Performance on Indirect Measures of Race Evaluation Predicts Amygdala Activation

We used fMRI to explore the neural substrates involved in the unconscious evaluation of Black and White social groups. Specifically, we focused on the amygdala, a subcortical structure known to play a role in emotional learning and evaluation. In Experiment 1, White American subjects observed faces of unfamiliar Black and White males. The strength of amygdala activation to Black-versus-White faces was correlated with two indirect (unconscious) measures of race evaluation (Implicit Association Test [IAT] and potentiated startle), but not with the direct (conscious) expression of race attitudes. In Experiment 2, these patterns were not obtained when the stimulus faces belonged to familiar and positively regarded Black and White individuals. Together, these results suggest that amygdala and behavioral responses to Black-versus-White faces in White subjects reflect cultural evaluations of social groups modified by individual experience.Psycholog

Intellectual functioning in pediatric patients with epilepsy: a comparison of medically controlled, medically uncontrolled and surgically controlled children

OBJETIVO: Comparar o quociente intelectual (QI) em três grupos de crianças com epilepsia: 1) controlados com medicação, 2) não controlados com medicação e 3) controlados com cirurgia. MÉTODOS: Noventa e oito pacientes pediátricos, com idades entre 6 e 12 anos, foram selecionados de dezembro de 2007 a julho de 2008. A Escala de Inteligência Wechsler para Crianças - terceira edição (WISC-III) foi utilizada para a avaliação neuropsicológica dos pacientes. Os resultados foram relacionados com a síndrome epiléptica, a etiologia da epilepsia, o tratamento medicamentoso, a idade do paciente no início da epilepsia e a duração da epilepsia. RESULTADOS: Os escores da WISC foram significativamente melhores no grupo controlado com medicação quando comparados aos do grupo não controlado com medicação. O grupo controlado com medicação obteve um desempenho significativamente melhor na maioria dos subtestes da WISC quando comparado ao grupo não controlado com medicação: vocabulário, aritmética, compreensão, memória de dígitos, completar figuras, arranjo de figuras e cubos. Um número significativamente maior de pacientes com epilepsia idiopática e uso de monoterapia foi observado no grupo controlado com medicação quando comparado ao grupo não controlado. O grupo controlado com cirurgia não apresentou diferença significativa no desempenho do QI quando comparado ao grupo controlado com medicação. CONCLUSÕES: As crianças com um bom controle de crises tiveram um melhor desempenho no QI geral, verbal e de execução quando comparadas às crianças com epilepsia refratária. Esses resultados podem ser influenciados por fatores clínicos como o uso de monoterapia, o tipo de droga antiepiléptica utilizada, a síndrome epiléptica e a etiologia da epilepsia. A cirurgia de epilepsia pode causar um impacto positivo no desempenho cognitivo das crianças que ficaram livres de crises após o procedimento cirúrgico.OBJECTIVE: To compare the intellectual coefficient (IQ) of three groups of children with epilepsy: 1) medically controlled, 2) medically uncontrolled and 3) surgically controlled. METHODS: From December 2007 until July 2008, 98 pediatric patients were selected, with an age range between 6 and 12 years. Neuropsychological assessment included the Wechsler Intelligence Scale for Children - third edition (WISC-III). Results are related to epileptic syndrome, etiology of epilepsy, drug therapy, age at epilepsy onset and epilepsy duration. RESULTS: WISC scores were significantly better in the medically controlled group when compared to the medically uncontrolled group. The medically controlled group performed significantly better in the majority of the WISC subtests when compared to the medically uncontrolled group: vocabulary, arithmetic, comprehension, digit span, picture completion, picture arrangement, and block design. A significantly higher number of idiopathic epilepsy and monotherapy cases was observed in the medically controlled group when compared to the medically uncontrolled group. Surgically controlled children had no significant differences in IQ performance when compared to medically controlled children. CONCLUSIONS: Children with good seizure control have higher general, verbal and performed intelligence when compared to children with refractory epilepsy. These results may be influenced by clinical factors such as use of monotherapy, drug type and epileptic syndrome and etiology. Epilepsy surgery can have a positive impact on cognitive performance of children who were free of seizures after surgery

Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Erros inatos do metabolismo no Hospital das Clínicas de Ribeirão Preto. Um legado de múltiplas especialidades

Inborn errors of metabolism (IEM) are genetic diseases, mostly due to enzyme deficiencies leading to severe metabolic damages, increasingly diagnosed. The aim is to describe the history of the development of IEM diagnosis and treatment in the Hospital of Clinics of Ribeirão Preto, São Paulo University (HCFMRP-USP). At the beginnings of the Post-Graduate Programs in the School of Medicine of Ribeirão Preto of São Paulo University (FMRP-USP), the first thesis on IEM was performed in 1980 on cystinuria in the area of Genetics; G6PD goal was the second in 1987 in Pediatrics. Since that time, IEM diagnosis was possible, in the sequence, due to the chromatography of amino acids routine by the Center for Protein Chemistry, FMRP-USP in 1984, the partnership with the Department of Genetics, Hospital of Clinics of Porto Alegre. RS in 1988 and the urine screening in the Nutrology Laboratory of FMRP-USP, that resulted of a Master in Neurology in 1990. In the last two decades: the specialized outpatients clinics, the Program for Neonatal Screening, treatment by enzyme replacement and support of the Stem Cell Transplantation Center were implemented. It is noteworthy that by 2009, just one more thesis was presented. The perspective for the development of this area is the consolidation of a line of research focused exclusively on the EIM in FMRP-USP.Erros inatos do metabolismo (EIM) são doenças genéticas decorrentes, em sua maioria, de deficiências enzimáticas que levam a graves distúrbios metabólicos, e que vem sendo cada vez mais diagnosticados. No presente texto relata-se um histórico sobre a evolução da abordagem diagnóstica e tratamento de EIM no HCFMRP-USP. Na FMRP-USP os EIM vêm sendo objeto de estudo em pós-graduação desde a década de 1980, dado o grande apelo clínico nas áreas de Genética Clínica, Pediatria e Neurologia Infantil, até então com auxílio do Laboratório de Patologia, além de convênio com a APAE de São Paulo para o diagnóstico de fenilcetonúria. Já iniciados os Programas de Pós-Graduação da FMRP-USP, a primeira tese a respeito foi realizada em 1980, sobre cistinúria, na Área de Genética; deficiência de glicose-6-fostato desidrogenase (G6PD) foi objetivo da segunda, em 1987, na de Pediatria. Desde essa época, garantem a rotina de investigação a realização da cromatografia de aminoácidos pelo Centro de Química de Proteínas da FMRP-USP, o convênio com o Serviço de Genética do HC de Porto Alegre-RS e a triagem urinária no Laboratório de Nutrologia, este, resultado de Mestrado em Neurologia em 1990. Nas duas últimas décadas vieram os ambulatórios especializados, o Programa de Triagem Neonatal, o tratamento por Reposição Enzimática e o apoio do Centro de Transplante de Células Tronco. Cabe ressaltar que até 2009, apenas mais uma tese foi apresentada. A perpectiva para o desenvolvimento dessa área é a consolidação de uma linha de pesquisa voltada exclusivamente para os EIM na FMRP-USP

Efeitos do chumbo sobre o cérebro em desenvolvimento

No presente trabalho procedeu-se à revisão de literatura dos efeitos do chumbo sobre o cérebro, com enfoque no desenvolvimento infantil. O chumbo pode permanecer no organismo durante toda a vida do indivíduo, sendo difícil a sua remoção. Não há nível estável seguro, considerando sua passagem lenta dos ossos para o sangue, com aceleração em condições como na gravidez. Há evidências de que o cérebro imaturo é um dos mais importantes alvos, e as pesquisas apontam para consequências mais tardias, em processos cerebrodegenerativos no adulto. Na infância, mesmo níveis sanguineos inferiores a 10 ?g/dL podem afetar a cognição. Estudos clínicos registram seus efeitos tóxicos na criança em idade escolar e na adolescência trazendo prejuízos motores, sensoriais, adaptativos, cognitivos e comportamentais, destacando-se a delinquência. Conclui-se, pela gravidade dos efeitos e dificuldade de tratamento, que o enfoque na orientação populacional sobre as medidas preventivas da exposição ao chumbo é prioritário.This work is a review of the lead effects on the brain, focusing on child development. Lead can remain in the body throughout the life, being difficulty its removal, and there is no safe stable level, considering its slow passage of the bones for blood, but acceleration in moments such as pregnancy. There is evidence that the immature brain is one of the most important targets. Surveys point to later consequence in adult life, as the degenerative brain disease. In the childhood, even blood levels under 10 ?g/dL may affect cognition. Clinical studies record their toxic effects in childhood and adolescence, bringing motor, sensory, adaptive, cognitive and behavioral losses, highlighting the crime itself. It is due to the severe effects on the developing nervous system and treatment difficulties, that the priority is the population guidance on the preventive measures of exposure to lead

The LRRK2 signalling system

The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease. Understanding the events in which LRRK2 is involved at a systems level is therefore critical to fully understand the biology and pathobiology of this protein and is the subject of this review

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases

Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition.

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa; Cancer Research UK grants A6691 and A9892 (M.N., N.K., C.J.T., D.C.B., C.J.C., L.S.G, and M.S.); a fellowship from the Uehara Memorial Foundation (M.S.).This is the author accepted manuscript. The final version is available from the American Society for Cell Biology via http://dx.doi.org/10.1091/mbc.E15-01-000