A long noncoding RNA influences the choice of the X chromosome to be inactivated

X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element (Xce). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA, one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist. This effect is counteracted by enhanced binding of Rex1 in DxPas34, another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34, and that Lppnx represents a decisive factor in explaining the action of the Xce

Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling

Gallium-68 (68Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. 68Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex 68Ga3+. Ideally, the chelator will rapidly, quantitatively and stably coordinate 68Ga3+ at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based 68Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with 68Ga3+ is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for 68Ga3+ under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5–50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective 68Ga3+ chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for 68Ga3+ complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of 68Ga-biomolecules for molecular PET imaging. LC-MS and 1H, 13C{1H} and 71Ga NMR studies of HBED complexes of Ga3+ showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral [Ga(HBED)(H2O)], with HBED coordinated in a pentadentate N2O3 mode, with only one phenolic group coordinated to Ga3+, and the remaining coordination site occupied by a water molecule

A feasibility trial to examine the social norms approach for the prevention and reduction of licit and illicit drug use in European University and college students.

Background: Incorrect perceptions of high rates of peer alcohol and tobacco use are predictive of increased personal use in student populations. Correcting misperceptions by providing feedback has been shown to be an effective intervention for reducing licit drug use. It is currently unknown if social norms interventions are effective in preventing and reducing illicit drug use in European students. The purpose of this paper is to describe the design of a multi-site cluster controlled trial of a web-based social norms intervention aimed at reducing licit and preventing illicit drug use in European university students. Methods/Design: An online questionnaire to assess rates of drug use will be developed and translated based on existing social norms surveys. Students from sixteen universities in seven participating European countries will be invited to complete the questionnaire. Both intervention and control sites will be chosen by convenience. In each country, the intervention site will be the university that the local principal investigator is affiliated with. We aim to recruit 1000 students per site (baseline assessment). All participants will complete the online questionnaire at baseline. Baseline data will be used to develop social norms messages that will be included in a web-based intervention. The intervention group will receive individualized social norms feedback. The website will remain online during the following 5 months. After five months, a second survey will be conducted and effects of the intervention on social norms and drug use will be measured in comparison to the control site. Discussion: This project is the first cross-national European collaboration to investigate the feasibility of a social norms intervention to reduce licit and prevent illicit drug use among European university students. Final trial registration number DRKS00004375 on the ‘German Clinical Trials Register’.This study is funded by the European Commission, Directorate General Justice, Freedom and Security (JLS/2009-2010/DPIP/AG

ABCD Neurocognitive Prediction Challenge 2019: Predicting individual residual fluid intelligence scores from cortical grey matter morphology

We predicted residual fluid intelligence scores from T1-weighted MRI data available as part of the ABCD NP Challenge 2019, using morphological similarity of grey-matter regions across the cortex. Individual structural covariance networks (SCN) were abstracted into graph-theory metrics averaged over nodes across the brain and in data-driven communities/modules. Metrics included degree, path length, clustering coefficient, centrality, rich club coefficient, and small-worldness. These features derived from the training set were used to build various regression models for predicting residual fluid intelligence scores, with performance evaluated both using cross-validation within the training set and using the held-out validation set. Our predictions on the test set were generated with a support vector regression model trained on the training set. We found minimal improvement over predicting a zero residual fluid intelligence score across the sample population, implying that structural covariance networks calculated from T1-weighted MR imaging data provide little information about residual fluid intelligence.Comment: 8 pages plus references, 3 figures, 2 tables. Submission to the ABCD Neurocognitive Prediction Challenge at MICCAI 201

Primate modularity and evolution: first anatomical network analysis of primate head and neck musculoskeletal system

Network theory is increasingly being used to study morphological modularity and integration. Anatomical network analysis (AnNA) is a framework for quantitatively characterizing the topological organization of anatomical structures and providing an operational way to compare structural integration and modularity. Here we apply AnNA for the first time to study the macroevolution of the musculoskeletal system of the head and neck in primates and their closest living relatives, paying special attention to the evolution of structures associated with facial and vocal communication. We show that well-defined left and right facial modules are plesiomorphic for primates, while anthropoids consistently have asymmetrical facial modules that include structures of both sides, a change likely related to the ability to display more complex, asymmetrical facial expressions. However, no clear trends in network organization were found regarding the evolution of structures related to speech. Remarkably, the increase in the number of head and neck muscles – and thus of musculoskeletal structures – in human evolution led to a decrease in network density and complexity in humans

Selective scattering between Floquet-Bloch and Volkov states in a topological insulator

The coherent optical manipulation of solids is emerging as a promising way to engineer novel quantum states of matter. The strong time periodic potential of intense laser light can be used to generate hybrid photon-electron states. Interaction of light with Bloch states leads to Floquet-Bloch states which are essential in realizing new photo-induced quantum phases. Similarly, dressing of free electron states near the surface of a solid generates Volkov states which are used to study non-linear optics in atoms and semiconductors. The interaction of these two dynamic states with each other remains an open experimental problem. Here we use Time and Angle Resolved Photoemission Spectroscopy (Tr-ARPES) to selectively study the transition between these two states on the surface of the topological insulator Bi2Se3. We find that the coupling between the two strongly depends on the electron momentum, providing a route to enhance or inhibit it. Moreover, by controlling the light polarization we can negate Volkov states in order to generate pure Floquet-Bloch states. This work establishes a systematic path for the coherent manipulation of solids via light-matter interaction.Comment: 21 pages, 6 figures, final version to appear in Nature Physic

Male characteristics as predictors of genital color and display variation in vervet monkeys

In the animal kingdom, conspicuous colors are often used for inter-and intra-sexual communication. Even though primates are the most colorful mammalian taxon, many questions, including what potential information color signals communicate to social partners, are not fully understood. Vervet monkeys (Chlorocebus pygerythrus) are ideal to examine the covariates of color signals. Males have multi-colored genitals, which they present during distinctive male-male interactions, known as the "Red-White-and-Blue" (RWB) display, but the genitals are also visible across a variety of other contexts, and it is unclear what this color display signals to recipients. We recorded genital color presentations and standardized digital photos of male genitals (N = 405 photos) over one mating season for 20 adult males in three groups at the Samara Private Game Reserve, South Africa. We combined these with data on male characteristics (dominance, age, tenure length, injuries, and fecal glucocorticoid metabolite concentrations). Using visual modeling methods, we measured single colors (red, white, blue) but also the contrasts between colors. We assessed the frequency of the RWB genital display and male variation in genital coloration and linked this to male characteristics. Our data suggest that the number of genital displays increased with male dominance. However, none of the variables investigated explained the inter-and intra-individual variation in male genital coloration. These results suggest that the frequency of the RWB genital display, but not its color value, is related to dominance, providing valuable insights on covariation in color signals and their display in primates. Significance statement Conspicuous colors in animals often communicate individual quality to mates and rivals. By investigating vervet monkeys, a primate species in which males present their colorful genitals within several behavioral displays, we aim to identify the covariates Communicated by E. Huchard Electronic supplementary material The online version of this article (https://doi.org/10

Understanding innovators' experiences of barriers and facilitators in implementation and diffusion of healthcare service innovations: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund - Copyright @ 2011 Barnett et al.Background: Healthcare service innovations are considered to play a pivotal role in improving organisational efficiency and responding effectively to healthcare needs. Nevertheless, healthcare organisations encounter major difficulties in sustaining and diffusing innovations, especially those which concern the organisation and delivery of healthcare services. The purpose of the present study was to explore how healthcare innovators of process-based initiatives perceived and made sense of factors that either facilitated or obstructed the innovation implementation and diffusion. Methods: A qualitative study was designed. Fifteen primary and secondary healthcare organisations in the UK, which had received health service awards for successfully generating and implementing service innovations, were studied. In-depth, semi structured interviews were conducted with the organisational representatives who conceived and led the development process. The data were recorded, transcribed and thematically analysed. Results: Four main themes were identified in the analysis of the data: the role of evidence, the function of inter-organisational partnerships, the influence of human-based resources, and the impact of contextual factors. "Hard" evidence operated as a proof of effectiveness, a means of dissemination and a pre-requisite for the initiation of innovation. Inter-organisational partnerships and people-based resources, such as champions, were considered an integral part of the process of developing, establishing and diffusing the innovations. Finally, contextual influences, both intra-organisational and extra-organisational were seen as critical in either impeding or facilitating innovators' efforts. Conclusions: A range of factors of different combinations and co-occurrence were pointed out by the innovators as they were reflecting on their experiences of implementing, stabilising and diffusing novel service initiatives. Even though the innovations studied were of various contents and originated from diverse organisational contexts, innovators' accounts converged to the significant role of the evidential base of success, the inter-personal and inter-organisational networks, and the inner and outer context. The innovators, operating themselves as important champions and being often willing to lead constructive efforts of implementation to different contexts, can contribute to the promulgation and spread of the novelties significantly.This research was supported financially by the Multidisciplinary Assessment of Technology Centre for Healthcare (MATCH)

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype

<p>Abstract</p> <p>Background</p> <p>Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant <it>in vitro </it>and <it>in vivo </it>PMP models.</p> <p>Methods</p> <p>Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development.</p> <p>Results</p> <p>Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category.</p> <p>Conclusion</p> <p>In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.</p