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The formation of the bone marrow cavity is a prerequisite for endochondral ossification. In reviews and textbooks, it is occasionally reported that osteoclasts are essential for bone marrow cavity formation removing hypertrophic chondrocytes. Mice lacking osteoclasts or having functionally defective osteoclasts have osteopetrotic bones, yet they still form a bone marrow cavity. Here, we investigated the role of osteoclasts and macrophages in bone marrow cavity formation during embryogenesis. Macrophages can assist osteoclasts in matrix removal by phagocytosing resorption byproducts. Rank-deficient mice, lacking osteoclasts, and Pu.1-deficient mice, lacking monocytes, macrophages, and osteoclasts, displayed a delay in bone marrow cavity formation and a lengthening of the zone of hypertrophic chondrocytes. F4/80-positive monocyte/macrophage numbers increased by about fourfold in the bone marrow cavity of E18.5 Rank-deficient mice. Based on lineage-tracing experiments, the majority of the excess F4/80 cells were derived from definitive hematopoietic precursors of the fetal liver. In long bones of both Rank

Das hier vorgestellte Forschungsprojekt Multilinguale und multimodale Erzählstrategien im bilingualen Unterricht wurde im Rahmen des bilingualen Lehramtsstudiums (Primarstufe Deutsch-Französisch) am Institut für Bildungswissenschaften der Universität Straßburg durchgeführt. Als Projektziel wurde die Analyse verschiedener Modalitäten des translingualen Erzählens von Bilderbuchgeschichten im Hinblick auf Spracherwerb, mündliche Kommunikation, Literalität und Literarität in bilingualen Vor- und Grundschulklassen angestrebt. Die vorgestellten Forschungsergebnisse zeigen, dass multimodale und translinguale Erzählmodi von Bilderbuchgeschichten als ein effizientes pädagogisches Medium für den mehrsprachigen und multimodalen Erwerb betrachtet werden können. Durch ihre Kombination von kinderliterarischen und ästhetisch-performativen Aspekten stellen multimodale Erzählstrategien einen innovativen pädagogischen Ansatz für ganzheitliches, kreatives und freudvolles Mehrsprachen-Lernen und -Lehren im bilingualen Bildungskontext dar.From collaborative imagination to translingual narration: Investigating multilingual and multimodal storytelling with bilingual student teachers The research project Multilingual and Multimodal Storytelling in Bilingual Education was carried out within the bilingual teacher education programme (German-French; primary level) at the Faculty of Teacher Education of the University of Strasbourg. The project sought to analyse different modalities of translingual storytelling based on picturebook stories for language and literacy acquisition as well as oral communication in bilingual preschool and primary classrooms. The research results show that multimodal and translingual storytelling with picturebook stories can be considered as an efficient pedagogical medium for multilingual and multimodal acquisition. Combining literary and aesthetic-performative aspects, multimodal storytelling represents an innovative pedagogical approach for holistic, creative, and joyful teaching and learning in multilingual contexts.De l'imagination collaborative à la narration translinguistique: exploration de stratégies narratives multilingues et multimodales par des enseignants stagiaires bilingues Le projet de recherche Stratégies de narration multilingues et multimodales dans l'enseignement bilingue a été réalisé dans le cadre de la formation des enseignants bilingues (allemand-français) du premier degré à l'INSPE de l’Université de Strasbourg. L’objectif du projet consistait en l'analyse didactique et l'expérimentation pédagogique de différentes modalités de narration translinguistique, fondées sur des albums de jeunesse et susceptibles de favoriser l'acquisition des langues et de la bilittéracie ainsi que la communication orale dans les classes bilingues. Les résultats de recherche présentés montrent que la narration multimodale et translinguistique fondée sur les albums de jeunesse peut être considérée comme un moyen pédagogique efficace pour l'acquisition multilingue et multimodale. En combinant des aspects littéraires et performatifs, la narration multimodale représente une approche pédagogique innovante pour un enseignement-apprentissage multilingue holistique et créatif., Zeitschrift für Interkulturellen Fremdsprachenunterricht Volume 28 Issue 1 2023

Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.

Scoliosis is an abnormal bending of the body axis. Truncated vertebrae or a debilitated ability to control the musculature in the back can cause this condition, but in most cases the causative reason for scoliosis is unknown (idiopathic). Using mutants for somite clock genes with mild defects in the vertebral column, we here show that early defects in somitogenesis are not overcome during development and have long lasting and profound consequences for muscle fiber organization, structure and whole muscle volume. These mutants present only mild alterations in the vertebral column, and muscle shortcomings are uncoupled from skeletal defects. None of the mutants presents an overt musculoskeletal phenotype at larval or early adult stages, presumably due to compensatory growth mechanisms. Scoliosis becomes only apparent during aging. We conclude that adult degenerative scoliosis is due to disturbed crosstalk between vertebrae and muscles during early development, resulting in subsequent adult muscle weakness and bending of the body axis.

Osteoarthritis (OA) is a common degenerative disease of the joint, with a complex multifactorial not yet fully understood etiology. Over the past years, the Wnt signaling pathway has been implicated in osteoarthritis. In a recent genomewide association study (GWAS), the chromosomal location on chromosome 1, linked to the Wnt3a-Wnt9a gene locus, was identified as the most significant locus associated with a thumb osteoarthritis endophenotype. Previously, it was shown that WNT9a is involved in maintaining synovial cell identity in the elbow joint during embryogenesis. Here, we report that the conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER expressing cells predispositions the mice to develop spontaneous OA-like changes with age. In addition, the trabecular bone volume is altered in these mice. Similarly, mice with a conditional loss of Wnt4 in the limb mesenchyme are also more prone to develop spontaneously OA-like joint alterations with age. These mice display additional alterations in their cortical bone. The combined loss of Wnt9a and Wnt4 increased the likelihood of the mice developing osteoarthritis-like changes and enhanced disease severity in the affected mice. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

As creative writing research has shown, literary education in the context of teacher education at university greatly benefits from the collaborative practice of creative forms of literary expression for the development of creative literacies and imaginative agency. Accordingly, this study analyses the creative processes and outcomes of a bilingual songwriting workshop that was carried out in 2022 at the University of Strasbourg with 18 bilingual student teachers, in collaboration with the Franco-German world hip-hop artists Zweierpasch. This creative action research was guided by the following research questions: What are the pedagogical affordances of translingual creative writing for the acquisition of multiliteracies in bilingual education? What are the impacts of this creative writing workshop on the bilingual student teachers’ attitudes and beliefs towards creative pedagogical approaches in bilingual education? What are the effects of this workshop on the development of their linguistic, cultural, and professional identities? This study presents a literary analysis of the poetic outcome of this creative action research, as well as an evaluation of the workshop in the form of a qualitative content analysis of the student teachers’ reflections and perspectives. Overall, the student teachers considered creative writing as a valuable pedagogical approach for multimodal literacy teaching and learning in bilingual education. Their discourses reveal the transformation process of their attitudes and beliefs towards creative pedagogical approaches, and the enrichment of their linguistic and cultural identity through multilingual creative writing. Keywords: Creative writing; multilingual writing; multiliteracies; creative literacies; Tomi Ungerer.

In summer 2020, 68 clinicians in the New England area caring for Veterans with dementia as part of a specialty team were surveyed regarding caregiver support services, with a 46% response rate (n=31). When faced with the need to abruptly discontinue in-person dementia support services, the majority of respondents offered caregivers support via telephone rather than video telehealth. Only 4 of 31 (13%) mentioned offering video visits for the first time to replace face-to-face visits. Clinician choice of modality largely reflected shifts among preestablished communication modalities/patterns and were influenced by clinician perception that older patients and their caregivers would prefer the telephone. Clinicians without experience using video telehealth with older adults were unlikely to offer video visits despite evidence that many older adults are willing and able to participate. Assessing caregiver wish/ability to participate in video visits may inform and shape clinician choice of telehealth modality.

The goal of the review is to summarize the current knowledge on the process of chondrocyte-to-osteoblast transdifferentiation during endochondral bone formation and its potential implications in fracture healing and disease. Lineage tracing experiments confirmed the transdifferentiation of chondrocytes into osteoblasts. More recent studies lead to the discovery of molecules involved in this process, as well as to the hypothesis that these cells may re-enter a stem cell-like phase prior to their osteoblastic differentiation. This review recapitulates the current knowledge regarding chondrocyte transdifferentiating into osteoblasts, the developmental and postnatal events where transdifferentiation appears to be relevant, and the molecules implicated in this process.

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2(−/−) mutant mice. In contrast, Ror1(−/−) mutant mice are viable and show no limb phenotype. Ror1(−/−);Ror2(−/−) double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1(hyp)) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a(−/−) single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2(−/−) mutants. Ror2(−/−);Wnt9a(−/−) double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1(hyp/hyp);Wnt9a(−/−) double mutants. In addition, Ror1(hyp/hyp);Wnt9a(−/−) double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.

In hypertrophic chondrocytes, β-catenin has two roles. First, it locally suppresses the differentiation of osteoclasts at the chondro-osseous junction by maintaining the pro-osteoclastic factor receptor activator of NF-κB ligand (RANKL) at low levels. Second, it promotes the differentiation of osteoblast-precursors from chondrocytes. Yet, β-catenin is a dual-function protein, which can either participate in cell-cell adherens junctions or serve as a transcriptional co-activator in canonical Wnt signaling interacting with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors. Hence, whenever studying tissue-specific requirements of β-catenin using a conventional conditional knockout approach, the functional mechanisms underlying the defects in the conditional mutants remain ambiguous. To decipher mechanistically which of the two molecular functions of β-catenin is required in hypertrophic chondrocytes, we used different approaches. We analyzed the long bones of newborn mice carrying either the null-alleles of Lef1 or Tcf7, or mice in which Tcf7l2 was conditionally deleted in the hypertrophic chondrocytes, as well as double mutants for Lef1 and Tcf7l2, and Tcf7 and Tcf7l2. Furthermore, we analyzed Ctnnb1 mutant newborns expressing a signaling-defective allele that retains the cell adhesion function in hypertrophic chondrocytes. None of the analyzed Tcf/Lef single or double mutants recapitulated the previously published phenotype upon loss of β-catenin in hypertrophic chondrocytes. However, using this particular Ctnnb1 allele, maintaining cell adhesion function, we show that it is the co-transcriptional activity of β-catenin, which is required in hypertrophic chondrocytes to suppress osteoclastogenesis and to promote chondrocyte-derived osteoblast differentiation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Maintaining the correct proportions of different cell types in the bone marrow is critical for bone function. Hypertrophic chondrocytes (HCs) and osteoblasts are a lineage continuum with a minor contribution to adipocytes, but the regulatory network is unclear. Mutations in transcription factors, IRX3 and IRX5, result in skeletal patterning defects in humans and mice. We found coexpression of Irx3 and Irx5 in late-stage HCs and osteoblasts in cortical and trabecular bone. Irx3 and Irx5 null mutants display severe bone deficiency in newborn and adult stages. Quantitative analyses of bone with different combinations of functional alleles of Irx3 and Irx5 suggest these two factors function in a dosage-dependent manner. In Irx3 and Irx5 nulls, the amount of bone marrow adipocytes was increased. In Irx5 nulls, lineage tracing revealed that removal of Irx3 specifically in HCs exacerbated reduction of HC-derived osteoblasts and increased the frequency of HC-derived marrow adipocytes. β-catenin loss of function and gain of function specifically in HCs affects the expression of Irx3 and Irx5, suggesting IRX3 and IRX5 function downstream of WNT signaling. Our study shows that IRX3 and IRX5 regulate fate decisions in the transition of HCs to osteoblasts and to marrow adipocytes, implicating their potential roles in human skeletal homeostasis and disorders.

Synovial joints are complex functional elements of the vertebrate body that provide the organism with motion capabilities and, thus, with the ability for locomotion and for direct physical interaction with its environment. They are composed of different connective tissues structures that are derived from the same developmental structures in the embryo, but have distinct cellular and biochemical properties. Articular cartilage and synovial membrane are key components of synovial joints and show a number of peculiarities that makes them different from other tissues in our body. An in-depth knowledge of these structural and functional peculiarities is not only important for understanding key features of articular function, but also provides explanations for important characteristics of both degenerative and inflammatory joint diseases. This chapter reviews the structure, biochemical composition, and function of articular cartilage and synovium, and points to important links between physiology and pathological conditions, particularly arthritis. Special emphasis is put on the interaction of resident cells with both the extracellular matrix and other neighbouring or invading cells.

The vertebrate skeleton is a widely distributed organ that plays vital roles in supporting and protecting soft tissues and organs. It also actively participates in metabolic and endocrine regulation by producing, storing, and releasing regulatory factors. During embryonic development, skeletal formation at specific locations and times is controlled by a network of signaling pathways and transcription factors that pattern the embryos. The skeletal system is formed by mesenchymal tissues with distinct lineage origins. The bone-forming osteoblasts and the cartilage-forming chondrocytes are the major skeletal cell types in development and their cell fate choices at the outset of skeletal development dictate which of the two essential ossification mechanisms, intramembranous and endochondral ossification, will occur. This chapter focuses on key aspects of intramembranous and endochondral bone formation, and its underlying molecular regulation, as well as skeletal birth defects and diseases caused by disrupted bone development.

β-Catenin recruits BRD4 and other coregulators to protect pluripotency gene transcription against network perturbation., Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

Im Marz 2018 wurde die Jugendserie DRUCK (D 2018–) auf Funk, dem Online-Medienangebot von ARD und ZDF fur 14- bis 29-Jahrige, publiziert. Fur die Veroffentlichung wurden verschiedene Plattformen benutzt, nach dem Vorbild von SKAM (Norwegen 2015–2017, NRK). Hinter der Produktion von DRUCK steht die Adaption jener erfolgreichen norwegischen Serie. Sowohl die Charaktere als auch die Handlung wurden kulturell angepasst. Ebenso wurde die Distributionsstrategie des transmedialen Erzahlens ubernommen. Vor dem Hintergrund der Einordnung von DRUCK und SKAM in das sogenannte Teen TV werden der kulturelle Adaptionsprozess und die transmediale Strategie dargestellt. Dabei wird ein besonderer Fokus auf Casting, Narration und Asthetik gelegt. Auf diese Weise werden die Unterschiede und Gemeinsamkeiten zwischen den beiden Jugendserien herausgearbeitet.

Saint-John Perse’s poem Amers (1956) was translated into English by the American translator and literary scholar Wallace Fowlie in 1957. The manuscripts of this translation, which present the main focus of this paper, are conserved in the archive of the Saint-John Perse Foundation in Aix-en-Provence (France), and reveal the genesis of a collaborative translation: Wallace Fowlie’s manuscript is paralleled by the work of an unofficial translator, John Marshall, whose manuscript appears to be the closest to the final version. Both manuscripts show the hand-written suggestions, corrections, and variants of the poet himself.Spanning the various stages of the writing process from which the generation of this collaborative translation progressively emerges, the two manuscripts show a fascinating interaction. Saint-John Perse constantly confronts the versions of his two translators, sculpting them according to his poetic art. He also creates numerous columns of variants in the margins that display the semantic treasure of the original expression.The reader approaching this translation from a genetic standpoint can discover the sinuous gestation of the translation process, as well as the semantic and phonetic laws that govern the poet’s choices. He can also make good hermeneutic use of the poet’s variants, revealing an unexpected interpretative key. Consequently, through analysis of these avant-textual discoveries, many metaphors in absentia can become metaphors in praesentia, leading to a better understanding both of the original poem and its translation. O poema de Saint-John Perse Amers (1956) foi traduzido para o inglês pelo tradutor americano e estudioso literário Wallace Fowlie em 1957. Os manuscritos desta tradução, que apresentam o foco principal deste artigo, são conservados no arquivo do Saint-John. Perse Foundation em Aix-en-Provence (França), e revelam a gênese de uma tradução colaborativa: o manuscrito de Wallace Fowlie é paralelo ao trabalho de um tradutor não oficial, John Marshall, cujo manuscrito parece ser o mais próximo da versão final. Ambos os manuscritos mostram as sugestões escritas à mão, correções e variantes do próprio poeta.Abrangendo as várias etapas do processo de escrita a partir do qual a geração desta tradução colaborativa emerge progressivamente, os dois manuscritos mostram uma interação fascinante. Saint-John Perse confronta constantemente as versões de seus dois tradutores, esculpindo-os de acordo com sua arte poética. Ele também cria numerosas colunas de variantes nas margens que exibem o tesouro semântico da expressão original.O leitor que aborda essa tradução do ponto de vista genético pode descobrir a gestação sinuosa do processo de tradução, bem como as leis semânticas e fonéticas que governam as escolhas do poeta. Ele também pode fazer um bom uso hermenêutico das variantes do poeta, revelando uma chave interpretativa inesperada. Consequentemente, através da análise dessas descobertas textuais, muitas metáforas à revelia podem se tornar metáforas na praesentia, levando a uma melhor compreensão tanto do poema original quanto de sua tradução.

The X-linked WTX/AMER1 protein constitutes an important component of the β-catenin destruction complex that can both enhance and suppress canonical β-catenin signaling. Somatic mutations in WTX/AMER1 have been found in a proportion of the pediatric kidney cancer Wilms' tumor. By contrast, germline mutations cause the severe sclerosing bone dysplasia osteopathia striata congenita with cranial sclerosis (OSCS), a condition usually associated with fetal or perinatal lethality in male patients. Here we address the developmental and molecular function of WTX by generating two novel mouse alleles. We show that in addition to the previously reported skeletal abnormalities, loss of Wtx causes severe midline fusion defects including cleft palate and ectopic synostosis at the base of the skull. By contrast, deletion of the C-terminal part of the protein results in only mild developmental abnormalities permitting survival beyond birth. Adult analysis, however, revealed skeletal defects including changed skull morphology and an increased whole-body bone density, resembling a subgroup of male patients carrying a milder, survivable phenotype. Molecular analysis in vitro showed that while β-catenin fails to co-immunoprecipitate with the truncated protein, partial recruitment appears to be achieved in an indirect manner using AXIN/AXIN2 as a molecular bridge. Taken together our analysis provides a novel model for WTX-caused bone diseases and explains on the molecular level how truncation mutations in this gene may retain some of WTX-protein functions. © 2018 American Society for Bone and Mineral Research.

Resident distress behavior, a prevalent challenge in long-term care, contributes to resident morbidity, staff burden, and turnover. We describe an education model developed in the Veterans Administration (VA) Community Living Centers (CLC) through a CONCERT (VA CLCs’ Ongoing Center for Enhancing Resources & Training) quality improvement series. The Distress Behavior Conversation (DBC) uses a team meeting structure and process. Informed by unmet need and relational coordination theories, it guides the whole team, inclusive of interdisciplinary team members and front-line staff with resident contact, through a collaborative problem-solving action-planning discussion. DBC uses facilitated round-robins to identify potential resident behavior causes and individualized solutions. DBC supports the team in maintaining whole person and whole team mindsets, thus challenging the narrower medical model of discipline-specific clinical mindsets and staff level hierarchies. Over two years we have co-created and refined DBC through trainings and team debriefings with over 80 CLCs. Care teams reported “aha” moments during DBCs their thinking shifted (“we are now looking at the REAL why”; “we went from asking, how did he fall? to, why did he fall?; “tended to try to treat falls in a standardized way, [but] when you focus on a specific person you get to focus on HIS needs”; “personal information about the Veteran is the 5th vital sign!”). Teams additionally reported reduced strain and improved collaborative thinking (“I feel better about what I’m doing...more motivated to keep going!; “Now I see it is a team approach – don’t have to do it by myself.”).

This study investigates translingual and multimodal teaching strategies in the context of multilingual literacy acquisition within a bilingual education program in France. It is based on a research project carried out at the Graduate School of Education of the University of Strasbourg, during the academic year 2017-2018. The purpose of our research is to analyze the student teachers’ representations and attitudes towards multilingual picturebooks, and to lead them to explore the pedagogical affordances of interlingual and intersemiotic mediation in the context of a multilingual reading project, built around the trilingual edition of Tomi Ungerer’s The Three Robbers. The qualitative analysis of the student teachers’ discourses allows us to discuss how translingual and multimodal activities give rise to a new pedagogical approach to literacy with young readers, specifically in a bilingual education context, and explain how picturebooks can foster integrated, multimodal, and translingual learning, as well as the development of biliteracy and metalinguistic awareness.

In the adult mammalian skin, cells are constantly renewing, differentiating and moving upward, to finally die in a yet not fully understood manner. Here, we provide evidence that macroautophagy/autophagy has a dual role in the skin. In addition to its known catabolic protective role as an evolutionary conserved upstream regulator of lysosomal degradation, we show that autophagy induced cell death (CDA) occurs in epithelial lineage-derived organs, such as the inter-follicular epidermis, the sebaceous- and the Harderian gland. By utilizing GFP-LC3 transgenic and ATG7-deficient mice, we show that CDA is initiated during terminal differentiation at a stage when the cells have become highly resistant to apoptosis. In these transitional cells, the Golgi compartment expands, which accounts for the formation of primary lysosomes, and the nucleus starts to condense. During CDA a burst of autophagosome formation is observed, first the endoplasmic reticulum (ER) is phagocytosed followed by autophagy of the nucleus. By this selective form of cell death, most of the cytoplasmic organelles are degraded, but structural proteins remain intact. In the absence of autophagy, consequently, parts of the ER, ribosomes, and chromatin remain. A burst of autophagy was stochastically observed in single cells of the epidermis and collectively in larger areas of ductal cells, arguing for a coordinated induction. We conclude that autophagy is an integral part of cell death in keratinocyte lineage cells and participates in their terminal cell fate. Abbreviations: Atg7: autophagy related 7; BECN1: beclin 1; CDA: cell death-induced autophagy; Cre: Cre-recombinase; DAPI: 4′,6-diamidino-2-phenylindole; ER: endoplasmatic reticulum; GFP: green fluorescent protein; HaGl: haderian gland; IVL: involucrin; KRT14: keratin 14; LD: lipid droplet; LSM: laser scanning microscope; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PN: perinuclear space; RB: residual body; rER: rough endoplasmatic reticulum; SB: sebum; SG-SC: stratum granulosum – stratum corneum; SGl: sebaceous gland; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labelling.

As the vertebrate skeleton develops it progresses from a solely cartilaginous scaffold to a mineralized bony skeleton. The cells that build up the skeleton, the chondrocytes and osteoblasts, are primarily of mesodermal origin. Yet, some facial bones, as well as the endocranium, are derived from neural crest cells. The differentiation of the mesenchymal cells to skeletal precursors as well as their subsequent differentiation and maturation along the two lineages, chondrogenic and osteogenic, is controlled by various different signaling pathways, among them Wnt-signaling. WNTs comprise a family of 19 secreted cysteine-rich glycoproteins and can signal through a variety of different intracellular pathways. Genetic loss- and gain-of-function experiments of Wnt-signaling pathway genes have helped to uncover their multiple roles in skeletogenesis, which will be discussed in this article primarily focusing on endochondral bone formation.

As the vertebrate skeleton develops it progresses from a solely cartilaginous scaffold to a mineralized bony skeleton. The cells that build up the skeleton, the chondrocytes and osteoblasts, are primarily of mesodermal origin. Yet, some facial bones, as well as the endocranium, are derived from neural crest cells. The differentiation of the mesenchymal cells to skeletal precursors as well as their subsequent differentiation and maturation along the two lineages, chondrogenic and osteogenic, is controlled by various different signaling pathways, among them Wnt-signaling. WNTs comprise a family of 19 secreted cysteine-rich glycoproteins and can signal through a variety of different intracellular pathways. Genetic loss- and gain-of-function experiments of Wnt-signaling pathway genes have helped to uncover their multiple roles in skeletogenesis, which will be discussed in this article primarily focusing on endochondral bone formation.

Current research shows that digital games can significantly enhance children's learning. The purpose of this study was to examine how design features in 12 digital math games influenced children's learning. The participants in this study were 193 children in Grades 2 through 6 (ages 8–12). During clinical interviews, children in the study completed pre-tests, interacted with digital math games, responded to questions about the digital math games, and completed post-tests. We recorded the interactions using two video perspectives that recorded children's gameplay and responses to interviewers. We employed mixed methods to analyze the data and identify salient patterns in children's experiences with the digital math games. The analysis revealed significant gains for 9 of the 12 digital games and most children were aware of the design features in the games. There were eight prominent categories of design features in the video data that supported learning and mathematics connections. Six categories focused on how the design features supported learning in the digital games. These categories included: accuracy feedback, unlimited/multiple attempts, information tutorials and hints, focused constraint, progressive levels, and game efficiency. Two categories were more specific to embodied cognition and action with the mathematics, and focused on how design features promoted mathematics connections. These categories included: linked representations and linked physical actions. The digital games in this study that did not include linked representations and opportunities for linked physical actions as design features did not produce significant gains. These results suggest the key role of mathematics-specific design features in the design of digital math games.

Since publication of the article, the authors became aware that Figure 6(A,D) contained errors in the bands and loading controls. The newly compiled Figure 6A and 6D is given below.

The X-linked WTX/AMER1 protein constitutes an important component of the β-catenin destruction complex that can both enhance and suppress canonical β-catenin signaling. Somatic mutations in WTX/AMER1 have been found in a proportion of the pediatric kidney cancer Wilms' tumor. By contrast, germline mutations cause the severe sclerosing bone dysplasia osteopathia striata congenita with cranial sclerosis (OSCS), a condition usually associated with fetal or perinatal lethality in male patients. Here we address the developmental and molecular function of WTX by generating two novel mouse alleles. We show that in addition to the previously reported skeletal abnormalities, loss of Wtx causes severe midline fusion defects including cleft palate and ectopic synostosis at the base of the skull. By contrast, deletion of the C-terminal part of the protein results in only mild developmental abnormalities permitting survival beyond birth. Adult analysis, however, revealed skeletal defects including changed skull morphology and an increased whole-body bone density, resembling a subgroup of male patients carrying a milder, survivable phenotype. Molecular analysis in vitro showed that while β-catenin fails to co-immunoprecipitate with the truncated protein, partial recruitment appears to be achieved in an indirect manner using AXIN/AXIN2 as a molecular bridge. Taken together our analysis provides a novel model for WTX-caused bone diseases and explains on the molecular level how truncation mutations in this gene may retain some of WTX-protein functions. © 2018 American Society for Bone and Mineral Research.

Multiple sclerosis is the most frequent demyelinating disease in the CNS that is characterized by inflammatory demyelinating lesions and axonal loss, the morphological correlate of permanent clinical disability. Remyelination does occur, but is limited especially in chronic disease stages. Despite effective immunomodulatory therapies that reduce the number of relapses the progressive disease phase cannot be prevented. Therefore, promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy. A number of pathways have been identified that may contribute to impaired remyelination in MS lesions, among them the Wnt/β-catenin pathway. Here, we demonstrate that indometacin, a non-steroidal anti-inflammatory drug (NSAID) that has been also shown to modulate the Wnt/β-catenin pathway in colorectal cancer cells promotes differentiation of primary human and murine oligodendrocytes, myelination of cerebellar slice cultures and remyelination in cuprizone-induced demyelination. Our in vitro experiments using GSK3β inhibitors, luciferase reporter assays and oligodendrocytes expressing a mutant, dominant stable β-catenin indicate that the mechanism of action of indometacin depends on GSK3β activity and β-catenin phosphorylation. Indometacin might represent a promising treatment option to enhance endogenous remyelination in MS patients.

The long bones of vertebrate limbs form by endochondral ossification, whereby mesenchymal cells differentiate into chondrogenic progenitors, which then differentiate into chondrocytes. Chondrocytes undergo further differentiation from proliferating to prehypertrophic, and finally to hypertrophic chondrocytes. Several signaling pathways and transcription factors regulate this process. Previously, we and others have shown in chicken that overexpression of an activated form of Calcium/calmodulin-dependent kinase II (CaMKII) results in ectopic chondrocyte maturation. Here, we show that this is not the case in the mouse. Although, in vitro Mef2c activity was upregulated by about 55-fold in response to expression of an activated form of CaMKII (DACaMKII), transgenic mice that expressed a dominant-active form of CaMKII under the control of the Col2a1 regulatory elements display only a very transient and mild phenotype. Here, only the onset of chondrocyte hypertrophy at E12.5 is accelerated. It is also this early step in chondrocyte differentiation that is temporarily delayed around E13.5 in transgenic mice expressing the peptide inhibitor CaM-KIIN from rat (rKIIN) under the control of the Col2a1 regulatory elements. Yet, ultimately DACaMKII, as well as rKIIN transgenic mice are born with completely normal skeletal elements with regard to their length and growth plate organization. Hence, our in vivo analysis suggests that CaMKII signaling plays a minor role in chondrocyte maturation in mice.

We calculate one loop $y_t$ and $\lambda$ dependent corrections to $\bar{\Gamma}_Z,\bar{R}_f^0$ and the partial $Z$ widths due to dimension six operators in the Standard Model Effective Field Theory (SMEFT), including finite terms. We assume $\rm CP$ symmetry and a $\rm U(3)^5$ symmetry in the UV matching onto the dimension six operators, dominantly broken by the Standard Model Yukawa matrices. Corrections to these observables are predicted using the input parameters $\{\hat{\alpha}_{ew}, \hat{M}_Z, \hat{G}_F, \hat{m}_t, \hat{m}_h\}$ extracted with one loop corrections in the same limit. We show that at one loop the number of SMEFT parameters contributing to the precise LEPI pseudo-observables exceeds the number of measurements. As a result the SMEFT parameters contributing to LEP data are formally unbounded when the size of loop corrections are reached until other data is considered in a global analysis. The size of these loop effects is generically a correction of order $\sim\%$ to leading effects in the SMEFT, but we find multiple large numerical coefficients in our calculation at this order. We use a $\rm \overline{MS}$ scheme, modified for the SMEFT, for renormalization. Some subtleties involving novel evanescent scheme dependence present in this result are explained., Comment: 38 pages + refs, 11 figures, v3: Acknowledgement updated with grant numbers

The epithelial derived Harderian gland consists of 2 types of secretory cells. The more numerous type A cells are responsible for the secretion of lipid droplets, while type B cells produce dark granules of multilamellar bodies. The process of autophagy is constitutively active in the Harderian gland, as confirmed by our analysis of LC3 processing in GFP-LC3 transgenic mice. This process is compromised by epithelial deletion of Atg7. Morphologically, the Atg7 mutant glands are hypotrophic and degenerated, with highly vacuolated cells and pyknotic nuclei. The mutant glands accumulate lipid droplets coated with PLIN2 (perilipin 2) and contain deposits of cholesterol, ubiquitinated proteins, SQSTM1/p62 (sequestosome 1) positive aggregates and other metabolic products such as porphyrin. Immunofluorescence stainings show that distinct cells strongly aggregate both proteins and lipids. Electron microscopy of the Harderian glands reveals that its organized structure is compromised, and the presence of large intracellular lipid droplets and heterologous aggregates. We attribute the occurrence of large vacuoles to a malfunction in the formation of multilamellar bodies found in the less abundant type B Harderian gland cells. This defect causes the formation of large tertiary lysosomes of heterologous content and is accompanied by the generation of tight lamellar stacks of endoplasmic reticulum in a pseudo-crystalline form. To test the hypothesis that lipid and protein accumulation is the cause for the degeneration in autophagy-deficient Harderian glands, epithelial cells were treated with a combination of the proteasome inhibitor and free fatty acids, to induce aggregation of misfolded proteins and lipid accumulation, respectively. The results show that lipid accumulation indeed enhanced the toxicity of misfolded proteins and that this was even more pronounced in autophagy-deficient cells. Thus, we conclude autophagy controls protein and lipid catabolism and anabolism to facilitate bulk production of secretory vesicles of the Harderian gland.

In order to elucidate the role of β-catenin in hypertrophic cartilage zone of the growth plate, we deleted the β-catenin gene ctnnb1 specifically from hypertrophic chondrocytes by mating ctnnb1 fl/fl mice with BAC-Col10a1-Cre -deleter mice. Surprisingly, this resulted in a significant reduction of subchondral trabecular bone formation in BACCol10Cre ; ctnnb1 Δ/Δ (referred to as Cat-ko) mice, although Cre expression was restricted to hypertrophic chondrocytes. The size of the Col10a1 positive hypertrophic zone was normal, but qRT-PCR revealed reduced expression of Mmp13 , and Vegfa in Cat-ko hypertrophic chondrocytes, indicating impaired terminal differentiation. Immunohistological and in situ hybridization analysis revealed the substantial deficiency of collagen I positive mature osteoblasts, but equal levels of osterix-positive cells in the subchondral bone marrow space of Cat-ko mice, indicating that the supply of osteoblast precursor cells was not reduced. The fact that in Cat-ko mice subchondral trabeculae were lacking including their calcified cartilage core indicated a strongly enhanced osteoclast activity. In fact, TRAP staining as well as in situ hybridization analysis of Mmp9 expression revealed denser occupation of the cartilage erosion zone with enlarged osteoclasts as compared to the control growth plate, suggesting increased RANKL or reduced osteoprotegerin (Opg) activity in this zone. This notion was confirmed by qRT-PCR analysis of mRNA extracted from cultured hypertrophic chondrocytes or from whole epiphyses, showing increased Rankl mRNA levels in Cat-ko as compared to control chondrocytes, whereas changes in OPG levels were not significant. These results indicate that β-catenin levels in hypertrophic chondrocytes play a key role in regulating osteoclast activity and trabecular bone formation at the cartilage–bone interface by controlling RANKL expression in hypertrophic chondrocytes.