243 research outputs found

    Deletion of the Coffin-Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

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    Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive function

    Modern rhodolith-dominated carbonates at Punta Chivato, Mexico

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    Rhodolith-dominated carbonate environments, characterized by high abundances of free-living coralline algae, have been described globally from a wide range of Recent and fossil shallow marine settings. In the present-day warm-temperate Gulf of California, Mexico, rhodolith-dominated systems are important contributors to carbonate production. One of the most prolific rhodolith factories is located on the Punta Chivato shelf, in the central Gulf of California, where due to a lack of input of terrigenous material from the arid hinterland, carbonate content averages 79%. Punta Chivato rhodoliths thrive above the shallow euphotic zone under normal saline, warm-temperate and meso- to eutrophic conditions. A detailed sedimentologic study combined with acoustic seafloor mapping indicates the presence of extensive rhodolith-dominated facies at subtidal water depth covering an area of \u3e17 km2. Additional facies, surrounding the rhodolith-dominated facies include a fine-grained molluscan, a transitional bivalve-rhodolith and a bivalve facies. While the Punta Chivato shelf yields average abundances of 38% rhodolith-derived coralline algal components in the gravel-sized sediment fraction, the rhodolith facies itself is characterized by more than 60% coralline algal components. Other important carbonate producers at Punta Chivato include bivalves (35%), bryozoa (11%) and gastropods (8%). The present study shows that acoustic sediment mapping yields highly resolved continuous coverage of the seafloor and can distinguish modern rhodolith facies from surrounding sediment. This has important implications for quantifying rhodolith-dominated settings globally, as well as for ecological and conservation studies. © Publications Scientifiques du Muséum national d\u27Histoire naturelle, Paris

    School-level factors associated with teacher connectedness: : A multilevel analysis of the structural and relational school determinants of young people’s health

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    © The Author 2017. Published by Oxford University Press on behalf of Faculty of Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT Background Conducting research on the antecedents of teacher connectedness (TC) is key to inform intervention and policy that can leverage the public health potential of teachers for young people’s well-being. As part of the EU-funded Teacher Connectedness Project, this study aims to examine the contribution of a variety of school-level factors (including type of school, school size, student–teacher ratio, students per class and teacher gender). Methods Sample consisted of 5335 adolescents aged 11, 13 and 15 years that had participated in the HBSC study in England. Multilevel multinomial regression was used to examine the contributions of sociodemographic and school-level factors to TC. Results TC was lower in older adolescents and those from less affluent families, but similar in boys and girls. Regarding school-level factors, it was not the size of the school but the ratio of students per teacher which was significantly associated to TC, with higher student–teacher ratio being significantly associated with lower odds of medium-to-high TC. Some differences between mixed and all-girls schools were also found. Conclusions Health promotion strategies targeting student–teacher relationships need to consider how TC changes by age and SES and give attention to school-level factors, in particular the student–teacher ratio. Keywords educational settings, social determinants, young peoplePeer reviewedFinal Published versio

    Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

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    FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08)
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