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Psychophysical studies have frequently found that adults with normal hearing exhibit systematic errors (biases) in their auditory localisation judgments. Here we tested (i) whether systematic localisation errors could reflect reliance on prior knowledge, as has been proposed for other systematic perceptual biases, and (ii) whether auditory localisation biases can be reduced following training with accurate visual feedback. Twenty-four normal hearing participants were asked to localise the position of a noise burst along the azimuth before, during, and after training with visual feedback. Consistent with reliance on prior knowledge to reduce sensory uncertainty, we found that auditory localisation biases increased when auditory localisation uncertainty increased. Specifically, participants mis-localised auditory stimuli as being more eccentric than they were, and did so more when auditory uncertainty was greater. However, biases also increased with eccentricity, despite no corresponding increase in uncertainty, which is not readily explained by use of a simple prior favouring peripheral locations. Localisation biases decreased (improved) following training with visual feedback, but the reliability of the visual feedback stimulus did not change the effects of training. We suggest that further research is needed to identify alternative mechanisms, besides use of prior knowledge, that could account for increased perceptual biases under sensory uncertainty.

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

DNA may be represented by sequences of four symbols, but it is often useful to convert those symbols into real or complex numbers for further analysis. Several mapping schemes have been used in the past, but most of them seem to be unrelated to any intrinsic characteristic of DNA. The objective of this work was to study a mapping scheme that is directly related to DNA characteristics, and that could be useful in discriminating between different species. Recently, we have proposed a methodology based on the inter-nucleotide distance, which proved to contribute to the discrimination among species. In this paper, we introduce a new distance, the distance to the nearest dissimilar nucleotide, which is the distance of a nucleotide to first occurrence of a different nucleotide. This distance is related to the repetition structure of single nucleotides. Using the information resulting from the concatenation of the distance to the nearest dissimilar and the inter-nucleotide distance, we found that this new distance brings additional discriminative capabilities. This suggests that the distance to the nearest dissimilar nucleotide might contribute with useful information about the evolution of the species.

Growth and relapse are driven by cancer stem cells (CSCs) in a subset of tumors, yet mechanisms driving cancer cell fate choices, maintenance and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity pathway (Wnt/PCP), regulates CSCs self-renewal in human rhabdomyosarcoma (RMS) – a common pediatric cancer of muscle. Wnt/PCP signaling is essential during development and recent work has linked this pathway to cancer growth, invasion and metastasis. However, roles for Vangl2 in regulating tumor self-renewal have not been previously described. Here, we show that VANGL2 is expressed in a majority of human RMS, specifically within early mononuclear progenitor-like cells. VANGL2 depletion inhibited proliferation, reduced self-renewal, and induced differentiation of human RMS. VANGL2 was also required for continued tumor growth and maintenance following engraftment of human RMS using mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS) and limiting dilution cell transplantation approaches, we identified that Vangl2 expression enriches for CSCs in vivo and when transgenically expressed, at high levels elevates cancer stem cell number by 9-fold. Mechanistic studies revealed a role for RhoA downstream of Vangl2 in regulating maintenance of stem cell programs in human RMS. Our studies offer novel opportunities to isolate and characterize RMS cancer stem cells in vivo, and identify potential therapeutic targets for patient treatment. Citation Format: Madeline Hayes, Karin McCarthy, Alexander Jin, Sowmya Iyer, Sara Garcia, Mariana L. Oliveira, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G Petur Nielsen, Jean-Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron Ignatius, David M. Langenau. Vangl2 regulates cancer stem cell self-renewal and growth in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3171.

Motivation: DNA sequences can be represented by sequences of four symbols, but it is often useful to convert the symbols into real or complex numbers for further analysis. Several mapping schemes have been used in the past, but they seem unrelated to any intrinsic characteristic of DNA. The objective of this work was to find a mapping scheme directly related to DNA characteristics and that would be useful in discriminating between different species. Mathematical models to explore DNA correlation structures may contribute to a better knowledge of the DNA and to find a concise DNA description. Results: We developed a methodology to process DNA sequences based on inter-nucleotide distances. Our main contribution is a method to obtain genomic signatures for complete genomes, based on the inter-nucleotide distances, that are able to discriminate between different species. Using these signatures and hierarchical clustering, it is possible to build phylogenetic trees. Phylogenetic trees lead to genome differentiation and allow the inference of phylogenetic relations. The phylogenetic trees generated in this work display related species close to each other, suggesting that the inter-nucleotide distances are able to capture essential information about the genomes. To create the genomic signature, we construct a vector which describes the inter-nucleotide distance distribution of a complete genome and compare it with the reference distance distribution, which is the distribution of a sequence where the nucleotides are placed randomly and independently. It is the residual or relative error between the data and the reference distribution that is used to compare the DNA sequences of different organisms. Contact: vera@ua.pt

It is not known whether the progressive airway changes in cystic fibrosis (CF) are all secondary to infection and inflammation. The CF mouse nose shares electrophysiologic and cellular properties with human CF airway epithelium. In the present work, we tested the hypothesis that structural abnormalities in the nasal mucosa of CF mice develop independent of infection and inflammation. We performed nasal lavage and subsequent serial coronal section through the nasal tissue of adult CF (mutations Cftr(TgHm1G551D) and Cftr(tm1Unc)-TgN((FABPCFTR))) and wild-type mice raised under normal housing conditions. Nasal tissue was also obtained from Day 17 embryos and newborn pups. Detailed histologic examination of the respiratory and olfactory epithelium within the nasal cavity was performed. Bacterial culture, cell count, and macrophage inflammatory protein-2 (MIP-2) concentration were assessed in nasal lavage fluid. Significantly thickened respiratory epithelium and increased mucous cell density was found in adult CF mice of both mutations compared with wild-type animals. In contrast, the olfactory epithelium was thinner, with a decreased cell density. Areas of lymphoid aggregates were found in CF mice but not in non-CF mice. There were no differences in bacterial growth, cell count, or MIP-2 concentrations. No genotype differences were observed in the embryonic or newborn periods. There are significant histologic changes in the nasal mucosa of adult CF mice, not associated with increased lumenal inflammation or bacterial content, and which are not present perinatally. These may be novel therapeutic targets.

Predictive modeling of natural resources has long relied on mechanistic descriptions incorporating various population attributes and to a lesser extent environmental conditions. A radical departure from this tradition is proposed, advocating the data-driven analysis and forecasting of population cycles from historical records, and using the Atlantic white shrimp, Litopenaeus setiferus, as a case study. The time series data were collected in the Charleston Harbor (32°47′00″N, 79°56′00″W), South Carolina, USA, and from the database of the National Marine Fisheries Service (http://www.st.nmfs.gov/st1/commercial/index.html), for the period between January 1986 and December 2004. Correlations between shrimp population cycles and environmental hydrological parameters were established by phase space reconstruction, a technique central to most nonlinear time series analysis methods. Predictive models of future shrimp population levels were built using feed-forward artificial neural networks, a well-known machine learning technique. From several attempted strategies, predicting the state commercial harvest from the sampling of populations in the Charleston Harbor conducted by the South Carolina Department of Natural Resources proved to be optimal, with an accuracy of 92% for 1-month and 79% for 3-month ahead predictions, as measured by the nonparametric and nonlinear Spearman’s correlation coefficient. In addition, the shrimp population levels seem to be more sensitively to changes in surface water temperature than salinity, but the latter is also an important consideration. These models also suggest that catch-per-unit-effort data are important indicators of commercial harvest and, thus, provide an important linkage between monitoring programs and commercial returns, enabling accurate predictions of natural resources to be made in near real time and extended beyond the critical time frames within which resource managers operate.

The vehicle suspension system is responsible for comfort, safety and vehicle control. In order to positively manipulate these properties, control and estimation theory are used to adapt the system to different road conditions. This paper considers three estimation methods, which are designed to retrieve the system states using only acceleration measures: the Kalman Filter, Particle Filter and Artificial Neuronal Network. Also it considers two control methods: LQR, pole location, which it minimizes, the chassis acceleration (a variable used to improve the vehicle comfort). Finally the controllers and estimators are implemented in simulation, using the model of the Quanser active suspension plant. This plant corresponds to a linear dynamic system and is considered in this paper because it resembles a quarter-car suspension.

Prescribing errors (PE) are frequent, cause significant harm to patients and prove costly. Few studies demonstrate the impact of pharmacist interventions. The objectives of this study were to characterize the severity and cost of the potential outcome of PE that pharmacists can prevent and to develop an economic analysis.We performed a non-randomized, prospective, observational study of all prescriptions made to adult patients admitted to a 1300-bed tertiary teaching hospital in Madrid (Spain) by means of a computerized physician order entry tool combined with a clinical decision support system. We analysed PE intercepted through the pharmacist validation process between January and June 2013. An independent team determined the severity of the potential adverse drug event (ADE) and the probability of causing an ADE (PAE). We estimated the cost avoidance and performed an economic analysis. A kappa statistic was used to verify inter-observer agreement.484 PE were intercepted: 36.2% of PE were classified as being of minor severity, 59.1% as moderate and 4.7% as serious. The most common type of moderate-serious PE found was excessive dose (30%, 94/309), followed by insufficient dose (20%, 62/309), and omission (19%, 58/309). The most frequent families of drugs involved in moderate-serious PE were antineoplastic agents (22.3%, 69/309) and antimicrobials (17.2%, 53/309). The PAE was higher than 40% in 49% of PE. We estimated a cost avoidance of €291,422 and a return on investment of €1.7 for each €1 spent on a pharmacist's salary. The overall inter-rater agreement for the participants was moderate for severity (κ = 0.57; P0.005) and strong for the PAE (κ = 0.77; P0.005).Pharmacists add important value in preventing PE, and their interventions are financially beneficial for the institution.

Made available in DSpace on 2016-02-05T18:29:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-09-04. Added 1 bitstream(s) on 2016-02-05T18:33:38Z : No. of bitstreams: 1 000857052.pdf: 1462313 bytes, checksum: 1130088ef99c05b4480965b6a879902e (MD5) O problema, alvo desta pesquisa, resume-se na seguinte pergunta: As práticas pedagógicas, exercidas no ciclo alfabetização do Ensino Fundamental, atendem às necessidades de aprendizado dos alunos com deficiência Intelectual em seu processo de inclusão escolar? Segundo relatos de docentes da rede municipal, o índice de insucesso no aprendizado entre alunos com deficiência intelectual, inclusos no ciclo alfabetização do Ensino Fundamental, é relevante e preocupante. A partir dos discursos dos professores, buscamos Identificar e analisar as práticas pedagógicas utilizadas pelos professores no ciclo alfabetização do Ensino Fundamental com alunos em processo de inclusão e a contribuição de tais práticas pedagógicas para o processo de aprendizagem e de inclusão escolar, as quais constituem os objetivos deste trabalho. Para isso, observamos quais são os critérios mais utilizados pelos professores para tratar com as diferenças em sala de aula, considerando-se a relações dessas práticas com os pressupostos oficiais da Educação Inclusiva. A pesquisa foi realizada em duas etapas. A primeira compõe-se do levantamento bibliográfico de referencial teórico e documentos, dentre eles o projeto político pedagógico e trabalhos de diversos autores que discorrem sobre a questão das práticas pedagógicas, inclusão e alfabetização. A segunda compõe-se do relato de pesquisa feito em escolas regulares municipais de Limeira/SP, por meio de observação nas salas de aula frequentadas por alunos deficientes intelectuais e entrevista estruturada com os professores das salas do ciclo alfabetização, sendo 11 professores participantes em 10 escolas da rede regular de ensino. Os resultados dessa pesquisa mostram que a alfabetização - aprendizagem da leitura e escrita do aluno incluso não integra o trabalho docente, isso se manifesta nas aulas pela ausência de empenho dos professores para a inserção dessas atividades, questão... The problem, this research focus, sum up in the following question: Do the pedagogical practices, performed in the literacy cycle of Elementary Education, meet the intellectually disabled students' learning needs in their process of school inclusion? According to the municipal schools teachers' reports, the index of failure in the learning among intellectually disabled students, included in the literacy cycle of Elementary Education is significant and worrisome. From the teachers' speaking, we sought to identify and analyze the pedagogical practices used by the teachers in the literacy cycle of Elementary Education with students in the process of inclusion and the contribution of such pedagogical practices to the learning process and school inclusion, which constitute the aims of this essay. For this purpose, we are going to observe what the most used criteria are to deal with the differences in class by teachers, considering the relation of these practices with the official prerequisites of the Inclusive Education. The research is performed in two stages. The first one consists of a bibliographical survey of theoretical framework and documents, among them the political pedagogical project and essays of several authors who argue about the matter of pedagogical practices, inclusion and literacy. The second one is composed of research reports done in regular municipal schools of Limeira/SP, by observing classrooms attended by intellectually disabled students and structured interviews with teachers of literacy cycle classrooms, being 11 participating teachers in 10 regular schools. The outcomes of this survey depict that the literacy, the included student's reading and writing learning, doesn't integrate the educator's work. This is evident in class due to the lack of teachers' commitment to the insertion of these activities, a point which gets worse faced with the possibility of these students, who took part in this research, ...

The aim of this review is to try to provide a conceptual framework on the mechanisms potentially responsible for sleep alteration in Parkinson’s disease (PD) based on data obtained in animals. We first provide state-of-the-art hypotheses on the mechanisms responsible for the succession of the three vigilance states, namely waking, non-rapid eye movement (non-REM) also called slow-wave sleep (SWS) and REM sleep also called paradoxical sleep (PS). We then review our knowledge on the role of dopamine in sleep-waking regulation. We pursue by discussing the results obtained on sleep in MPTP animal model of PD. We complete our review by providing hypotheses on the mechanisms responsible for REM sleep behavior disorder known to occur in half of the Parkinson’s patients based on studies of RBD animal models.

Resumen Fundamento El sindrome de Down (SD) es una alteracion genetica debida a la presencia de tres copias del cromosoma 21. Variaciones en los alelos del gen receptor de la vitamina D se han asociado a gran variedad de fenotipos y se han considerado factores de riesgo en determinadas poblaciones. En el presente trabajo se analiza si alguno de los genotipos del polimorfismo Bsm I del receptor de la vitamina D se presenta con mayor frecuencia en personas con SD con respecto a la poblacion general y la influencia que puede tener en diferentes fenotipos del SD. Pacientes y metodos Se estudiaron los polimorfismos del gen del receptor de la vitamina D en DNA de sangre periferica de 85 personas con SD y de 122 controles sin el sindrome. La determinacion de cada genotipo se realizo con amplificacion por tecnica de reaccion en cadena de la polimerasa (PCR) de los segmentos que contienen los polimorfismos situados en el intron 8 ( Bsm I ) . Se analizaron las diferencias de distribucion de genotipos entre los dos grupos, en el grupo con SD se relacionaron con diferentes parametros antroponometricos (edad, talla e indice de masa corporal), bioquimicos (calcio, vitamina D y paratohormona intacta) y con valores de masa osea por densitometria (DEXA). Resultados El analisis de distribucion del polimorfismo para Bsm I muestra una mayor frecuencia del alelo B en el grupo con SD y del b en los controles ( p = 0,015). En las personas con SD la combinacion de genotipos con respecto a los datos bioquimicos analizados y el resultado de la densitometria no muestra diferencias estadisticamente significativas. Sin embargo, el genotipo homocigoto bb es mas frecuente en los de talla alta ( p = 0,04) y el genotipo homocigoto BB en los de mayor edad ( p = 0,03). Conclusiones El alelo B del polimorfismo del intron 8 ( Bsm I ) del gen del receptor de la vitamina D es mas prevalente en personas con el SD. Los genotipos bb y BB son mas frecuentes en aquellas con el SD de mayor talla y mas longevas respectivamente, lo que hace pensar que estos podrian participar en estas dos caracteristicas fenotipicas del SD.

Background Down syndrome (DS) is a genetic alteration caused by having three copies of chromosome 21. Variations in the presence of alleles in the vitamin D receptor (VDR) gene have been linked to a variety in the phenotype and also considered a risk factor in some populations. In the present paper, we analyze whether a variation of the BsmI polymorphism in the VDR gene is overexpressed in patients with DS and whether it is related to any phenotype of the patients. Patients and methods We studied the BsmI polymorphism of the vitamin D receptor in DNA from peripheral blood of 85 patients with DS and 122 controls. The detection of each phenotype is performed by amplification of the DNA sequences of intron 8 of the VDR gene by polymerase chain reaction (PCR). We analyzed the differences in distribution of the alleles in patients with DS and the correlation of the genotype to different anthropometric (age, height, body mass index) and biochemical parameters (calcium, vitamin D,{PTH hormone, bone mass). Results The analysis of the distribution of the BsmI polymorphism showed a higher frequency of the B allele in the DS patients with respect to controls. In the same group of patients, regression analysis showed no link with any biochemical parameter. However, the homozygous genotype bb is more frequently found in taller individuals ( p = 0.04) and the BB in older individuals ( p = 0.03). Conclusions The B allele of the BsmI polymorphism of the VDR gene is more frequent in people with DS. The genotypes bb and BB are more frequent in taller and longer-living DS patients respectively. This result points out the possibility that VDR genotype could influence these two phenotypic characteristics of DS patients.

The phase behaviour of the binary mixture of carbon dioxide and the cobalt complex dicarbonyl(η 5 -cyclopentadienyl)-cobalt, CpCo(CO) 2 , has been investigated. This organometallic compound is one of the most effective catalysts of cyclotrimerization reactions of arylisocyanates and alkynes. Vapour–liquid equilibrium (VLE) measurements were undertaken in a static analytical apparatus at 313.15, 323.15 and 363.15 K at pressures up to 15 MPa. p , T isopleths were measured by a synthetic method in a Cailletet apparatus. Nine different compositions ranging from 17.56 to 94.23 mol% of CO 2 were measured up to 15 MPa. Modelling with the Peng–Robinson equation of state (PR EOS) gave reasonable results in the correlation of the experimental phase equilibrium compositions using two temperature-dependent interaction parameters.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of young children. The only current curative treatment is bone marrow transplantation. Yet even with this aggressive therapy, ~50% of children still die from their disease. Somatic mutations leading to constitutive activation of the non-receptor tyrosine phosphatase Shp2 (also called PTPN11) or of RAS signaling occur in >70% of JMML cases. However, the transcription factors that act downstream of these aberrant signaling events have not been identified. We recently showed that the key myelomonocytic transcription factor RUNX1 is inactivated by src-family kinase-mediated tyrosine phosphorylation (Huang et al. Genes Dev 2012;26:1587-1601). Moreover, we demonstrated that Shp2 directly dephosphorylates RUNX1 leading to RUNX1 relative activation. We now show that overexpression of a mutant RUNX1 that is resistant to SFK-mediated tyrosine phosphorylation (RUNX1Y260F, Y375F, Y378F, Y379F, Y386F—“RUNX1-5F”), mimicking constitutive dephosphorylation, causes cytokine-independent growth of Ba/F3 cells. Overexpression of RUNX15F in murine Lin- Sca-1+ c-kit+, (LSK) bone marrow cells leads to a dramatic expansion of Gr1+, Mac-1+ cells, and CFU-M/CFU-GM in vitro and in vivo. These effects are not seen when wild-type RUNX1 or RUNX1Y260D, Y375D, Y378D, Y379FD,Y386FD (“RUNX1-5D”; mimicking constitutive RUNX1 tyrosine phosphorylation) are overexpressed. The RUNX1-5F expressing cells have increased proliferation (BrdU incorporation), decreased apoptosis, and reduced cytokine dependence. Flow sorted Gr1+Mac1+ cells from the RUNX1-5F transduced cultures express higher levels of the direct RUNX1 target genes PU.1 and cyclin D1. RUNX1 haploinsufficiency in a Shp2 LSL-D61Y conditional knock-in JMML mouse model reduces the disease phenotype, and treatment with the RUNX1 inhibitor Ro5-3335 ameliorates cytokine-independent in vitro bone marrow colony growth from this mouse model. Gene expression analysis of CD34+ cells from JMML patients versus controls combined with RUNX1 CD34+ cell ChIP-seq data shows significant enrichment for RUNX1 chromatin occupancy at differentially expressed genes compared to all expressed genes. To test whether RUNX1 is required for the myelomonocytic hyperproliferation in JMML, CD34+ peripheral blood cells from a patient with JMML due to an activating Shp2 mutation (Shp2E78G) were lentivirally transduced with doxycylcine-inducible RUNX1-5D or RUNX1-5F expression constructs and cultured under myeloid growth conditions. Upon doxycycline induction, the RUNX1-5D overexpressing cells (resistant to Shp2) exhibited at 32% reduction in BrdU incorporation. In contrast, the control RUNX1-5F expressing cells had no significant reduction in proliferation. RUNX1 is also by direct ERK mediated phosphorylation (which is downstream of RAS/MEK). We propose that RUNX1 activation is an important common downstream consequence of both activated Shp2 and RAS signaling in the pathogenesis of JMML, and that RUNX1 inhibition may represent a novel therapeutic approach for this disorder. Citation Format: Elisa Dorantes-Acosta, Hui Huang, Sara P. Garcia, Elliot Stieglitz, Mignon Loh, Guo-Cheng Yuan, Alan B. Cantor. RUNX1 as a transcriptional target of activated Shp2 (PTPN11) in juvenile myelomonocytic leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 26.

GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine. The work described in this manuscript was primarily supported by the European Commission Seventh Framework Program through the BLUEPRINT grant with code HEALTH-F5-2011-282510 (DH, FB, GC, JHAM, KD, LC, MF, SC, SF and SPG). Research in the Ouwehand laboratory is further supported by program grants from the National Institute for Health Research (NIHR, http://www.nihr.ac.uk; to AA, MK, PP, SBGJ, SN, and WHO); and the British Heart Foundation under numbers RP-PG-0310-1002 and RG/09/12/28096 (http://www.bhf.org.uk; to AR and WJA). KF and MK were supported by Marie Curie funding from the NETSIM FP7 program funded by the European Commission. The Cambridge BioResource (http://www.cambridgebioresource.org.uk), the Cell Phenotyping Hub, and the Cambridge Translational GenOmics laboratory (http://www.catgo.org.uk) are supported by an NIHR grant to the Cambridge NIHR Biomedical Research Centre (BRC). Research in the Soranzo laboratory (LV, NS and SW) is further supported by the Wellcome Trust (Grant Codes WT098051 and WT091310) and the EU FP7 EPIGENESYS initiative (Grant Code 257082). Research in the Cvejic laboratory (AC and CL) is funded by the Cancer Research UK under grant number C45041/A14953. SJS is funded by NIHR. MEF is supported by a British Heart Foundation Clinical Research Training Fellowship, number FS/12/27/29405. EBM is supported by a Wellcome Trust grant, number 084183/Z/07/Z. FAC, CL and SW are supported by MRC Clinical Training Fellowships and TB by a British Society of Haematology/NHS Blood and Transplant grant. RJR is a Principal Research Fellow of the Wellcome Trust, grant No. 082961/Z/07/Z. Research in the Flicek laboratory is also supported by the Wellcome Trust (grant number 095908) and EMBL. Research in the Bertone laboratory is supported by EMBL. KF and CvG are supported by FWO-Vlaanderen through grant G.0B17.13N

Resumen La discinesia tardia es un efecto secundario grave de los antipsicoticos. A pesar de la introduccion de los nuevos antipsicoticos, siguen existiendo casos de discinesias tardias. Hay pocos estudios sobre el tratamiento de estos trastornos del movimiento, pero la clozapina sigue siendo el farmaco mas utilizado. A continuacion presentamos un caso de un paciente con esquizofrenia que sufrio discinesias tardias tras la supresion de un tratamiento con zuclopentixol. Posteriormente se introdujo clozapina, mejorando el cuadro hasta la remision clinica y consiguiendo una rehabilitacion psico-social del paciente.

This study investigates whether students’ assessments of male and female professors are influenced by traditional gender schema. Nearly 500 university students were surveyed about their perceptions of male and female faculty. Analysis of five factors reflecting teaching characteristics consistent with both stereotypically masculine and feminine traits revealed a significant interaction between student gender and professor gender. Female students rated female faculty especially high across five teaching dimensions and male faculty comparatively lower, while male students did not evaluate male and female professors as significantly different. Qualitative analysis reveals, however, that assessments of faculty were further influenced by the strength of students’ gender schema, and that gender schema may also lead to differential preference for particular teaching styles.

Single-incision laparoscopic surgery seems destined to take its place in the evolution of minimally invasive surgery. Although isolated cases have been reported in the literature, no series has yet been published on the use of this approach to treat colorectal cancer. We describe the surgical technique and perioperative outcomes of this approach in 15 patients diagnosed for colorectal cancer.We have used several devices to gain transumbilical access to the abdominal cavity, usually working with 3 cannulae to insert the instruments. We used a 5 mm endograsper, and articulated rotating (roticulating) endoscissors and endodissector to assist dissection. Vascular control and section of the rectum were performed using roticulating endostaplers. We combined the use of curved and straight instruments as required for each step during surgery. The dissection technique performed was the same as the one we normally use in conventional laparoscopy. Specimens were extracted through the umbilical incision.The most commonly performed procedure was sigmoidectomy (n=7), followed by high anterior resection of the rectum (n=5). The mean surgical time was 185±44.9 minutes. The mean hospital stay was 6.2±4.7 days. Three cases (20%) were converted to conventional laparoscopy. Surgery was curative in all of the patients.Single-access transumbilical laparoscopic surgery is feasible and safe for treating colorectal carcinoma when performed by surgeons with ample experience in laparoscopic colorectal resection. Further studies are needed to determine the advantages and drawbacks of this procedure.

Genome sequencing centers are flooding the scientific community with data. A single sequencing machine can nowadays generate more data in one day than any existing machine could have produced throughout the entire year of 2005. Therefore, the pressure for efficient sequencing data compression algorithms is very high and is being felt worldwide. Here, we describe GReEn (Genome Resequencing Encoding), a compression tool recently proposed for compressing genome resequencing data using a reference genome sequence.

Single strand symmetry has been observed in several genomes, and some authors have associated this phenomenon to genome evolution. However, it is still not clear how strong and exceptional this phenomenon is. We use next-generation sequencing data from a sample of 1,092 human individuals made available by the 1000 Genomes Project. To evaluate the phenomenon of symmetry of single-strand human genomic DNA, we explore and analyze these 1,092 human genomes and 1,092 randomly generated sequences, each forced to mimic the nucleotide frequency distribution of their real counterpart. Our methodology is based on measurements, traditional and equivalence statistical tests using different parameters. By statistical testing we find that the global symmetries phenomenon is significant for word lengths smaller than 8. When we evaluate the global symmetry scores, we obtain strong values for all word lengths and both types of sequences under study. However, the symmetry scores in human genomes reach higher values and have lower dispersion than those in random sequences. We also find that human and random symmetry scores are significantly different. We conclude that in the human genome, the differences between symmetric words are higher than in random sequences, but the correlation between symmetric words in human genomes is higher.

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Orientador: Marco Antonio Bueno Filho. Dissertação (mestrado) - Universidade Federal do ABC. Programa de Pós-Graduação em Ensino, História e Filosofia das Ciências e Matemática, 2013

Genome sequencing centers are flooding the scientific community with data. A single sequencing machine can nowadays generate more data in one day than any existing machine could have produced throughout the entire year of 2005. Therefore, the pressure for efficient sequencing data compression algorithms is very high and is being felt worldwide. Here, we describe GReEn (Genome Resequencing Encoding), a compression tool recently proposed for compressing genome resequencing data using a reference genome sequence.

We investigate Chargaff’s second parity rule and its extensions in the human genome, and evaluate its statistical significance. This phenomenon has been previously investigated in the reference human genome, but this sequence does not represent a proper sampling of the human population. With the 1000 genomes project, we have data from next-generation sequencing of different human individuals, constituting a sample of 1092 individuals. We explore and analyze this new type of data to evaluate the phenomenon of symmetry globally and for pairs of symmetric words.

In this study we set to explore the potentialities of the inter-genomic symbols distance for finding the coding regions in DNA sequences. We use the distance between STOP symbols in the DNA sequence and a chi-square statistic to evaluate the nonhomogeneity of the three possible reading frames. The results of this exploratory study suggest that inter-STOP symbols distance has strong ability to discriminate coding regions. published

Juvenile Myelomonocytic Leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm. Mutations leading to constitutive activation of the non-receptor tyrosine phosphatase Shp2 (PTPN11) and/or RAS signaling are driver events. Yet, the key downstream transcriptional effectors of this aberrant signaling have not been defined. We previously found that Shp2 dephosphorylates the hematopoietic transcription factor RUNX1, leading to its activation. Overexpression of a mutant RUNX1 molecule that mimics constitutive RUNX1 tyrosine dephosphorylation in murine hematopoietic stem/progenitor cells led to massive expansion of myelomonocytic cells and growth under low cytokine conditions. Likewise, RUNX1 is known to be activated by extracellular signal-related kinase (ERK) mediated phosphorylation, which is downstream of activated RAS. To further investigate the role of RUNX1 in JMML, we analyzed gene expression datasets derived from CD34+ cells from JMML patients versus healthy controls. Thirty-four genes were down regulated and 13 were up regulated in the JMML versus control CD34+ cells using a cut-off of a log2-fold change > 0 and false-discovery rate (FDR) adjusted p-value ≤ 0.1. H3K27Ac and K3K4Me1 peaks located between -50 kb 5' of the transcriptional start site (TSS) to +50 kb 3' of the transcriptional end site (TES) of the differentially expressed genes were used to identify putative enhancer elements. DNA-binding factor motif enrichment analysis was then performed at these regions. This revealed a significant enrichment for RUNX DNA consensus binding sequences in the putative enhancer elements (p-value 8.05e-03). There was also significant enrichment for ETS family transcription factors, including Spi1 (PU.1) (p-values 1.94e-06 to 1.21e-03) and for Serum Response Factor (SRF) (p-value 1.11e-04). ETS factors frequently physically and functionally cooperate with RUNX transcription factors. Analysis of the proximal promoters showed only enrichment for ETS factors (p-value 2.42e-04 to 4.02e-03) and BATF::JUN (4.64e-03). Examination of ChIP-seq datasets for RUNX1 and PU.1 in CD34+ cells from healthy controls demonstrated that many of these putative sites are occupied by RUNX1, and some with PU.1. Overall, this data supports a model in which RUNX1 (and likely ETS factors) are important transcriptional effectors of aberrant cell signaling in JMML. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

Single-cell gene expression data provide invaluable resources for systematic characterization of cellular hierarchy in multi-cellular organisms. However, cell lineage reconstruction is still often associated with significant uncertainty due to technological constraints. Such uncertainties have not been taken into account in current methods. We present ECLAIR (Ensemble Cell Lineage Analysis with Improved Robustness), a novel computational method for the statistical inference of cell lineage relationships from single-cell gene expression data. ECLAIR uses an ensemble approach to improve the robustness of lineage predictions, and provides a quantitative estimate of the uncertainty of lineage branchings. We show that the application of ECLAIR to published datasets successfully reconstructs known lineage relationships and significantly improves the robustness of predictions. ECLAIR is a powerful bioinformatics tool for single-cell data analysis. It can be used for robust lineage reconstruction with quantitative estimate of prediction accuracy.

Recent advances in DNA sequencing methodologies have caused an exponential growth of publicly available genomic sequence data. By consequence, many computational biologists have intensified studies in order to understand the content of these sequences and, in some cases, to search for association to disease. However, the lack of public available tools is an issue, specially when related to efficiency and usability. In this paper, we present Exon, a user-friendly solution containing tools for online analysis of DNA sequences through compression based profiles.

Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we explore different sets of minimal absent words in the genomes of 22 organisms (one archaeota, thirteen bacteria and eight eukaryotes). We investigate if the mutational biases that may explain the deficit of the shortest absent words in vertebrates are also pervasive in other absent words, namely in minimal absent words, as well as to other organisms. We find that the compositional biases observed for the shortest absent words in vertebrates are not uniform throughout different sets of minimal absent words. We further investigate the hypothesis of the inheritance of minimal absent words through common ancestry from the similarity in dinucleotide relative abundances of different sets of minimal absent words, and find that this inheritance may be exclusive to vertebrates.

We developed a methodology to process DNA sequences based on the inter-dinucleotide distances and we characterized the inter-dinucleotide distance distributions of the human genome. The distance distribution of each dinucleotide was compared to the distance distribution of all the other dinucleotides using the Kullback-Leibler divergence. We found out that the divergence between the distribution of the distances of a dinucleotide and that of its reversed complement is very small, indicating that these distance distributions are very similar. This is an interesting finding that might give evidence of a stronger parity rule than the one provided by Chargaff’s second parity rule. Furthermore, we also compared the distance distribution of each dinucleotide to a reference distribution, that of a random sequence generated with the same dinucleotide abundances, revealing the CG dinucleotide as the one with the highest cumulative relative error for the first 60 distances.

Gene therapy for cystic fibrosis (CF) is making encouraging progress into clinical trials. However, further improvements in transduction efficiency are desired. To develop a novel gene transfer vector that is improved and truly effective for CF gene therapy, a simian immunodeficiency virus (SIV) was pseudotyped with envelope proteins from Sendai virus (SeV), which is known to efficiently transduce unconditioned airway epithelial cells from the apical side. This novel vector was evaluated in mice in vivo and in vitro directed toward CF gene therapy. Here, we show that (i) we can produce relevant titers of an SIV vector pseudotyped with SeV envelope proteins for in vivo use, (ii) this vector can transduce the respiratory epithelium of the murine nose in vivo at levels that may be relevant for clinical benefit in CF, (iii) this can be achieved in a single formulation, and without the need for preconditioning, (iv) expression can last for 15 months, (v) readministration is feasible, (vi) the vector can transduce human air–liquid interface (ALI) cultures, and (vii) functional CF transmembrane conductance regulator (CFTR) chloride channels can be generated in vitro. Our data suggest that this lentiviral vector may provide a step change in airway transduction efficiency relevant to a clinical programme of gene therapy for CF.

The three-base periodicity usually found in exons has been used for several purposes, as for example the prediction of potential genes. In this paper, we use a data model, previously proposed for encoding protein-coding regions of DNA sequences, to build signatures capable of supporting the construction of meaningful dendograms. The model relies on the three-base periodicity and provides an estimate of the entropy associated with each of the three bases of the codons. We observe that the three entropy values vary among themselves and also from species to species. Moreover, we provide evidence that this makes it possible to associate a three-state entropy vector with each species, and we show that similar species are characterized by similar three-state entropy vectors.

We study charged Higgs production in the process $\gamma\gamma\to A^0\to W^- H^+$. The processes $\gamma\gamma\to A^0$ are loop mediated in a 2HDM. This is due to the fact that photons only couple directly to charged particles and the Higgs only couples to particles with mass acquired via Higgs mechanism. Although in MSSM the contribution from the process $\gamma\gamma\to A^0$ is too small, it has been found that in a more general 2HDM it could be enhanced. On the other hand, the boson $A^0$ can decay in $W^- H^+$ at tree level and the charged Higgs can decay in fermions. So, the whole process under study is $\gamma\gamma\to A^0\to (W^-\to l\nu) (H^+\to f_if_j)$ in 2HDM-III. Evidence about charged Higgs existence could demonstrate that structure of the Higgs sector has several multiplets., Comment: 5 pages, 4 figures, to appear Brazilian Journal of Physics

We propose a rationale for experimentally studying the intricate relationship between the rate of information transmission and synchronization level in active networks, applying theoretical results recently proposed. We consider two non-identical coupled Chua’s circuit with non-identical coupling strengths in order to illustrate the proceeding for experimental scenarios of very few data points coming from highly non-coherent coupled systems, such that phase synchronization can only be detected by methods that do not rely explicitely on the calculation of the phase. A relevant finding is to show that for the coupled Chua’s circuit, the larger the level of synchronization the larger the rate of information exchanged between both circuits. We further validate our findings with data from numerical simulations, and discuss an extension to arbitrarily large active networks.

Common genetic variation associated with fetal hemoglobin (HbF) level and β-hemoglobin disorder clinical severity marks an erythroid enhancer within the BCL11A gene. The 12 kb intronic enhancer contains three ~1 kb erythroid DNase I hypersensitive sites (DHSs), termed +55, +58, and +62. Here we utilized a human adult-stage erythroid cell line to show by CRISPR-Cas9 mediated targeted deletion that the composite enhancer is required both for BCL11A expression and HbF repression. Because deletion of the entire enhancer is currently too inefficient to consider for a gene editing approach to hemoglobin disorders, we sought to define the critical features of the enhancer in its natural genomic context. We designed and synthesized a tiling pooled guide RNA (gRNA) library to conduct saturating mutagenesis of the enhancer sequences in situ using the CRISPR-Cas9 gene editing platform. The gRNAs direct Cas9 cleavage and non-homologous end-joining repair at discrete sites throughout the enhancer. By comparing the representation of lentiviral gRNA integrants in high and low HbF pools of the adult erythroid cells, we generated a functional map approaching nucleotide resolution of sequences within the enhancer influencing BCL11A regulation. We observed several discrete enhancer regions required for maximal expression. The largest effect was observed by producing mutations within a narrow functional core of the +58 DHS. These sequences include a GATA1 motif conserved among vertebrates located within a primate-specific context. This region constitutes an Achilles Heel for functional inactivation of the enhancer. We also identified rare genetic variants within the +58 DHS core in individuals with sickle cell disease that are associated with HbF level, independent of all known associations of common genetic variants. In parallel, we performed a similar saturating CRISPR mutagenesis screen of the corresponding murine Bcl11a enhancer. To our surprise, despite low-resolution evidence of conservation by primary sequence homology, syntenic genomic position, and shared chromatin signature, the mouse enhancer sequence determinants of BCL11A expression showed substantial functional divergence. The +58 orthologous sequences were dispensable whereas the +62 orthologous sequences were critically required in murine adult erythroid cells. These results were validated by producing targeted deletions in mouse and human adult erythroid cell lines. Furthermore we subjected cells to individual gRNAs to correlate individual nucleotide disruptions with loss of BCL11A expression. To substantiate the tissue-restricted effect of the enhancer mutations, we generated transgenic mice with deletion of the Bcl11a enhancer and found these sequences were dispensable for expression in developing neurons and B-lymphocytes (unlike conventional Bcl11a knockout) but essential for appropriate hemoglobin switching in vivo. We showed that in primary CD34+ hematopoietic stem and progenitor derived human erythroid precursors that delivery of an individual gRNA and Cas9 is sufficient to produce robust reinduction of HbF. These results validate the BCL11A erythroid enhancer as a promising therapeutic target. Our findings define the most favorable regions for generation of indel mutations in the BCL11A erythroid enhancer as a therapeutic genome editing strategy for HbF reinduction for the β-hemoglobin disorders. Disclosures Bauer: Biogen: Research Funding; Editas Medicine: Consultancy. Zhang:Editas Medicine: Membership on an entity's Board of Directors or advisory committees; Horizon Discovery: Membership on an entity's Board of Directors or advisory committees. Orkin:Editas Medicine: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Research Funding; Sangamo Biosciences: Consultancy.

Introduction Mean platelet volume is increased in the setting of acute myocardial infarction (AMI) and is a poor prognostic marker despite antiplatelet use. The megakaryocyte (platelet precursor) that resides in the bone marrow has a mean physiological ploidy of 16n. Megakaryocyte size and DNA content are also shown to be increased in AMI. To investigate if megakaryocytes of higher ploidy are transcriptionally different and therefore have the ability to produce larger and more active platelets we performed RNA sequencing in megakaryocytes cultured with or without dimethylfasudil (diMF), an exogenous peptide that drives megakaryocyte ploidy further than previously documented by non-selective aurora kinase inhibition. Methods Human adult blood CD34 + derived megakaryocytes from 4 individuals underwent 3 days of culture with or without 5 µM diMF. RNA from untreated and treated cells was sequenced and used for differential gene and transcript expression analysis. Results Mean ploidy in the untreated megakaryocytes was 2n while diMF treatment drove mean ploidy to approximately 8n. This was associated with a morphological increase in size and nuclear multilobulation. Differential gene expression analysis revealed that in megakaryocytes that had been driven to high ploidy levels, 33 genes were downregulated while 65 genes underwent significant upregulation when compared with untreated megakaryocytes. Gene ontology analysis demonstrated that the downregulated genes were significantly enriched for transcripts involved in the cell cycle including CDC45, chromatin assembly factor 1β, and MCMs. In contrast, genes that were upregulated in higher ploidy megakaryocytes were significantly enriched for transcripts involved in haemostatic and coagulation pathways including VWF, coagulation factor XIII, thrombin receptor-like 2, PDGFβ, angiopoietin 1, thrombospondin 1 and plasminogen activator inhibitor type 1. Furthermore, glycoprotein IIIa (part of the fibrinogen/VWF receptor) and tubulin β1 (involved in microtubule changes in platelet release) were both significantly upregulated in higher ploidy megakaryocytes. Both of these genes are specific to megakaryocytes and platelets. Conclusion This is the first analysis of megakaryocytes driven to high ploidy level in vitro using RNA sequencing. Our results demonstrate that along with the anticipated modulation of cell cycle genes with increasing ploidy, higher ploidy megakaryocytes significantly overexpress genes that are involved in megakaryocyte function, platelet activation and thrombosis. These results therefore support a role for platelet production from megakaryocytes of higher ploidy in thrombotic disease.

A recently proposed nearest neighbor based selection of time delays for phase space reconstruction is extended to multivariate time series, with an iterative selection of variables and time delays. A case study of numerically generated solutions of the x- and z coordinates of the Lorenz system, and an application to heart rate and respiration data, are used for illustration., Comment: 4 pages, 3 figures

A nearest neighbor based selection of time delays for phase space reconstruction is proposed and compared to the standard use of time delayed mutual information. The possibility of using different time delays for consecutive dimensions is considered. A case study of numerically generated solutions of the Lorenz system is used for illustration. The effect of contamination with various levels of additive Gaussian white noise is discussed., 4 pages, 5 figures, updated to final version

Since December 1999, ESA's large X-ray space observatory XMM-Newton operates in a highly eccentric 48-h orbit which allows for long uninterrupted exposure times. The three payload instruments EPIC, RGS, and OM yield scientific data of high quality and sensitivity. We report here on the current timing capabilities of all three instruments by showing results from analyses on relative and absolute timing. In this context we discuss the process of correlating local onboard event arrival times to terrestrial time frames and present some detailed results from time correlation analyses. This involves investigations on the performance of the onboard quartz oscillator that have been performed. In addition we describe problematic timing data anomalies in the EPIC-pn data and their treatment by the SAS. We show recent examples of timing analyses.

Introduction Substance P (SP) is a neuropeptide present in enteric neurons, involved not only in the control of intestinal motility, but also in the development of inflammation in the gastrointestinal tract (GIT). The increase in the SP production is associated with the progress of inflammatory process, since SP leads directly to the secretion of cytokines, such as IL-6, IL-8, and TNFα. The GIT is considered the main route of F exposure. Daily, high F concentrations are ingested through dental products, water and food consumption, and in cases of intoxication, important intestinal symptoms are described. Aim To evaluate SP-containing enteric neurons, in the myenteric plexus of the small intestine, since there is no information about F effects on enteric neurons, even with the report of intestinal symptomatology as result of excessive F intake. Thus, we analysed the effects of an acute F exposure by the morphology evaluation of the SP varicosities, which are the axonal portion that concentrates SP. Methods 12 male rats ( Rattus norvegicus – Wistar type) were divided into 2 groups: Control (C) and Acute Dose (AD). The animals received deionized water for 29 days, and at the 30th day they received 0 or 25 mgF/kg orally by gavage. The segments of the small intestine (duodenum, jejunum, and ileum) were collected, and processed for immunohistochemical technique for the SP identification. Morphometric analyses were carried out in 400 varicosities from each animal. The groups were compared by Student’s t -test ( p Results The 3 segments (duodenum, jejunum, and ileum) presented a statistically significant increase (44.6%, 57.1%, and 56.1%, respectively) in the mean value of the areas of the SP myenteric varicosities for DA in relation to C. Conclusion: we may infer that the dose of 25 mgF/kg could lead to an increase in the production of SP, which could impair the intestinal motility, and induce an intestinal inflammatory process.