The influence of the cross -race effect on lineup construction and fairness

Lineup procedures have recently garnered extensive empirical attention, in an effort to reduce the number of mistaken identifications that plague the criminal justice system. Relatively little attention, however, has been paid to the influence of the lineup constructor or the lineup construction technique on the quality of the lineup. This study examined whether the cross-race effect has an influence on the quality of lineups constructed using a match-to-suspect or match-to-description technique in a series of three phases. Participants generated descriptions of same- and other-race targets in Phase 1, which were used in Phase 2. In Phase 2, participants were asked to create lineups for own-race targets and other-race targets using one of two techniques. The lineups created in this phase were examined for lineup quality in Phase 3 by calculating lineup fairness assessments through the use of a mock witness paradigm. ^ Overall, the results of these experiment phases suggest that the race of those involved in the lineup construction process influences lineups. There was no difference in witness description accuracy in Phase 1, which ran counter to predictions based on the cross-race effect. The cross-race effect was observed, however, in Phases 2 and 3. The lineup construction technique used also influenced several of the process measures, selection estimates, and fairness judgments in Phase 2. Interestingly, the presence of the cross-race effect was in the opposite direction as predicted for some measures in both phases. In Phase 2, the cross-race effect was as predicted for number of foils viewed, but in the opposite direction for average time spent viewing each foil. In Phase 3, the cross-race effect was in the opposite direction than predicted, with higher levels of lineup fairness in other-race lineups. The practical implications of these findings are discussed in relation to lineup fairness within the legal system. ^

Predicting the in-term persistence of community college English-as-a-second-language students

The English-as-a-second-language (ESL) community college student population has increased notably in the past decade, but a decreasing number of these students are completing courses, programs, or degrees (Erisman & Looney, 2008). These students come to college with unique background experiences, and once in college, deal with challenging linguistic, academic, and social integration issues. Though they are not linguistically homogenous, and they do not have a common purpose, ESL students share the common goal of attending community college to learn to speak English (Szelényi & Chang, 2002). Course completion is a primary measure of progress toward that goal, and is therefore an issue of concern for both ESL students and community colleges, which continue to be the access point for language-minority students progressing into higher education (Laden, 2004).^ The purpose of this study was to investigate the factors that predict in-term persistence of community college ESL students. A mixed methods research design consisting of two phases was utilized, and participants in this study were ESL students enrolled in a large community college in south Florida. Phase 1 students completed the Community College ESL Student Questionnaire (CCSEQ), which collected demographic data and data on entry characteristics, academic integration, and social integration. Discriminant and descriptive analyses were used to report the data collected in Phase I. Phase 2 students were a matching cohort of completing and non-completing students who participated in semi-structured interviews at the end of the term. Data collected in the interviews were analyzed thematically, using a constant comparative method as described by Glaser and Strauss (1967).^ Students’ self reported demographic data, background characteristics, goal commitment, and integration factors on the CCSEQ showed no significance between the students who completed the term and the students who did not complete the term. However, several differentiating themes emerged from the interview data, which indicated differences in goal commitment and integration between the two groups. The focus of non-completers on getting good grades rather than completing the course, and the commitment of completers to the goal of finishing the class in order to go forward, both raise questions for future research studies.^

Distribution of light in the human retina under natural viewing conditions

Age-related macular degeneration (AMD) is the leading cause of blindness inAmerica. The fact that AMD wreaks most of the damage in the center of the retina raises the question of whether light, integrated over long periods, is more concentrated in the macula. A method, based on eye-tracking, was developed to measure the distribution of light in the retina under natural viewing conditions. The hypothesis was that integrated over time, retinal illumination peaked in the macula. Additionally a possible relationship between age and retinal illumination was investigated. The eye tracker superimposed the subject's gaze position on a video recorded by a scene camera. Five informed subjects were employed in feasibility tests, and 58 naïve subjects participated in 5 phases. In phase 1 the subjects viewed a gray-scale image. In phase 2, they observed a sequence of photographic images. In phase 3 they viewed a video. In phase 4, they worked on a computer; in phase 5, the subjects walked around freely. The informed subjects were instructed to gaze at bright objects in the field of view and then at dark objects. Naïve subjects were allowed to gaze freely for all phases. Using the subject's gaze coordinates, and the video provided by the scene camera, the cumulative light distribution on the retina was calculated for ∼15° around the fovea. As expected for control subjects, cumulative retinal light distributions peaked and dipped in the fovea when they gazed at bright or dark objects respectively. The light distribution maps obtained from the naïve subjects presented a tendency to peak in the macula for phases 1, 2, and 3, a consistent tendency in phase 4 and a variable tendency in phase 5. The feasibility of using an eye-tracker system to measure the distribution of light in the retina was demonstrated, thus helping to understand the role played by light exposure in the etiology of AMD. Results showed that a tendency for light to peak in the macula is a characteristic of some individuals and of certain tasks. In these situations, risk of AMD could be increased. No significant difference was observed based on age.

Phonics Instruction using Pseudowords for Success in Phonetic Decoding

This study examined a Pseudoword Phonics Curriculum to determine if this form of instruction would increase students’ decoding skills compared to typical real-word phonics instruction. In typical phonics instruction, children learn to decode familiar words which allow them to draw on their prior knowledge of how to pronounce the word and may detract from learning decoding skills. By using pseudowords during phonics instruction, students may learn more decoding skills because they are unfamiliar with the “words” and therefore cannot draw on memory for how to pronounce the word. It was hypothesized that students who learn phonics with pseudowords will learn more decoding skills and perform higher on a real-word assessment compared to students who learn phonics with real words. Students from two kindergarten classes participated in this study. An author-created word decoding assessment was used to determine the students’ ability to decode words. The study was broken into three phases, each lasting one month. During Phase 1, both groups received phonics instruction using real words, which allowed for the exploration of baseline student growth trajectories and potential teacher effects. During Phase 2, the experimental group received pseudoword phonics instruction while the control group continued real-word phonics instruction. During Phase 3, both groups were taught with real-word phonics instruction. Students were assessed on their decoding skills before and after each phase. Results from multiple regression and multi-level model analyses revealed a greater increase in decoding skills during the second and third phases of the study for students who received the pseudoword phonics instruction compared to students who received the real-word phonics instruction. This suggests that pseudoword phonics instruction improves decoding skills quicker than real-word phonics instruction. This also suggests that teaching decoding with pseudowords for one month can continue to improve decoding skills when children return to real-word phonics instruction. Teacher feedback suggests that confidence with reading increased for students who learned with pseudowords because they were less intimidated by the approach and viewed pseudoword phonics as a game that involved reading “silly” words. Implications of these results, limitations of this study, and areas for future research are discussed.

Spatial and temporal stability of soil microbial properties in the Jena Experiment (Germany) from 2003-2014

The study was carried out on the main plots of a large grassland biodiversity experiment (the Jena Experiment). In the main experiment, 82 grassland plots of 20 x 20 m were established from a pool of 60 species belonging to four functional groups (grasses, legumes, tall and small herbs). In May 2002, varying numbers of plant species from this species pool were sown into the plots to create a gradient of plant species richness (1, 2, 4, 8, 16 and 60 species) and functional richness (1, 2, 3, 4 functional groups). Plots were maintained by bi-annual weeding and mowing. We tracked soil microbial basal respiration (BR; µlO2/g dry soil/h) and biomass carbon (Cmic; µgC/g dry soil) over a time period of 12 years (2003-2014) and examined the role of plant diversity and plant functional group composition for the spatial and temporal stability (calculated as mean/SD) of soil microbial properties (basal respiration and biomass) in bulk-soil. Our results highlight the importance of plant functional group composition for the spatial and temporal stability of soil microbial properties, and hence for microbially-driven ecosystem processes, such as decomposition and element cycling, in temperate semi-natural grassland.

Simulação de desempenho luminoso para salas de aula em Natal-RN

The city of Natal has a significant daylight availability, although it use isn’t systematically explored in schools architecture. In this context, this research aims to determine procedures for the analysis of the daylight performance in school design in Natal-RN. The method of analysis is divided in Visible Sky Factor (VSF), simulating and analyzing the results. The annual variation of the daylight behavior requires the adoption of dynamic simulation as data procedure. The classrooms were modelled in SketchUp, simulated in Daysim program and the results were assessed by means of spreadsheets in Microsoft Excel. The classrooms dimensions are 7.20mx 7.20m, with windows-to-wall-ratio (WWR) of 20%, 40% and 50%, and with different shading devices, such as standard horizontal overhang, sloped overhang, standard horizontal overhang with side view protection, standard horizontal overhang with a dropped edge, standard horizontal overhang with three horizontal louvers, double standard horizontal overhang, double standard horizontal overhang with three horizontal louvers, plus the use of shelf light in half the models with WWR of 40% and 50%. The data was organized in spreadsheets, with two intervals of UDI: between 300lux and 2000 lux and between 300lux and 3000lux. The simulation was performed with the weather file of 2009 to the city of NatalRN. The graphical outputs are illuminance curves, isolines of UDI among 300lux and 2000 lux and tables with index of occurrences of glare and to an UDI among 300lux 3000lux. The best UDI300-2000lux performance was evidenced to: Phase 1 (models with WWR of 20%), Phase 2 (models with WWR of 40% and 50% with light shelf). The best UDI300-3000lux performance was evidenced to: Phase 1 (models with WWR of 20% and 40% with light shelf) and Phase 2 (models with WWR of 40% and 50% with light shelf). The outputs prove that the daylight quality mainly depends on the shading system efficacy to avoid the glare occurrence, which determines the daylight discomfort. The bioclimatic recommendations of big openings with partial shading (with an opening with direct sunlight) resulted in illuminances level higher than the acceptable upper threshold. The improvement of the shading system percentage (from 73% to 91%) in medium-size of openings (WWR 40% and 50%) reduced or eliminate the glare occurrence without compromising the daylight zone depth (7.20m). The passive zone was determined for classrooms with satisfactory daylight performance, it was calculated the daylight zone depth rule-of-thumb with the ratio between daylight zone depth and the height of the window for different size of openings. The ratio ranged from 1.54 to 2.57 for WWR of 20%, 40% and 50% respectively. There was a reduction or elimination of glare in the passive area with light shelf, or with awning window shading.

A influência da perda de peso no perfil inflamatório de mulheres com síndrome dos ovários policísticos

The polycystic ovary syndrome (PCOS) is considered the most common endocrine disorder in reproductive age women, with a prevalence ranging from 15 to 20%. In addition to hormonal and reproductive changes, it is common in PCOS the presence of risk factors for developing cardiovascular disease (CVD) and diabetes mellitus, insulin resistance (IR), visceral obesity, chronic low-grade inflammation and dyslipidemia. Due to the high frequency of obesity associated with PCOS, weight loss is considered as the first-line treatment for the syndrome by improving metabolic and normalizes serum androgens, restoring reproductive function of these patients. Objectives: To evaluate the inflammatory markers and IR in women with PCOS and healthy ovulatory with different nutritional status and how these parameters are displayed after weight loss through caloric restriction in with Down syndrome. Methods: Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in serum samples from 40 women of childbearing age. The volunteers were divided into four groups: Group I (not eutrophic with PCOS, n = 12); Group II (not eutrophic without PCOS, n = 10), Group III (eutrophic with PCOS, n = 08) and Group IV (eutrophic without PCOS, n = 10). The categorization of groups was performed by body mass index (BMI), according to the World Health Organization (WHO) does not eutrophic, overweight and obesity (BMI> 25 kg / m²) and normal weight (BMI <24.9 kg / m²). IR was determined by HOMA-IR index. In the second phase of the study a controlled dietary intervention was performed and inflammatory parameters were evaluated in 21 overweight and obese women with PCOS, before and after weight loss. All patients received a low-calorie diet with reduction of 500 kcal / day of regular consumption with standard concentrations of macronutrients. Results: Phase 1: PCOS patients showed increased levels of CRP (p <0.01) and HOMAIR (p <0.01). When divided by BMI, both not eutrophic group with PCOS (I) as eutrophic with PCOS (III) showed increased levels of CRP (I = 2.35 ± 0,55mg / L and 2.63 ± III = 0,65mg / L; p <0.01) and HOMA-IR (I = 2.16 ± 2.54 and III = 1.07 ± 0.55; p <0.01). There were no differences in TNF-α and IL-6 between groups. Step 2: After the weight loss of 5% of the initial weight was reduced in all of the components of serum assessed inflammatory profile, PCR (154.75 ± 19:33) vs (78.06 ± 8.9) TNF α (10.89 ± 5.09) vs (6:39 ± 1:41) and IL6 (154.75 ± 19:33) vs (78.06 ± 08.09) (p <0:00) in association with improvement some hormonal parameters evaluated. Conclusion: PCOS contributed to the development of chronic inflammation and changes in glucose metabolism by increasing CRP, insulin and HOMA-IR, independent of nutritional status. The weight loss, caloric restriction has improved the inflammatory condition and hormonal status of the evaluated patients.

Operacionalização do processo de treino no futebol feminino:situações de bola parada no meio campo ofensivo

Relatório de Estágio apresentado para a obtenção do grau de Mestre em Desporto com especialização em Treino Desportivo – Futebol

RNA Localization and Translational Regulation on the Endoplasmic Reticulum

mRNA localization is emerging as a critical cellular mechanism for the spatiotemporal regulation of protein expression and serves important roles in oogenesis, embryogenesis, cell fate specification, and synapse formation. Signal sequence-encoding mRNAs are localized to the endoplasmic reticulum (ER) membrane by either of two mechanisms, a canonical mechanism of translation on ER-bound ribosomes (signal recognition particle pathway), or a poorly understood direct ER anchoring mechanism. In this study, we identify that the ER integral membrane proteins function as RNA-binding proteins and play important roles in the direct mRNA anchoring to the ER. We report that one of the ER integral membrane RNA-binding protein, AEG-1 (astrocyte elevated gene-1), functions in the direct ER anchoring and translational regulation of mRNAs encoding endomembrane transmembrane proteins. HITS-CLIP and PAR-CLIP analyses of the AEG-1 mRNA interactome of human hepatocellular carcinoma cells revealed a high enrichment for mRNAs encoding endomembrane organelle proteins, most notably encoding transmembrane proteins. AEG-1 binding sites were highly enriched in the coding sequence and displayed a signature cluster enrichment downstream of encoded transmembrane domains. In overexpression and knockdown models, AEG-1 expression markedly regulates translational efficiency and protein functions of two of its bound transcripts, MDR1 and NPC1. This study reveals a molecular mechanism for the selective localization of mRNAs to the ER and identifies a novel post-transcriptional gene regulation function for AEG-1 in membrane protein expression.

A Jaworskian analysis of four senior class primary teachers endeavouring to teach mathematics from a constructivist-compatible perspective

A constructivist philosophy underlies the Irish primary mathematics curriculum. As constructivism is a theory of learning its implications for teaching need to be addressed. This study explores the experiences of four senior class primary teachers as they endeavour to teach mathematics from a constructivist-compatible perspective with primary school children in Ireland over a school-year period. Such a perspective implies that children should take ownership of their learning while working in groups on tasks which challenge them at their zone of proximal development. The key question on which the research is based is: to what extent will an exposure to constructivism and its implications for the classroom impact on teaching practices within the senior primary mathematics classroom in both the short and longer term? Although several perspectives on constructivism have evolved (von Glaserfeld (1995), Cobb and Yackel (1996), Ernest (1991,1998)), it is the synthesis of the emergent perspective which becomes pivotal to the Irish primary mathematics curriculum. Tracking the development of four primary teachers in a professional learning initiative involving constructivist-compatible approaches necessitated the use of Borko’s (2004) Phase 1 research methodology to account for the evolution in teachers’ understanding of constructivism. Teachers’ and pupils’ viewpoints were recorded using both audio and video technology. Teachers were interviewed at the beginning and end of the project and also one year on to ascertain how their views had evolved. Pupils were interviewed at the end of the project only. The data were analysed from a Jaworskian perspective i.e. using the categories of her Teaching Triad of management of learning, mathematical challenge and sensitivity to students. Management of learning concerns how the teacher organises her classroom to maximise learning opportunities for pupils. Mathematical challenge is reminiscent of the Vygotskian (1978) construct of the zone of proximal development. Sensitivity to students involves a consciousness on the part of the teacher as to how pupils are progressing with a mathematical task and whether or not to intervene to scaffold their learning. Through this analysis a synthesis of the teachers’ interpretations of constructivist philosophy with concomitant implications for theory, policy and practice emerges. The study identifies strategies for teachers wishing to adopt a constructivist-compatible approach to their work. Like O’Shea (2009) it also highlights the likely difficulties to be experienced by such teachers as they move from utilising teacher-dominated methods of teaching mathematics to ones in which pupils have more ownership over their learning.

A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA

BACKGROUND The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODS In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels — 1×1010 viral particles, 2.5×1010 viral particles, and 5×1010 viral particles — with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glyco- protein, in 30 of the 60 participants and evaluated a reduced prime–boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus–based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTS No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geo- metric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONS The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.)

If People Were Kaleidoscopes: Sharpening the Resolution on Patient Engagement in Safety

Healthcare is unacceptably error prone. The question remains why, with 20 years of evidence, is error and harm reduction not being effective? While precise numbers may be debated, all stakeholders recognize the frequency of healthcare errors is unacceptable, and greater efforts to ensure safety must occur. In recent years, one of these strategies has been the inclusion of the patient and their family as partners in safety, and has been a required organizational practice of Accreditation Canada in many of their standard sets. Existing patient advisories created to encourage engagement, have typically not included patient perspectives in their development or been comprehensively evaluated. There are no existing tools to determine if and how a patient wants to be involved in safety engagement. As such, a multi-phased study was undertaken to advance our knowledge about the client’s and family’s role in promoting safety. Phase 1 of the study was a scoping review to methodically review the existing literature about patients’ and families’ attitudes, beliefs and behaviours about their involvement in healthcare safety. Phase 2 was designed to inductively explore how a group of patients in an Ontario, Canada, community hospital, describe healthcare safety and see their role in preventing error. The study findings, which include the narratives of 30 patients and 4 family members, indicate that although there are shared themes that influence a patient’s engagement in patient safety, every individual has unique, changing beliefs, experiences and reasons for involvement. Five conceptual themes emerged from their narratives: Personal Capacity, Experiential Knowledge, Personal Character, Relationships, and Meaning of Safety. These study results will be used to develop and test a pragmatic, accessible tool to enable providers a way to collaborate with patients for determining their personal level and type of safety involvement. The most ethical and responsible approach to healthcare safety is to consider every facet and potential way for improvement. This exploratory study provides fundamental insights into the complexity of patient engagement in safety, and evidence for future steps.

An exploration of men’s experiences of undergoing active surveillance for favourable-risk prostate cancer: A mixed methods study protocol

Background
Prostate cancer is one of the most common male cancers worldwide. Active Surveillance (AS) has been developed to allow men with lower risk disease to postpone or avoid the adverse side effects associated with curative treatments until the disease progresses. Despite the medical benefits of AS, it is reported that living with untreated cancer can create a significant emotional burden for patients.

Methods/design
The aim of this study is to gain insight into the experiences of men eligible to undergo AS for favourable-risk PCa.

This study has a mixed-methods sequential explanatory design consisting of two phases: quantitative followed by qualitative. Phase 1 has a multiple point, prospective, longitudinal exploratory design. Ninety men diagnosed with favourable-risk prostate cancer will be assessed immediately post-diagnosis (baseline) and followed over a period of 12 months, in intervals of 3 month. Ninety age-matched men with no cancer diagnosis will also be recruited using peer nomination and followed up in the same 3 month intervals. Following completion of Phase 1, 10–15 AS participants who have reported both the best and worst psychological functioning will be invited to participate in semi-structured qualitative interviews. Phase 2 will facilitate further exploration of the quantitative results and obtain a richer understanding of participants’ personal interpretations of their illness and psychological wellbeing.

Discussion
To our knowledge, this is the first study to utilise early baseline measures; include a healthy comparison group; calculate sample size through power calculations; and use a mixed methods approach to gain a deeper more holistic insight into the experiences of men diagnosed with favourable-risk prostate cancer.

An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Exploration génétique de l'hypothyroïdie congénitale par dysgénésie thyroïdienne

L'hypothyroïdie congénitale par dysgénésie thyroïdienne (HCDT, ectopie dans plus de 80 %) a une prévalence de 1 cas sur 4000 naissances vivantes. L’HCDT est la conséquence d'une défaillance de la thyroïde embryonnaire à se différencier, à se maintenir ou à migrer vers sa localisation anatomique (partie antérieure du cou), qui aboutit à une absence totale de la thyroïde (athyréose) ou à une ectopie thyroïdienne (linguale ou sublinguale). Les HCDT sont principalement non-syndromiques (soit 98% des cas sont non-familiale), ont un taux de discordance de 92% chez les jumeaux monozygotes, et ont une prédominance féminine et ethnique (i.e., Caucasienne). La majorité des cas d’HCDT n’a pas de cause connue, mais est associée à un déficit sévère en hormones thyroïdiennes (hypothyroïdie). Des mutations germinales dans les facteurs de transcription liés à la thyroïde (NKX2.1, FOXE1, PAX8, NKX2.5) ont été identifiées dans seulement 3% des patients atteints d’HCDT sporadiques et l’analyse de liaisons exclue ces gènes dans les rares familles multiplex avec HCDT. Nous supposons que le manque de transmission familiale claire d’HCDT peut résulter de la nécessité d’au moins deux « hits » génétiques différents dans des gènes importants pour le développement thyroïdien. Pour répondre au mieux nos questions de recherche, nous avons utilisé deux approches différentes: 1) une approche gène candidat, FOXE1, seul gène impliqué dans l’ectopie dans le modèle murin et 2) une approche en utilisant les techniques de séquençage de nouvelle génération (NGS) afin de trouver des variants génétiques pouvant expliquer cette pathologie au sein d’une cohorte de patients avec HCDT. Pour la première approche, une étude cas-contrôles a été réalisée sur le promoteur de FOXE1. Il a récemment été découvert qu’une région du promoteur de FOXE1 est différentiellement méthylée au niveau de deux dinucléotides CpG consécutifs, définissant une zone cruciale de contrôle de l’expression de FOXE1. L’analyse d’association basée sur les haplotypes a révélé qu’un haplotype (Hap1: ACCCCCCdel1C) est associé avec le HCDT chez les Caucasiens (p = 5x10-03). Une réduction significative de l’activité luciférase est observée pour Hap1 (réduction de 68%, p<0.001) comparé au promoteur WT de FOXE1. Une réduction de 50% de l’expression de FOXE1 dans une lignée de cellules thyroïdienne humaine est suffisante pour réduire significativement la migration cellulaire (réduction de 55%, p<0.05). Un autre haplotype (Hap2: ACCCCCCC) est observé moins fréquemment chez les Afro-Américain comparés aux Caucasiens (p = 1.7x10-03) et Hap2 diminue l’activité luciférase (réduction de 26%, p<0.001). Deux haplotypes distincts sont trouvés fréquemment dans les contrôles Africains (Black-African descents). Le premier haplotype (Hap3: GTCCCAAC) est fréquent (30.2%) chez les contrôles Afro-Américains comparés aux contrôles Caucasiens (6.3%; p = 2.59 x 10-9) tandis que le second haplotype (Hap4: GTCCGCAC) est trouvé exclusivement chez les contrôles Afro-Américains (9.4%) et est absent chez les contrôles Caucasiens (P = 2.59 x 10-6). Pour la deuxième approche, le séquençage de l’exome de l’ADN leucocytaire entre les jumeaux MZ discordants n’a révélé aucune différence. D'où l'intérêt du projet de séquençage de l’ADN et l’ARN de thyroïdes ectopiques et orthotopiques dans lesquelles de l'expression monoallélique aléatoire dans a été observée, ce qui pourrait expliquer comment une mutation monoallélique peut avoir des conséquences pathogéniques. Finalement, le séquençage de l’exome d’une cohorte de 36 cas atteints d’HCDT a permis d’identifier de nouveaux variants probablement pathogéniques dans les gènes récurrents RYR3, SSPO, IKBKE et TNXB. Ces quatre gènes sont impliqués dans l’adhésion focale (jouant un rôle dans la migration cellulaire), suggérant un rôle direct dans les défauts de migration de la thyroïde. Les essais de migration montrent une forte diminution (au moins 60% à 5h) de la migration des cellules thyroïdiennes infectées par shRNA comparés au shCtrl dans 2 de ces gènes. Des zebrafish KO (-/- et +/-) pour ces nouveaux gènes seront réalisés afin d’évaluer leur impact sur l’embryologie de la thyroïde.