The Role of TET Proteins in the Epigenetic Regulation of Neural Gene Expression and Behavior

Understanding how genes affect behavior is critical to develop precise therapies for human behavioral disorders. The ability to investigate the relationship between genes and behavior has been greatly advanced over the last few decades due to progress in gene-targeting technology. Recently, the Tet gene family was discovered and implicated in epigenetic modification of DNA methylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). 5hmC and its catalysts, the TET proteins, are highly abundant in the postnatal brain but with unclear functions. To investigate their neural functions, we generated new lines of Tet1 and Tet3 mutant mice using a gene targeting approach. We designed both mutations to cause a frameshift by deleting the largest coding exon of Tet1 (Tet1Δe4) and the catalytic domain of Tet3 (Tet3Δe7-9). As Tet1 is also highly expressed in embryonic stem cells (ESCs), we generated Tet1 homozygous deleted ESCs through sequential targeting to compare the function of Tet1 in the brain to its role in ESCs. To test our hypothesis that TET proteins epigenetically regulate transcription of key neural genes important for normal brain function, we examined transcriptional and epigenetic differences in the Tet1Δe4 mouse brain. The oxytocin receptor (OXTR), a neural gene implicated in social behaviors, is suggested to be epigenetically regulated by an unknown mechanism. Interestingly, several human studies have found associations between OXTR DNA hypermethylation and a wide spectrum of behavioral traits and neuropsychiatric disorders including autism spectrum disorders. Here we report the first evidence for an epigenetic mechanism of Oxtr transcription as expression of Oxtr is reduced in the brains of Tet1Δe4-/- mice. Likewise, the CpG island overlapping the promoter of Oxtr is hypermethylated during early embryonic development and persists into adulthood. We also discovered altered histone modifications at the hypermethylated regions, indicating the loss of TET1 has broad effects on the chromatin structure at Oxtr. Unexpectedly, we discovered an array of novel mRNA isoforms of Oxtr that are selectively reduced in Tet1Δe4-/- mice. Additionally, Tet1Δe4-/- mice display increased agonistic behaviors and impaired maternal care and short-term memory. Our findings support a novel role for TET1 in regulating Oxtr expression by preventing DNA hypermethylation and implicate TET1 in social behaviors, offering novel insight into Oxtr epigenetic regulation and its role in neuropsychiatric disorders.

The Role of Dopaminergic Systems in the Neurobehavioral Teratology of Organophosphates in Zebrafish

Background: Organophosphate (OP) pesticides are well-known developmental neurotoxicants that have been linked to abnormal cognitive and behavioral endpoints through both epidemiological studies and animal models of behavioral teratology, and are implicated in the dysfunction of multiple neurotransmitters, including dopamine. Chemical similarities between OP pesticides and organophosphate flame retardants (OPFRs), a class of compounds growing in use and environmental relevance, have produced concern regarding whether developmental exposures to OPFRs and OP pesticides may share behavioral outcomes, impacts on dopaminergic systems, or both. Methods: Using the zebrafish animal model, we exposed developing fish to two OPFRs, TDCIPP and TPHP, as well as the OP pesticide chlorpyrifos, during the first 5 days following fertilization. From there, the exposed fish were assayed for behavioral abnormalities and effects on monoamine neurochemistry as both larvae and adults. An experiment conducted in parallel examined how antagonism of the dopamine system during an identical window of development could alter later life behavior in the same assays. Finally, we investigated the interaction between developmental exposure to an OPFR and acute dopamine antagonism in larval behavior. Results: Developmental exposure to all three OP compounds altered zebrafish behavior, with effects persisting into adulthood. Additionally, exposure to an OPFR decreased the behavioral response to acute D2 receptor antagonism in larvae. However, the pattern of behavioral effects diverged substantially from those seen following developmental dopamine antagonism, and the investigations into dopamine neurochemistry were too variable to be conclusive. Thus, although the results support the hypothesis that OPFRs, as with OP pesticides such as chlorpyrifos, may present a risk to normal behavioral development, we were unable to directly link these effects to any dopaminergic dysfunction.

Rupturas y subjetividades : Un acercamiento a la perspectiva de las Trayectorias Laborales

El objetivo del trabajo es estudiar los aportes teóricos que brinda el enfoque de las trayectorias laborales para comprender el conjunto de recorridos heterogéneos, impredecibles y discontinuos que se delinean en la vida laboral de los sujetos. Desde este lugar, realizamos una reflexión crítica junto a una sistematización teórica de aquellas investigaciones que nos aproximen a comprender cómo se construyen las biografías laborales en un contexto de intermitencia e incertidumbre. La perspectiva escogida brinda al análisis social la posibilidad de analizar estos nuevos fenómenos desde su complejidad analítica, al aprehender la dimensión objetiva y subjetiva en su articulación temporal

Rupturas y subjetividades : Un acercamiento a la perspectiva de las Trayectorias Laborales

El objetivo del trabajo es estudiar los aportes teóricos que brinda el enfoque de las trayectorias laborales para comprender el conjunto de recorridos heterogéneos, impredecibles y discontinuos que se delinean en la vida laboral de los sujetos. Desde este lugar, realizamos una reflexión crítica junto a una sistematización teórica de aquellas investigaciones que nos aproximen a comprender cómo se construyen las biografías laborales en un contexto de intermitencia e incertidumbre. La perspectiva escogida brinda al análisis social la posibilidad de analizar estos nuevos fenómenos desde su complejidad analítica, al aprehender la dimensión objetiva y subjetiva en su articulación temporal

Rupturas y subjetividades : Un acercamiento a la perspectiva de las Trayectorias Laborales

El objetivo del trabajo es estudiar los aportes teóricos que brinda el enfoque de las trayectorias laborales para comprender el conjunto de recorridos heterogéneos, impredecibles y discontinuos que se delinean en la vida laboral de los sujetos. Desde este lugar, realizamos una reflexión crítica junto a una sistematización teórica de aquellas investigaciones que nos aproximen a comprender cómo se construyen las biografías laborales en un contexto de intermitencia e incertidumbre. La perspectiva escogida brinda al análisis social la posibilidad de analizar estos nuevos fenómenos desde su complejidad analítica, al aprehender la dimensión objetiva y subjetiva en su articulación temporal

Bridging the Gap: Developing a Palliative Approach to Care for Young Adults with Life Limiting Conditions

Bridging the Gap: Developing a Palliative Approach to Care for Young Adults with Life Limiting Conditions

More young adults (YAs) with life limiting conditions (LLC) are surviving into adulthood as earlier diagnosis and improved medical management in pediatric care lead to higher rates of survival for cancer, congenital heart and neuromuscular conditions. When these YAs leave pediatric care, they leave behind comprehensive and coordinated health, social and education services for uncoordinated adult systems, with limited access to palliative services they received in pediatric care.

YAs with LLCs will benefit from a public health palliative approach to care. This approach better matches their chronic disease trajectories of a series of declining plateaus over a period of months to years, punctuated by unpredictable periodic crises. Public health palliative care is a blended provision of health care and community services based on evidence that health care is most effective and least expensive when offered in conjunction with a complement of services that reflects social determinants of health and well-being. For YAs with LLCs, these resources will support their health, social, vocational, independent living, and educational goals to maximize their opportunities in an abbreviated time frame.


The objectives of this workshop are to:

1. Provide an overview of the young adult population with palliative care needs.
2. Discuss current care of this population.
3. Highlight results from three recent projects to examine and address needs of this population.
4. Dialogue with audience about other programs, initiatives, or ideas to address the needs of this population.

We look forward to robust conversations and ideas from your practice and research.

Ethical reasoning through simulation: a phenomenological analysis of student experience

Background
Medical students transitioning into professional practice feel underprepared to deal with the emotional complexities of real-life ethical situations. Simulation-based learning (SBL) may provide a safe environment for students to probe the boundaries of ethical encounters. Published studies of ethics simulation have not generated sufficiently deep accounts of student experience to inform pedagogy. The aim of this study was to understand students’ lived experiences as they engaged with the emotional challenges of managing clinical ethical dilemmas within a SBL environment.

Methods
This qualitative study was underpinned by an interpretivist epistemology. Eight senior medical students participated in an interprofessional ward-based SBL activity incorporating a series of ethically challenging encounters. Each student wore digital video glasses to capture point-of-view (PoV) film footage. Students were interviewed immediately after the simulation and the PoV footage played back to them. Interviews were transcribed verbatim. An interpretative phenomenological approach, using an established template analysis approach, was used to iteratively analyse the data.

Results
Four main themes emerged from the analysis: (1) ‘Authentic on all levels?’, (2)‘Letting the emotions flow’, (3) ‘Ethical alarm bells’ and (4) ‘Voices of children and ghosts’. Students recognised many explicit ethical dilemmas during the SBL activity but had difficulty navigating more subtle ethical and professional boundaries. In emotionally complex situations, instances of moral compromise were observed (such as telling an untruth). Some participants felt unable to raise concerns or challenge unethical behaviour within the scenarios due to prior negative undergraduate experiences.

Conclusions
This study provided deep insights into medical students’ immersive and embodied experiences of ethical reasoning during an authentic SBL activity. By layering on the human dimensions of ethical decision-making, students can understand their personal responses to emotion, complexity and interprofessional working. This could assist them in framing and observing appropriate ethical and professional boundaries and help smooth the transition into clinical practice.

Envelhecer… Embelecer… Envilecer: comprometimento ou desvinculação com a vida? Atividade e sociabilidade dos idosos da Alta de Coimbra

Este estudo surgiu com o intuito de compreender se os mais velhos continuam, após a transição para a reforma, a participar na esfera da economia, formal e informal, e da sociabilidade, analisando com mais pormenor no que se refere a esta última faceta o sentimento de solidão. Partindo dos diferentes enquadramentos teóricos sobre o contributo socioeconómico dos idosos o objetivo foi compreender, no campo empírico, a posição dos sujeitos relativamente à transição para a reforma e de que forma os mesmos se percecionavam em áreas ligadas à produtividade e sociabilidade. A amostra foi intencional (N=30) e abrangeu sujeitos com idade igual ou superior a sessenta e cinco anos, com pelo menos um ano de reforma e residentes na Alta de Coimbra. A entrevista semiestruturada e a observação direta foram os instrumentos selecionados para aprofundar as vivências dos participantes. No que respeita ao tratamento dos dados recorremos à técnica da análise de conteúdo, com base em Bardin, que nos permitiu captar a singularidade de cada sujeito, sem descurar a totalidade das observações. No final concluiu-se que os sujeitos entrevistados vivenciam a transição para a reforma de maneiras distintas, reforçando assim a heterogeneidade deste grupo, e que são dotados de um capital social e económico que urge potencializar, quer no seio da sociedade civil, quer de forma específica no âmbito da Gestão de Recursos Humanos. / This study aims to understand if, after they retire, the elderly continue to get involved in areas like economy, formal and informal, and sociability, analyzing in detail the feeling of loneliness. Bearing in mind the different theories about the elderly’s social and economic contribution, the goal was to empirically understand the attitude of these individuals towards their transition to retirement, and to see how they perceive themselves and their role in productivity and sociability. The sample was intentional (N=30) and has included people aged sixty five and over sixty five, who have been retired for at least one year, and living in Alta de Coimbra. The semisstructured interview and direct observation were used to know the participants’ way of live. In what comes to data processing, we followed the content analysis technique, based on Bardin, which allows us to capture the singularity of each individual, without forgetting the whole set of observations. In the end we have concluded that the interviewed individuals live the transition into retirement in different ways, thus reinforcing the heterogeneity of this group and their social and economic capital, which needs to be put to use, both in civil society and more specifically in the sphere of the human management resources.

Homo e Heterossexuais: o papel das memórias de vergonha, das memórias precoces de calor e segurança, e qualidade de vinculação ao pai, à mãe e ao par amoroso

As experiências precoces de vergonha, na infância e adolescência, cujas memórias assumem características traumáticas, e de centralidade para a identidade, estão associadas a maior propensão para a vergonha e psicopatologia na adultez. O presente estudo visou clarificar o impacto das características traumáticas e da centralidade, das memórias de vergonha, e das memórias precoces de calor e segurança, na qualidade de vinculação aos pais e ao par amoroso, apreciando a orientação sexual. Nesse sentido, 123 sujeitos, homossexuais masculinos (N = 53) e heterossexuais masculinos e femininos (N = 70), completaram a bateria de questionários de autorresposta, para avaliar as caraterísticas traumáticas e a centralidade das memórias de vergonha, as memórias precoces de calor e segurança, a qualidade de vinculação ao pai, à mãe e ao par amoroso, recolhidos a partir de amostra de conveniência não aleatória da população geral. Os resultados mostram que os homossexuais, comparativamente com os heterossexuais, apresentam níveis mais elevados de caraterísticas traumáticas e de centralidade para a identidade, das memórias de vergonha, a par de níveis inferiores de memórias precoces positivas. As caraterísticas traumáticas e de centralidade, das memórias de vergonha, surgem associadas, com intensidade tendencialmente superior nos homossexuais, à restrição da aquisição de autonomia, conferida pelo pai, à sua desvalorização e à ansiedade de separação materna. O vínculo inseguro, aos progenitores, perpetua-se à adultez e ao par amoroso. Relativamente aos heterossexuais, apurámos que o laço emocional e a ansiedade de separação e dependência, paterna e materna, surgem associados a maior confiança e menor evitamento, respetivamente, ao par amoroso. Paralelamente, a ansiedade de separação e dependência materna surge, ainda, associada a maior dependência daquela figura. Este estudo conclui que as experiências precoces de vergonha, na infância e adolescência, podem funcionar como memórias com caraterísticas traumáticas e autobiográficas, constituir marcos de referência centrais no que concerne à identidade e história de vida, sobretudo em homossexuais, com atribuição de significado a outras experiências de vida, nomeadamente no que respeita à vinculação ao par romântico. / Early experiences of shame, in childhood and adolescence, whose memories assume traumatic characteristics, and centrality to identity, are associated with greater propensity to shame and psychopathology in adulthood. The present study aimed to clarify the impact of traumatic features and centrality to identity of shame memories, and of early memories of warmth and safety, on quality of attachment to parents and the loving couple`s bond, considering sexual orientation. Accordingly, 123 subjects, male homosexuals (N = 53) and male and female (N = 70) heterosexuals, completed the battery of self-report questionnaires, to assess trauma characteristics and centrality of shame memories, early memories of warmth and safeness, quality of attachment to the father, mother and loving couple, collected from a non-random convenience sample from general population. The results point that homosexual men, compared with heterosexuals, show higher levels of traumatic characteristics and centrality to identity of shame memories, along with lower levels of early positive memories. Traumatic characteristics and centrality of shame memories arise associated, tendentiously with higher intensity in homosexuals, to restriction of autonomy`s acquisition, conferred by the father, his devaluation and maternal separation anxiety. The unsecured bond, to parents, perpetuates into adulthood and loving couple. Regarding heterosexuals, we found that emotional bond and separation anxiety and dependency, paternal and maternal, arise associated with greater confidence, and less avoidance, respectively, to the loving couple. Further, separation anxiety and mother`s dependency also appears associated with greater dependency to that figure. This study concludes that early experiences of shame, in childhood and adolescence, might function as memories with traumatic and autobiographical characteristics, produce landmarks of central reference regarding identity and life`s history, particularly in homosexual, with attribution of meaning to other life experiences, particularly in the linking to the romantic couple.

Exploring the safety of chemotherapy for treating breast cancer during pregnancy

Introduction: The diagnosis of breast cancer during pregnancy (BCP) represents a unique challenge to the patient, her family and the treating physician. The proper management of this critical clinical situation is crucial, and requires a multidisciplinary approach. A proper understanding of the safety of chemotherapy during pregnancy is a vital step to avoid detrimental consequences on the mother and the fetus.Areas covered: The aim of this article is to review the available evidence on the safety of chemotherapy administration in managing BCP.Expert opinion: The rule of thumb of chemotherapy - avoiding first trimester exposure and starting therapy in the second trimester - can be considered applicable for classic agents that are used in managing pregnant breast cancer patients. Anthracycline-based regimens are considered the standard of care in managing BCP. Recently, a growing amount of data suggests the safety of taxanes during pregnancy. Pregnancy in cancer patients should be considered as "high risk": once the systemic treatment is initiated, regular fetal monitoring is highly recommended. Emerging data are available on the relative long-term safety secondary to anthracycline exposure during pregnancy. A continued monitoring of the health of individuals with prenatal exposure to chemotherapy into adulthood is recommended for the possible occurrence of long-term side effects.

(Quantum-) critical dynamics of magnetoelectric materials

In this thesis the critical dynamics of several magnetoelectric compounds at their phase transition were examined. Mostly measurements of the dielectric properties in the frequency range of below 1 Hz up to 5 GHz were employed to evaluate the critical exponents for both magnetic field and temperature-dependent measurements. Most of the materials that are part of this work show anomalous behavior, especially at very low temperatures where quantum fluctuations are of the order of or even dominate those induced thermally. This anomalous behavior manifests in different forms. In Dy2Ti2O7 we demonstrate the existence of electric dipoles on magnetic monopoles. Here the dynamics at the critical endpoint located at 0.36K and in a magnetic field of 1T parallel to the [111] direction are of special interest. At this critical endpoint the expected critical slowing down of the dynamics could not only not be observed but instead the opposite, critical speeding-up by several orders of magnitude, could be demonstrated. Furthermore, we show that the phase diagram of Dy2Ti2O7 in this field direction can be reproduced solely from the dynamical properties, for example the resonance frequency of the observed relaxation that is connected to the monopole movement. Away from this point of the phase diagram the dynamics are slowing-down with reduction of temperature as one would expect. Additional measurements on Y2Ti2O7, a structurally identical but non-magnetic material, show only slowing down with reduction of temperature and no additional features. A possible explanation for the observed critical speeding-up is a coherent movement of magnetic monopoles close to the critical field that increases the resonance frequency by reducing the damping of the process. LiCuVO4 on the other hand behaves normally at its phase transition as long as the temperature is higher than 0.4 K. In this temperature regime the dynamics show critical slowing-down analogous to classical ferroelectric materials. This analogy extends also towards higher frequencies where the permittivity displays a ‘dispersion’ minimum that is temperature-dependent but of the order of 2 GHz. Below 0.4K the observed behavior changes drastically. Here we found no longer relaxational behavior but instead an excitation with very low energy. This low energy excitation was predicted by theory and is caused by nearly gapless soliton excitations within the 1D Cu2+ chains of LiCuVO4. Finally, in TbMnO3 the dynamics of the phase transition into the multiferroic phase was observed at roughly 27 K, a much higher temperature compared to the other materials. Here the expected critical slowing-down was observed, even though in low-frequency measurements this transition into the ferroelectric phase is overshadowed by the so-called c-axis relaxation. Therefore, only frequencies above 1MHz could be used to determine the critical exponents for both temperatureand magnetic-field-dependent measurements. This was done for both the peak frequency as well as the relaxation strength. In TbMnO3 an electromagnetic soft-mode with small optical weight causes the observed fluctuations, similar to the case of multiferroic MnWO4.

Neutron Scattering Studies on Complex Magnetic Structures in Magnetoelectric Materials

In this thesis, the magnetic properties of four transition-metal oxides are presented. Their multiferroic and magnetoelectric phases have been investigated by means of different neutron scattering techniques. The materials TbMnO3 and MnWO4 belong to the group of spin-induced multiferroics. Their ferroelectric polarization can be explained by the inverse DzyaloshinskiiMoriya interaction. Another common feature of both materials is the presence of subsequent magnetic transitions from a spin-density wave to a spin spiral. The features of the phase transitions have been studied in both materials and it could be shown that diffuse magnetic scattering from the spin spiral is present even in the ordered spin-density wave phase. The excitation spectrum in the multiferroic phase of TbMnO3 was investigated in detail and a comprehensive dataset was obtained using time-of-flight spectroscopy. A spin-wave model could be obtained which can quantitatively describe the full dispersion. Furthermore, the polarization of the zone-center excitations could be derived which fit well to data from inelastic neutron spectroscopy and infrared spectroscopy. With the combination of spherical neutron polarimetry and a poling of the sample by an electric field, it was possible to observe the chiral magnetic component of the magnetic excitations in TbMnO3 and MnWO4. The spin-wave model for TbMnO3 obtained in this thesis is able to correctly describe the dispersion of this component. The double tungstate NaFe(WO4)2 is isostructural to the multiferroic MnWO4 and develops a complex magnetic phase diagram. By the use of neutron diffraction techniques, the zero-field structure and high-field structures in magnetic field applied along the b-axis could be determined. The data reveal a direct transition into an incommensurate spin-spiral structure. The value of the incommensurability is driven by anharmonic modulations and shows strong hysteresis effects. The static and dynamic properties in the magnetoelectric spin-glass phase of Ni0.42Mn0.58TiO3 were studied in detail. The spin-glass phase is composed of short-ranged MnTiO3 and NiTiO3-type order. The antiferromagnetic domains could be controlled by crossed magnetic and electric fields, which was visualized using spherical neutron polarimetry. A comprehensive dataset of the magnetic excitations in the spin-glass phase was collected. The dataset revealed correlations in the hexagonal plane which are only weakly coupled along the c-axis. The excitation spectra could be simulated by taking into account the MnTiO3-type order.

Comparison between CDC and WHO BMI z-score and their relation with metabolic risk markers in Northern Portuguese obese adolescents

Growth-curves are an important tool for evaluating the anthropometric development in pediatrics. The different growth-curves available are based in different populations, what leads to different cut-offs. Pediatric obesity tracks into adulthood and is associated with increased cardiovascular risk. The accurate assessment of a child nutritional status using growth-curves can indicate individuals that are either obese or in risk of becoming obese, allowing an early intervention. Moreover, the association between the data obtained from growth-curves with specific metabolic risk factors further highlights the importance of these charts. This study aimed to evaluate the associations between body mass index z-score (BMIzsc), determined using the growth-curves from the Centre for Disease Control and Prevention (CDC) and from the World Health Organization (WHO), with cardiovascular risk factors, represented here by metabolic syndrome (MS) and insulin resistance (IR) related parameters. The study involved 246 obese adolescents (10-18 years, 122 females). MS was defined according to the International Diabetes Federation. IR was considered for HOMA-IR greater than 2.5.

Plano curricular dos currículos específicos individuais - 2.º e 3.º ciclos: representações dos professores

Dissertação apresentada à Escola Superior de Educação de Paula Frassinetti para a obtenção do grau de Mestre em Ciências da Educação – Especialização em Educação Especial

Soziale Ungleichheiten beim Übergang von der Grundschule in die Sekundarstufe I. Theorie, Forschungsstand, Interventions- und Fördermöglichkeiten

Auf der Basis eines theoretischen Modells zum Übergangsprozess, in dem primäre und sekundäre Herkunftseffekte nach Boudon unterschieden werden, fasst der vorliegende Beitrag den empirischen Kenntnisstand zum Einfluss der familiären Herkunft auf den Übergang von der Grundschule in die Sekundarstufe I zusammen. Dabei wird neben den primären Effekten zwischen verschiedenen Arten von sekundären Herkunftseffekten unterschieden: sekundäre Effekte der Leistungsbeurteilung, der Schullaufbahnempfehlung und des Übergangsverhaltens. Die Befunde sprechen für die Existenz primärer und sekundärer Herkunftseffekte im deutschen Schulsystem: Kinder aus sozial schwachen Familien haben schlechtere Schulleistungen, erhalten jedoch selbst bei gleichen Testleistungen noch schlechtere Beurteilungen durch die Lehrkräfte (Noten und Schullaufbahnempfehlungen) und gehen bei gleichen Testleistungen und Schulnoten und gleicher Empfehlung häufiger auf niedrigere Schulformen über. Weiterhin werden Ergebnisse aus Studien zur Quantifizierung und Neutralisation von primären und sekundären Herkunftseffekten vorgestellt und diskutiert sowie mögliche Interventions- und Fördermöglichkeiten zur Verringerung der Herkunftseffekte beim Übergang aufgezeigt.