IMPLEMENTACIÓN DE JUEGOS DE REHABILITACIÓN EN UN NIÑO CON SÍNDROME FOXP1

O presente estudo teve como objetivo desenvolver e validar uma estratégia de jogo adaptado à reabilitação da função psicomotora numa criança portadora de FOXP1, indo de encontro às necessidades identificadas pelos cuidadores. Participou neste estudo uma criança de 4 anos com síndrome de FOXP1. Realizou-se uma entrevista semiestruturada com a cuidadora, que foi transcrita e codificada com base na Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF). Foi ainda implementada a Medida Canadense de Desempenho Ocupacional. Posteriormente, prosseguiu-se a testes de implementação adaptada dos jogos analógicos Crazy Cups e Go Go Gelato! e de componentes de um jogo digital. Durante estas sessões realizou-se registo em vídeo para permitir a análise qualitativa e quantitativa do comportamento psicomotor. Os resultados demonstraram que as componentes como os autocuidados, independência fora de casa, mobilidade, socialização e recreação tranquila foram destacados como importantes para a cuidadora, estando modificados por dificuldades marcadas na organização motora e na integração de estímulos. Na implementação dos jogos ocorreram diferenças no número interações entre o jogo analógico e o jogo digital, com destaque para um maior número de interações no jogo digital. Foi ainda percetível uma evolução no número das interações positivas da primeira para a segunda sessão. Este estudo contribuiu para a adaptação de jogos na população pediátrica. A perspetiva do cuidador constitui-se uma ferramenta essencial para desenvolver as dinâmicas do jogo, destacando o controlo do ambiente sensorial.This study aimed to develop and validate a game strategy adapted to the rehabilitation of psychomotor function in a child with FOXP1, meeting the needs identified by the caregivers. A 4-years-old child with FOXP1 syndrome participated in this study. A semi-structured interview was conducted with the caregiver, which was transcribed and coded based on the International Classification of Functioning, Disability and Health (ICF). The Canadian Occupational Performance Measure was also implemented. An implementation testing of adapted rules of the Crazy Cups and Go Go Gelato analog games was conducted and components of a digital game were implemented. During these sessions it was recorded a video to allow qualitative and quantitative analysis of psychomotor behavior. The results showed that the components such as self-care, independence mobility in the community, general mobility, socialization and quiet recreation were highlighted as important for the caregiver, being modified by marked difficulties in motor organization and stimulus integration. There were differences in the number of interactions between the analog game and the digital game, highlighting the greater number of interactions in the digital game. It was also noticeable an evolution in the number of positive interactions from the first to the second session. This study contributed to the adaptation of games in the pediatric population. The caregiver's perspective is an essential tool to develop the game dynamics, highlighting the control of the sensory environment.El propósito de este estudio fue desarrollar y validar una estrategia de juego adaptada a la rehabilitación de la función psicomotora en un niño con FOXP1, que satisfaga las necesidades identificadas por los cuidadores. Un niño de 4 años con síndrome FOXP1 participó en este estudio. Se realizó una entrevista semiestructurada con el cuidador, que se transcribió y codificó según la Clasificación Internacional de Funcionamiento, Discapacidad y Salud (ICF). También se implementó la Medida de desempeño ocupacional canadiense. Posteriormente, se continuaron las pruebas de implementación adaptadas de los juegos analógicos Crazy Cups y Go Go Gelato. y componentes de un juego digital. Durante estas sesiones, se realizó una grabación de video para permitir el análisis cualitativo y cuantitativo del comportamiento psicomotor. Los resultados mostraron que los componentes como el autocuidado, la independencia del hogar, la movilidad, la socialización y la recreación tranquila se destacaron como importantes para el cuidador, siendo modificados por marcadas dificultades en la organización motora y la integración de estímulos. En la implementación de los juegos han sido idenitifacadas diferencias en el número de interacciones entre el juego analógico y el juego digital, destacando el mayor número de interacciones en el juego digital. También se observó una evolución en el número de interacciones positivas de la primera a la segunda sesión. Este estudio contribuyó a la adaptación de los juegos en la población pediátrica. La perspectiva del cuidador es una herramienta esencial para desarrollar la dinámica del juego, destacando el control del entorno sensorial. &nbsp

Transient cardiac dysfunction but elevated cardiac and kidney biomarkers 24 h following an ultra-distance running event in Mexican Tarahumara.

BACKGROUND: The Mexican Tarahumara are accustomed to running ultra-distance races. No data exist on the acute physiological changes following ultra-distance running and physiological-biomarker associations in this population. Thus, we aimed to investigate the acute impact (≤ 24 h) on functional and biochemical changes of the cardiac muscle and biochemical changes associated with kidney function following a 63-km ultra-distance race with an altitude difference of 1800 m in Mexican Tarahumara athletes. METHODS: Ten Tarahumara male athletes (mean ± SD age = 29.9 ± 6.6 years) volunteered to participate in the study. VO2max was assessed by a sub-maximal step test individually calibrated combining heart rate and accelerometry. Standard transthoracic echocardiography methodology and venipuncture blood tests were carried out at four time points: pre-race, immediately post-race, 6 h, and 24 h post-race. RESULTS: Estimated mean VO2max was 54.5 (± 8.8) mL O2 min-1 kg-1 and average physiological activity intensity was 746 (± 143) J min-1 kg -1 (~ 11.5 METs). When compared to pre-race values, significant changes in left ventricular ejection fraction (LVEF) and LV end-diastolic volume (- 15%, p < 0.001 for both parameters), cardiac output (39%, p < 0.001), and maximal longitudinal velocity (- 13%, p < 0.009) were seen post-race with LVEF also being decreased at < 6 h post-race (- 8%, p < 0.014). Plasma biomarkers mid-regional pro-atrial natriuretic peptide, copeptin-ultra sensitive, and high-sensitivity cardiac troponin T remained significantly elevated at 24 h post-race, and the two latter were inversely associated with LVEF (p < 0.04). Kidney dysfunction was indicated by increased post-race copeptin-ultra sensitive. CONCLUSIONS: The athletes participating in this study had acute transient cardiac dysfunction as assessed by echocardiography but elevated cardiac and kidney biomarkers at 24 h following a 63-km race with extreme altitude variation

Toxicological effects of the rare earth element neodymium in Mytilus galloprovincialis

The wide range of applications of rare earth elements (REE) is leading to their occurrence in worldwide aquatic environments. Among the most popular REE is Neodymium (Nd), being widely used in permanent magnets, lasers, and glass additives. Neodymium–iron–boron (NdFeB) magnets is the main application of Nd since they are used in electric motors, hard disk drives, speakers and generators for wind turbines. Recent studies have already evaluated the toxic potential of different REE, but no information is available on the effects of Nd towards marine bivalves. Thus, the present study evaluated the biochemical alterations caused by Nd in the mussel Mytilus galloprovincialis exposed to this element for 28 days. The results obtained clearly demonstrated that Nd was accumulated by mussels, leading to mussel’s metabolic capacity increase and GLY expenditure, in an attempt to fuel up defense mechanisms. Antioxidant and biotransformation defenses were insufficient in the elimination of ROS excess, resulting from the presence of Nd and increased electron transport system activity, which caused cellular damages (measured by lipid peroxidation) and loss of redox balance (assessed by the ratio between reduced and oxidized glutathione). The results obtained clearly highlight the potential toxicity of REEs and, in particular of Nd, with impacts at cellular level, which may have consequences in mussel’s survival, growth and reproduction, affecting mussel’s population.publishe

Detección de bajos niveles de Mg en leche materna en la ciudad de La Plata

El Mg es el cuarto catión más importante del cuerpo humano, luego del Na, K y Ca. Es cofactor para numerosos sistemas enzimáticos y energéticos, mantiene el potencial eléctrico en nervios y membranas musculares y es crítico para el metabolismo de la glucosa. Su déficit produce bradicardia, hipotensión, apneas, hiperexcitabilidad, convulsiones, y tetania similar a aquella producida por el déficit de calcio. El principal depósito lo constituye el tejido óseo, representando en la vida adulta el 60 - 65 % del Mg corporal. Dicho mineral compone el 1.43 - 2.45 % de la masa mineral de la leche materna siendo constante sus concentraciones en las distintas etapas de la lactancia. El valor promedio es 3.1±2 mg/dl con un rango de 1.5 a 6.4 mg/dl. Las mayores fuentes de Mg son la leche materna y los vegetales. Teniendo en cuenta que los recién nacidos no comienzan su alimentación complementaria hasta pasado el 6 to mes, resulta importante determinar el valor de Mg en la leche materna y detectar aquellas situaciones en las cuales existe déficit de dicho ion, con el fin de corregir esta anomalía.Facultad de Ciencias Médica

Productive performance of tambacus fed diets supplemented with vitamin E

O objetivo deste trabalho foi avaliar os efeitos da suplementação da dieta de tambacus com concentrações de vitamina E sobre variáveis de desempenho e hematológicas, bem como determinar a relação da atividade da glutationa peroxidase com a inclusão de vitamina E e selênio na dieta. Foram utilizados 250 juvenis de tambacu, divididos em 25 aquários. A dieta basal constituiu-se de ração peletizada com 32% de proteína bruta e 3.300 kcal kg-1 de energia digestível, e inclusão de 0,40 mg kg-1 de Se. As dietas-teste - isoprotéicas e isoenergéticas - foram compostas da dieta basal com diferentes concentrações de vitamina E (0, 100, 200, 300, 400 mg kg-1), em delineamento inteiramente ao acaso, com cinco tratamentos e cinco repetições. Não foi observado efeito significativo da suplementação com vitamina E sobre o comprimento total, volume corpuscular médio, concentração de hemoglobina corpuscular média e número de eritrócitos, nem sobre a atividade da glutationa peroxidase. Peso final e conversão alimentar aparente, no entanto, sofreram efeito dos tratamentos suplementados. O teor de 400 mg kg-1 de vitamina E melhorou o comprimento padrão e ganho de peso. A suplementação da dieta com vitamina E resulta em melhor desempenho produtivo de tambacus.The objective of this work was to evaluate the effects of tambacu vitamin E dietary supplementation on performance and hematological variables, and determine the relationship of glutathione peroxidase activity with vitamin E and selenium suplementation. Two hundred and fifty juvenile tambacus were used, divided into 25 aquaria. The basal diet was pelleted with 32% of crude protein and 3,300 kcal kg-1 of digestible energy, with 0.40 mg kg-1 Se. Test diets – isoproteic and isocaloric – were composed of the basal diet with increasing vitamin E concentrations (0, 100, 200, 300, 400 mg kg-1), in a completely randomized design, with five treatments and five replications. No significant effect of vitamin E supplementation was observed on total length, mean corpuscular volume, mean corpuscular hemoglobin concentration and total erythrocyte, and on the enzymatic activity of glutathione peroxidase. However, final weight and apparent feed conversion were significantly affected by supplemented treatments. Standard length and weight gain improved using diets supplemented with 400 mg kg-1 of vitamin E. Dietary vitamin E supplementation results in better tambacu performance

Effects of copy number variations on brain structure and risk for psychiatric illness: large-scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.Funding information: European Union's Horizon2020 Research and Innovation Programme, Grant/Award Number: CoMorMent project; Grant #847776; KG Jebsen Stiftelsen; National Institutes of Health, Grant/Award Number: U54 EB020403; Norges Forskningsråd, Grant/Award Number: #223273; South-Eastern Norway Regional Health Authority, Grant/Award Number: #2020060ACKNOWLEDGMENTS: The ENIGMA Consortium is supported by the NIH Big Data to Knowledge (BD2K) program under consortium grant number U54 EB020403 (PI: Thompson). OAA is supported by the Research Council of Norway, South East Norway Health Authority, KG Jebsen Stiftelsen, EU H2020. C. A. has been funded by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/ 024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds; European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241,909 (Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603,196 (Project PSYSCAN) and FP7- HEALTH-2013- 2.2.1-2-602,478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative two Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. R. A-A is funded by a Miguel Servet contract from the Carlos III Health Institute (CP18/00003). G. B. is supported by the Dutch Organization for Health Research and Development ZonMw (grants 91112002 & 91712394). A. S. B. is supported by the Dalglish Family Chair in 22q11.2 Deletion Syndrome, Canadian Institutes of Health Research (CIHR) grants MOP-79518, MOP89066, MOP-97800 and MOP-111238, and NIMH grant number U01 MH101723–01(3/5). C. E. B. is also supported by the National Institute of Mental Health: RO1 MH085953, R01 MH100900 and 1U01MH119736. N. E. B. is granted the KNAW Academy Professor Award (PAH/6635). V. D. C. is supported by NIH R01 MH094524. S. C. is supported by the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3); Helmholtz Initiative and Networking Fund. C. R. K. C. is supported by NIA T32AG058507. E. W. C. C. is supported by the Canadian Institutes of Health Research, Ontario Mental Health Foundation grant MOP-74631 and NIMH grant U01MH101723–01(3/5). S. Ci. has received funding from the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3). M. C. C. is supported by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. N. A. C. is supported by Agencia Nacional de Investigación y Desarrollo (ANID Chile) PIA ACT192064. GId. Z. is supported by the NHMRC. J. L. D. and D. E. J. L. are supported by the Wellcome Trust. T. B. C. is supported by NICHD grant PO1-HD070454, NIH grant UO1-MH191719, and NIMH grant R01 MH087636-01A1. AMD is supported by U24DA041147. B. D. is supported by the Swiss National Science Foundation (NCCR Synapsy, project grant numbers 32003B_135679, 32003B_159780, 324730_192755 and CRSK3_190185), the Leenaards Foundation and the Roger De Spoelberch Foundation. SE is supported by the NARSAD-Young Investigator Grant “Epigenetic Regulation of Intermediate Phenotypes in Schizophrenia”. B. E. S. is supported by the NIH (NIMH). D. C. G. is supported by NIH grant numbers MH078143, MH083824, AG058464. W. R. K. is supported by NIH/MH R0106824. R. E. G. is supported by NIH/NIMH grant numbers MH087626, MH119737. DMMcD-McG is supported by National Institutes of Mental Health (NIMH), grant numbers MH119737-02; MH191719; and MH087636-01A1. S. E. M. is supported by NHMRC grants APP1103623; APP1158127; APP1172917. TM is supported by Research Council of Norway - grant number 273345. D. G. M. is supported by the National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London and S (European Autism Interventions)/EU AIMS-2-TRIALS, a European Innovative Medicines Initiative Joint Undertaking under grant agreements 115300 and 777394. T. N. was supported by Stiftelsen KG Jebsen under grant number SKGJ-MED-021. R. A. O. is supported by NIMH R01 MH090553. S. Y. S. has been funded by the Canadain Institutes of Health Research. M. J. O. is supported by MRC Centre grant MR/L010305/1 and Wellcome Trust grant 100,202/Z/12/Z; Dr. Owen has received research support from Takeda. Z. P. is supported by CIHR, CFI, HSFC. B. G. P. is supported by CIHR FDN 143290 and CAIP Chair. G. M. R. is supported by Fondecyt-Chile #1171014 and ANID-Chile ACT192064. A. Re. was supported by a grant from the Swiss National Science Foundation (31003A_182632). DRR is supported by R01 MH120174 (PI: Roalf). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London (to J. J. R). PSS is supported by NHMRC (Australia) program grant 1093083. J. E. S. is supported by NIH K01-ES026840. S. M. S. is supported by the Epilepsy Society. T. J. S. is supported by NIH grants R01MH107108, R01HD042794, and HDU54079125. I. E. S. is supported by South-Eastern Norway Regional Health Authority (#2020060), European Union's Horizon2020 Research and Innovation Programme (CoMorMent project; grant #847776) and the KG Jebsen Foundation (SKGJ-MED-021). V. M. S. is supported by Research Council of Norway (CoE funding scheme, grant number 223273). D. J. S. is supported by the SA MRC. C. K. T. is supported by Research Council of Norway (#230345, #288083, #223273) and South-Eastern Norway Regional Health Authority (#2019069, #2021070, #500189). D. T.-G. was supported by the Instituto de Salud Carlos III (PI14/00639 and PI14/00918) and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363). Dvd. M. is supported by Research Council of Norway #276082. F. V. R. is supported by the Michael Smith Foundation for Health Research Scholar Award. deCODE genetics has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreements' no. 115008 (NEWMEDS) and no. 115300 (EUAIMS), of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (EU-FP7/ 2007–2013). L. T. W. is supported by Research Council of Norway, European Research Council. The IDIVAL neuroimage unit is supported by Instituto de Salud Carlos III PI020499, research funding SCIII-INT13/0014, MICINN research funding SAF2010-20840-C02- 02, SAF2013-46292-R. The TOP/NORMENT study are supported by the Research Council of Norway (#223273). The GOBS study data collection was supported in part by the National Institutes of Health (NIH) grants: R01 MH078143, R01 MH078111, and R01 MH083824 with work conducted in part in facilities constructed under the support of NIH grant number C06 RR020547. The Sydney Memory and Ageing Study has been funded by three National Health & Medical Research Council (NHMRC) Program Grants (ID No. ID350833, ID568969, and APP1093083). We thank the participants and their informants for their time and generosity in contributing to this research. We also acknowledge the MAS research team: https://cheba.unsw.edu.au/researchprojects/sydney-memory-and-ageing-study. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/ project/older-australian-twins-study) to this study. The OATS study has been funded by a National Health & Medical Research Council (NHMRC) and Australian Research Council (ARC) Strategic Award Grant of the Aging Well, Aging Productively Program (ID No. 401162); NHMRC Project (seed) Grants (ID No. 1024224 and 1025243); NHMRC Project Grants (ID No. 1045325 and 1085606); and NHMRC Program Grants (ID No. 568969 and 1093083). We thank the participants for their time and generosity in contributing to this research. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID No. 1079102) from the National Health and Medical Research Council. The NCNG sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the KG Jebsen Foundation, the Research Council of Norway, to S. L. H., V. M. S., A. J. L., and T. E. The authors thank Dr. Eike Wehling for recruiting participants in Bergen, and Professor Jonn-Terje Geitung and Haraldplass Deaconess Hospital for access to the MRI facility. Additional support by RCN grants 177458/V50 and 231286/F20. The Betula study was supported by a Wallenberg Scholar Grant (KAW). The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU—Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. Research for the GAP cohort was supported by the Department of Health via the National Institute for Health Research (NIHR) Specialist Biomedical Research Center for Mental Health award to South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry at King's College London, London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. S.J. is supported by Calcul Quebec (http:// www.calculquebec.ca), Compute Canada (http://www.computecanada. ca), the Brain Canada Multi investigator research initiative (MIRI), the Institute of Data Valorization (Canada First Research Excellence Fund), CHIR, Canada Research Chairs and the Jeanne et Jean Louis Levesque Foundation. The NTR cohort was supported by the Netherlands Organization for Scientific Research (NWO), MW904-61-193 (de Geus & Boomsma), MaGWnr: 400-07-080 (van 't Ent), MagW 480-04-004 (Boomsma), NWO/SPI 56-464-14,192 (Boomsma), the European Research Council, ERC-230374 (Boomsma), and Amsterdam Neuroscience. Funding for genotyping was obtained from the National Institutes of Health (NIMH U24 MH068457-06; Grand Opportunity grants 1RC2 MH089951, and 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Boomsma), 51.02.060 (Hilleke Hulshoff Pol), 668.772 (Boomsma & Hulshoff Pol); NWO/SPI 56-464-14192 (Boomsma), the European Research Council (ERC230374) (Boomsma), High Potential Grant Utrecht University (Hulshoff Pol), NWO Brain and Cognition 433-09-220 (Hulshoff Pol). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide SNP typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The ENIGMA-22q11.2 Deletion Syndrome Working Group wishes to acknowledge our dear colleague Dr. Clodagh Murphy, who sadly passed away in April 2020. Open access funding enabled and organized by Projekt DEAL

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis.

Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently in pre-clinical and clinical development for this manifestation of leishmaniasis, there have been limited advances in drug research and development (R & D) for cutaneous leishmaniasis (CL). Here we review the need for new treatments for CL, describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the discovery, and pre-clinical development of new drugs for CL. These recent advances include novel mouse models of infection using bioluminescent Leishmania, the introduction of PK/PD approaches to skin infection, and defined pre-clinical candidate profiles

Development of SNP markers present in expressed genes of the plant-pathogen interaction: Theobroma cacao - Moniliophtora perniciosa

We report the detection, validation and analysis of SNPs in the plant-pathogen interaction between cacao and Moniliophthora perniciosa ESTs using resequencing. This analysis in 73 EST sequences allowed the identification of 185 SNPs, 57% of them corresponding to transversion, 29% to transition and 14% to indels. The ESTs containing SNPs were classified into 14 main functional categories. After validation, 91 SNPs were confirmed, categorized and the parameters of nucleotide diversity and haplotype were calculated. Haplotype-based gene diversity and polymorphic information content (PIC) ranged from 0.559 to 0.56 and 0.115 to 0.12; respectively. Also, it was the advantage when considering haplotypes structure for each locus in place of single SNPs. Most of the gene fragments had a major haplotype combined to a series of low frequency haplotypes. Thus, the re-sequencing approach proved to be a valuable resource to identify useful SNPs for wide genetic applications. Furthermore, the cacao genome sequence availability allow a positional selection of DNA fragments to be re-sequenced enhancing the usefulness of the discovered SNPs. These results indicate the potential use of SNPs markers to identify allelic status of cacao resistance genes through marker-assisted selection to support the development of promising genotypes with high resistance to witch's broom disease. (Résumé d'auteur

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)