend on the dose administered, network meta-analysis applications typically ignore the role that drugs dosage plays in the results. This leads to more heterogeneity in the network. In this paper, we present a suite of network meta-analysis models that incorporate the dose-effect relationship using restricted cubic splines. We extend existing models into a dose-effect network meta-regression to account for study-level covariates and for groups of agents in a class-effect dose-effect network meta-analysis model. We apply our models to a network of aggregate data about the efficacy of 21 antidepressants and placebo for depression. We find that all antidepressants are more efficacious than placebo after a certain dose. Also, we identify the dose level at which each antidepressant's effect exceeds that of placebo and estimate the dose beyond which the effect of antidepressants no longer increases. When covariates were introduced to the model, we find that studies with small sample size tend to exaggerate antidepressants efficacy for several of the drugs. Our dose-effect network meta-analysis model with restricted cubic splines provides a flexible approach to modelling the dose-effect relationship in multiple interventions. Decision-makers can use our model to inform treatment choice.