A simple approach to the supernova progenitor–explosion connection

We present a new approach to understand the landscape of supernova explosion energies, ejected nickel masses, and neutron star birth masses. In contrast to other recent parametric approaches, our model predicts the properties of neutrino-driven explosions based on the pre-collapse stellar structure without the need for hydrodynamic simulations. The model is based on physically motivated scaling laws and simple differential equations describing the shock propagation, the contraction of the neutron star, the neutrino emission, the heating conditions, and the explosion energetics. Using model parameters compatible with multi-D simulations and a fine grid of thousands of supernova progenitors, we obtain a variegated landscape of neutron star and black hole formation similar to other parametrized approaches and find good agreement with semi-empirical measures for the ‘explodability’ of massive stars. Our predicted explosion properties largely conform to observed correlations between the nickel mass and explosion energy. Accounting for the coexistence of outflows and downflows during the explosion phase, we naturally obtain a positive correlation between explosion energy and ejecta mass. These correlations are relatively robust against parameter variations, but our results suggest that there is considerable leeway in parametric models to widen or narrow the mass ranges for black hole and neutron star formation and to scale explosion energies up or down. Our model is currently limited to an all-or-nothing treatment of fallback and there remain some minor discrepancies between model predictions and observational constraints.

Progenitor-Dependent Explosion Dynamics in Self-Consistent, Axisymmetric Simulations of Neutrino-Driven Core-Collapse Supernovae

We present self-consistent, axisymmetric core-collapse supernova simulations performed with the Prometheus-Vertex code for 18 pre-supernova models in the range of 11–28 M ⊙, including progenitors recently investigated by other groups. All models develop explosions, but depending on the progenitor structure, they can be divided into two classes. With a steep density decline at the Si/Si–O interface, the arrival of this interface at the shock front leads to a sudden drop of the mass-accretion rate, triggering a rapid approach to explosion. With a more gradually decreasing accretion rate, it takes longer for the neutrino heating to overcome the accretion ram pressure and explosions set in later. Early explosions are facilitated by high mass-accretion rates after bounce and correspondingly high neutrino luminosities combined with a pronounced drop of the accretion rate and ram pressure at the Si/Si–O interface. Because of rapidly shrinking neutron star radii and receding shock fronts after the passage through their maxima, our models exhibit short advection timescales, which favor the efficient growth of the standing accretion-shock instability. The latter plays a supportive role at least for the initiation of the re-expansion of the stalled shock before runaway. Taking into account the effects of turbulent pressure in the gain layer, we derive a generalized condition for the critical neutrino luminosity that captures the explosion behavior of all models very well. We validate the robustness of our findings by testing the influence of stochasticity, numerical resolution, and approximations in some aspects of the microphysics.

The dynamics of neutrino-driven supernova explosions after shock revival in 2D and 3D

We study the growth of the explosion energy after shock revival in neutrino-driven explosions in two and three dimensions (2D/3D) using multi-group neutrino hydrodynamics simulations of an 11.2 M⊙ star. The 3D model shows a faster and steadier growth of the explosion energy and already shows signs of subsiding accretion after one second. By contrast, the growth of the explosion energy in 2D is unsteady, and accretion lasts for several seconds as confirmed by additional long-time simulations of stars of similar masses. Appreciable explosion energies can still be reached, albeit at the expense of rather high neutron star masses. In 2D, the binding energy at the gain radius is larger because the strong excitation of downward-propagating g modes removes energy from the freshly accreted material in the downflows. Consequently, the mass outflow rate is considerably lower in 2D than in 3D. This is only partially compensated by additional heating by outward-propagating acoustic waves in 2D. Moreover, the mass outflow rate in 2D is reduced because much of the neutrino energy deposition occurs in downflows or bubbles confined by secondary shocks without driving outflows. Episodic constriction of outflows and vertical mixing of colder shocked material and hot, neutrino-heated ejecta due to Rayleigh–Taylor instability further hamper the growth of the explosion energy in 2D. Further simulations will be necessary to determine whether these effects are generic over a wider range of supernova progenitors.

The Status of Multi-Dimensional Core-Collapse Supernova Models

Models of neutrino-driven core-collapse supernova explosions have matured considerably in recent years. Explosions of low-mass progenitors can routinely be simulated in 1D, 2D, and 3D. Nucleosynthesis calculations indicate that these supernovae could be contributors of some lighter neutron-rich elements beyond iron. The explosion mechanism of more massive stars remains under investigation, although first 3D models of neutrino-driven explosions employing multi-group neutrino transport have become available. Together with earlier 2D models and more simplified 3D simulations, these have elucidated the interplay between neutrino heating and hydrodynamic instabilities in the post-shock region that is essential for shock revival. However, some physical ingredients may still need to be added/improved before simulations can robustly explain supernova explosions over a wide range of progenitors. Solutions recently suggested in the literature include uncertainties in the neutrino rates, rotation, and seed perturbations from convective shell burning. We review the implications of 3D simulations of shell burning in supernova progenitors for the ‘perturbations-aided neutrino-driven mechanism,’ whose efficacy is illustrated by the first successful multi-group neutrino hydrodynamics simulation of an 18 solar mass progenitor with 3D initial conditions. We conclude with speculations about the impact of 3D effects on the structure of massive stars through convective boundary mixing.

Analyzing Gene Centres with the Help of the Checklist Method – the Case of Syria

The present survey of species diversity of cultivated plants is the first for Syria. Some cultivated species will be added in the future, because due to the civil war in Syria, it was not possible to visit the country in the frame of the present work, as initially planned. Checklists proved to be a useful tool for overviewing the cultivated plants of selected areas and allow a characterization of the state of plant genetic resources of Syria. Syria has experienced several civilizations. Man settled in this productive land since ancient times and used its resources. However, such use has led to changes in vegetation and decline of wildlife through the country, in seashore areas, interior, mountains, and grassland. Plant domestication and growing started more than 10,000 years ago in West Asia. Since then, plentiful of economic plant species were present and used by man and his domesticated animals. Forming a part of the Fertile Crescent, where many of the world’s agricultural plants have evolved, Syria is extremely rich in agrobiodiversity. Wild progenitors of wheat and barley and wild relatives of many fruit trees such as almonds and pistachio as well as forage species are still found in marginal lands and less disturbed areas. These are threatened by a wide range of human activities, notably modern, extensive agriculture, overgrazing, overcutting and urban expansion. Syria is also considered as part of one of the main centres of origin, according to Vavilov, who had collected in Syria in 1926. The first expeditions to crop fields showed the exclusive nature of cultivated plants in Syria with a high number of endemic forms. Furthermore, Syria is a part of a biodiversity hotspot. Several studies have been performed to study agrobiodiversity in different parts of Syria, but usually on wild species. Many collections have been carried out; however, they focussed preferably on cereals and pulses, and particularly on wheat, like Vavilov’s expedition. Only 30 crops make up the major part of the conserved Syrian crop plant material in the genebank, indicating that most of the remaining 7,000 species of cultivated plants and many other valuable genetic resources species have only been included on a limited scale in the genebank collections. Although a small country (185,180 km2), Syria accommodates numerous ecosystems that allow for a large diversity of plant genetic resources for agriculture ranging from cold-requiring to subtropical crops to live and thrive. Only few references are available in this respect. The aim of the present study was to complete a checklist of Syria’s cultivated plants of agriculture and horticulture excluding plants only grown as ornamental or for forestry. Furthermore, plants taken for reforestation have not been included, if they do not have also agricultural or horticultural uses. Therefore, the inclusion of plants into the checklist follows the same principles as “Mansfeld’s Encyclopedia”. Main sources of information were published literature, floras of Syria, Lebanon and the Mediterranean, as well as Syrian printed sources in Arabic and/or English, reports from FAO on agricultural statistics in Syria, and data from ICARDA and Bioversity International. In addition, personal observations gathered during professional work in the General Commission for Scientific Agricultural Research (GCSAR) in Syria (since 1989) and participation in projects were taken into account. These were: (1) A project on “Conservation and Sustainable Use of Dry Land Agrobiodiversity in the Near East” with participation of Jordan, Lebanon, Syria, and the Palestinian Authority, focussing on landraces and wild relatives of barley, wheat, lentil, alliums, feed legumes, and fruit trees (1999–2005). (2) A project for vegetable landraces (1993–1995) in collaboration with the former International Plant Genetic Resources Institute and the UN Development Programme, in which 380 local vegetable accessions were evaluated. For medicinal plants and fruit trees I was in personal contact with departments of GCSAR and the Ministry of Agriculture and Agrarian Reform, as well as with private organizations. The resulting checklist was compared with the catalogues of crop plants of Italy and a checklist of cultivated plants of Iraq. The cultivated plant species are presented in alphabetical order according to their accepted scientific names. Each entry consists of a nomenclatural part, folk names, details of plant uses, the distribution in Syria (by provinces), a textual description, and references to literature. In total, 262 species belonging to 146 genera and 57 families were identified. Within-species (intraspecific) diversity is a significant measure of the biodiversity. Intraspecific diversity for wild plants has been and remains to be well studied, but for crop plants there are only few results. Mansfeld’s method is an actual logical contribution to such studies. Among the families, the following have the highest number of crop species: Leguminosae (34 spp.), Rosaceae (24), Gramineae (18), Labiatae (18), Compositae (14), Cruciferae (14), Cucurbitaceae (11), Rutaceae (10), Malvaceae (9), Alliaceae (7), and Anacardiaceae (7). The establishment of an effective programme for the maintenance of plant genetic resources in Syria started in the mid-1970s. This programme considered ex situ and in situ collection of the genetic resources of various field crops, fruit trees and vegetables. From a plant genetic resources viewpoint, it is clear that the homegarden is an important location for the cultivation of so-called neglected and underutilized species (neglected from a research side and underutilized from a larger economic side). Such species have so far not received much care from ecologists, botanists and agronomists, and they are considerably under-represented in genebanks.

Objetivos de Vida e Satisfação na Vida Conjugal em Pais/Progenitores de Crianças com Autismo

Introdução: A presença do diagnóstico de autismo numa criança é algo marcante no seio familiar. Implica inúmeros desafios para os seus pais/progenitores, podendo influenciar os objetivos delineados para as suas vidas e a satisfação na relação conjugal. Os nossos objetivos foram: caraterizar progenitores de crianças com autismo quanto aos objetivos de vida e satisfação na vida conjugal e explorar as associações existentes entre estas duas variáveis (e com variáveis sociodemográficas e relativas ao apoio recebido). Não deixamos de explorar os níveis de depressão, ansiedade, e stress, vivenciados por estes pais. Metodologia: 66 progenitores (sexo feminino, n = 52, 78,8%; idade média, M = 40,2, DP = 6,45) de crianças com autismo preencheram um questionário sociodemográfico, o Teste dos objetivos de vida/PIL-R, a Escala de Avaliação da Satisfação em Áreas da Vida Conjugal/EASAVIC e a Depression, Anxiety and Stress Scale-21/DASS-21. Resultados: Os progenitores revelaram valores médios de objetivos de vida (PIL-R). Foi na dimensão vivencial (PIL-R) e nas dimensões Comunicação e Intimidade Emocional (satisfação em áreas da vida conjugal/EASAVIC) que os progenitores apresentaram valores médios mais elevados. No caso da DASS-21, foi na escala Stress que os progenitores apresentaram valores mais elevados. Porém, em todas as dimensões da DASS-21, os níveis encontrados foram normais. Não se verificaram diferenças estatisticamente significativas por sexo em todas as dimensões do PIL-R, da EASAVIC e DASS-21. Ambas as dimensões do PIL-R, dimensional e existencial, bem como a sua pontuação total mostraram estar associadas com todas as dimensões da EASAVIC (satisfação em áreas da vida conjugal). As três dimensões da DASS-21 (Depressão, Ansiedade e Stress) revelaram estar associada (negativamente) com praticamente todas as dimensões da EASAVIC e do PIL-R. Os progenitores que pertenciam a associações de apoio apenas se diferenciaram dos progenitores que pertenciam a um grupo (de apoio e partilha) numa rede social na dimensão Ansiedade, com estes últimos a apresentarem um nível mais elevado. Discussão: Neste estudo (ainda que numa amostra de tamanho reduzido), inovador pelo tema explorado, os níveis dos objetivos de vida e de satisfação em áreas da vida conjugal (bem como de sintomas de psicopatologia) pareceram “não sofrer” o impacto associado ao facto dos progenitores terem um filho com autismo. Os objetivos de vida mantidos por estes pais influenciam a sua satisfação com a vida conjugal e vice-versa, indicando a importância das equipas que trabalham com estes pais não esquecerem a promoção destas variáveis. / Introduction: The presence of the diagnosis of autism in a child is something remarkable in the family. Involves many challenges for parents/progenitors, which can influence the goals they define in their lives and their satisfaction with the marital relationship. Our objectives were to characterize parents of children with autism on the objectives of life and satisfaction with marital life and explore the associations between these two variables (and with sociodemographic and support variables). We will not forget to explore the levels of depression, anxiety, and stress, experienced by these parents. Methodology: 66 parents (females, n = 52, 78.8%, mean age, M = 40.2, SD = 6.45) of children with autism completed a sociodemographic questionnaire, the Test of Life Goals/PIL-R, the Areas of Marital Satisfaction Rating Scale/EASAVIC and the Depression, Anxiety and Stress Scale-21/DASS-21. Results: Parents showed a mean value of life goals (PIL-R). Was in the experiential dimension (PIL-R) and the Communication and Emotional Intimacy dimensions (satisfaction in areas of marital life/EASAVIC) that the parents presented higher mean values. Regarding DASS-21, Stress was the scale in which the parents had higher values. However, in all the DASS-21, levels were “normal”. There were no statistically significant differences by gender in all the PIL-R, EASAVIC and DASS-21 scales. Both dimensions of the PIL-R, dimensional and existential, as well as the total score were found to be associated with all the dimensions of EASAVIC (satisfaction in areas of marital life). The three dimensions of the DASS-21 (Depression, Anxiety and Stress) revealed to be associated (negatively) with virtually all dimensions of the EASAVIC and the PIL-R. Parents who belonged to associations only differed from the parents from a social network group (of support and sharing) in the anxiety dimension, with the later presenting an higher level. Discussion: In this study (even if in a small sample size), innovative by the theme explored, levels of life goals and satisfaction in areas of marital life (as well as symptoms of psychopathology) seemed not to suffer from the impact of the parents having a child with autism. The life goals held by these parents influence their satisfaction with marital life and vice versa, indicating the importance of teams working with these parents of not forgetting the promotion of these variables.

Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling

Clinical studies of large human populations and pharmacological interventions in rodent models have recently suggested that anti-hypertensive drugs that target angiotensin II (Ang II) activity may also improve loss of bone mineral density. Here we identified in a genetic screen the Ang II type I receptor (AT1R) as a potential determinant of osteogenic differentiation and, implicitly, bone formation. Silencing of AT1R expression by RNA interference severely impaired the maturation of a multipotent mesenchymal cell line (W20-17) along the osteoblastic lineage. The same effect was also observed after the addition of the AT1R antagonist losartan but not the AT2R inhibitor PD123,319. Additional cell culture assays traced the time of greatest losartan action to the early stages of W20-17 differentiation, namely during cell proliferation. Indeed, addition of Ang II increased proliferation of differentiating W20-17 and primary mesenchymal stem cells and this stimulation was reversed by losartan treatment. Cells treated with losartan also displayed an appreciable decrease of activated (phosphorylated)-Smad2/3 proteins. Moreover, Ang II treatment elevated endogenous transforming growth factor β (TGFβ) expression considerably and in an AT1R-dependent manner. Finally, exogenous TGFβ was able to restore high proliferative activity to W20-17 cells that were treated with both Ang II and losartan. Collectively, these results suggest a novel mechanism of Ang II action in bone metabolism that is mediated by TGFβ and targets proliferation of osteoblast progenitors.

Regenerative Cues of Myeloid Cells on Pancreatic Epithelium

Thesis (Ph.D.)--University of Washington, 2016-07

The Influence of Age, Cardiorespiratory Fitness, Exercise and Sedentary Behaviours on Circulating Angiogenic Cells and Cell Surface Receptor Expression.

Cardiovascular disease (CVD) is the biggest killer of people in western civilisation. Age is a significant risk factor for the development for CVD, and treatments and therapies to address this increased risk are crucial to quality of life and longevity. Exercise is one such intervention which has been shown to reduce CVD risk. Age is also associated with endothelial dysfunction, reduced angiogenic capabilities, and reduced ability to repair the vessel wall. Circulating angiogenic cells (CACs) are a subset of circulating cells which assist in the repair and growth of the vasculature and in the maintenance of endothelial function. Reductions in these cells are observed in those with vascular disease compared to age-matched healthy controls. Exercise may reduce CVD risk by improvements in number and/or function of these CACs. Data was collected from human volunteers of various ages, cardiorespiratory fitness (CRF) levels and latent viral infection history status to investigate the effects of chronological age, CRF, viral serology and other lifestyle factors, such as sedentary behaviours and exercise on CACs. The levels of CACs in these volunteers were measured using four colour flow cytometry using various monoclonal antibodies specific to cell surface markers that are used to identify specific subsets of these CACs. In addition, the response to acute exercise of a specific subset of these CACs, termed ‘angiogenic T-cells’ (TANG) were investigated, in a group of well-trained males aged 20-40 years, using a strenuous submaximal exercise bout. Advancing age was associated with a decline in various subsets of CACs, including bone marrow-derived CD34+ progenitors, putative endothelial progenitor cells (EPCs) and also TANG cells. Individuals with a higher CRF were more likely to have higher circulating numbers of TANG cells, particularly in the CD4+ subset. CRF did not appear to modulate CD34+ progenitors or EPC subsets. Increasing sitting time was associated with reduction in TANG cells, but after correcting for the effects of fitness, sitting time no longer negatively affected the circulating number of these cells. Acute exercise was a powerful stimulus for increasing the number of TANG cells (140% increase), potentially through an SDF-1:CXCR4-dependent mechanism, but more studies are required to investigate this. Latent CMV infection was associated with higher number of TANG cells (CD8+), but only in 18-40 year old individuals, and not in an older age group (41-65 year old). The significance of this has yet to be understood. In conclusion, advancing age may contribute to increased CVD risk partly due to the observed reductions in angiogenic cells circulating in the peripheral compartment. Maintaining a high CRF may attenuate this CVD reduction by modulating TANG cell number, but potentially not CD34+ progenitor or EPC subsets. Acute exercise may offer a short window for vascular adaptation through the mobilisation of TANG cells into the circulation.

TRIB2 in normal and malignant hematopoiesis - a transcription factor network

Hematopoiesis is the tightly controlled and complex process in which the entire blood system is formed and maintained by a rare pool of hematopoietic stem cells (HSCs), and its dysregulation results in the formation of leukaemia. TRIB2, a member of the Tribbles family of serine/threonine pseudokinases, has been implicated in a variety of cancers and is a potent murine oncogene that induces acute myeloid leukaemia (AML) in vivo via modulation of the essential myeloid transcription factor CCAAT-enhancer binding protein α (C/EBPα). C/EBPα, which is crucial for myeloid cell differentiation, is commonly dysregulated in a variety of cancers, including AML. Two isoforms of C/EBPα exist - the full-length p42 isoform, and the truncated oncogenic p30 isoform. TRIB2 has been shown to selectively degrade the p42 isoform of C/EBPα and induce p30 expression in AML. In this study, overexpression of the p30 isoform in a bone marrow transplant (BMT) leads to perturbation of myelopoiesis, and in the presence of physiological levels of p42, this oncogene exhibited weak transformative ability. It was also shown by BMT that despite their degradative relationship, expression of C/EBPα was essential for TRIB2 mediated leukaemia. A conditional mouse model was used to demonstrate that oncogenic p30 cooperates with TRIB2 to reduce disease latency, only in the presence of p42. At the molecular level, a ubiquitination assay was used to show that TRIB2 degrades p42 by K48-mediated proteasomal ubiquitination and was unable to ubiquitinate p30. Mutation of a critical lysine residue in the C-terminus of C/EBPα abrogated TRIB2 mediated C/EBPα ubiquitination suggesting that this site, which is frequently mutated in AML, is the site at which TRIB2 mediates its degradative effects. The TRIB2-C/EBPα axis was effectively targeted by proteasome inhibition. AML is a very difficult disease to target therapeutically due to the extensive array of chromosomal translocations and genetic aberrations that contribute to the disease. The cell from which a specific leukaemia arises, or leukaemia initiating cell (LIC), can affect the phenotype and chemotherapeutic response of the resultant disease. The LIC has been elucidated for some common oncogenes but it is unknown for TRIB2. The data presented in this thesis investigate the ability of the oncogene TRIB2 to transform hematopoietic stem and progenitor cells in vitro and in vivo. TRIB2 overexpression conferred in vitro serially replating ability to all stem and progenitor cells studied. Upon transplantation, only TRIB2 overexpressing HSCs and granulocyte/macrophage progenitors (GMPs) resulted in the generation of leukaemia in vivo. TRIB2 induced a mature myeloid leukaemia from the GMP, and a mixed lineage leukaemia from the HSC. As such the role of TRIB2 in steady state hematopoiesis was also explored using a Trib2-/- mouse and it was determined that loss of Trib2 had no effect on lineage distribution in the hematopoietic compartment under steady-state conditions. The process of hematopoiesis is controlled by a host of lineage restricted transcription factors. Recently members of the Nuclear Factor 1 family of transcription factors (NFIA, NFIB, NFIC and NFIX) have been implicated in hematopoiesis. Little is known about the role of NFIX in lineage determination. Here we describe a novel role for NFIX in lineage fate determination. In human and murine datasets the expression of Nfix was shown to decrease as cells differentiated along the lymphoid pathway. NFIX overexpression resulted in enhanced myelopoiesis in vivo and in vitro and a block in B cell development at the pre-pro-B cell stage. Loss of NFIX resulted in disruption of myeloid and lymphoid differentiation in vivo. These effects on stem and progenitor cell fate correlated with changes in the expression levels of key transcription factors involved in hematopoietic differentiation including a 15-fold increase in Cebpa expression in Nfix overexpressing cells. The data presented support a role for NFIX as an important transcription factor influencing hematopoietic lineage specification. The identification of NFIX as a novel transcription factor influencing lineage determination will lead to further study of its role in hematopoiesis, and contribute to a better understanding of the process of differentiation. Elucidating the relationship between TRIB2 and C/EBPα not only impacts on our understanding of the pathophysiology of AML but is also relevant in other cancer types including lung and liver cancer. Thus in summary, the data presented in this thesis provide important insights into key areas which will facilitate the development of future therapeutic approaches in cancer treatment.

Adipose-derived stem cell adhesion on laminin-coated microcarriers improves commitment toward the cardiomyogenic lineage

International audience

Neurofilaments and NFL-TBS.40-63 peptide penetrate oligodendrocytes through clathrin-dependent endocytosis to promote their growth and survival in vitro.

International audience

Myeloid precursors, osteoclastogenesis, and Spondyloarthropathies

Spondyloarthropathies (or Spondyloarthritides; SpAs) are a group of heterogeneous but genetically related inflammatory disorders in which ankylosing spondylitis (AS) is considered the prototypic form. Among the genes associated with AS, HLA-B27 allele has the strongest association although the cause is still not clear. Rats transgenic for the human HLA-B27 gene (B27 rats) develop a systemic inflammation mirroring the human SpA symptoms and thus provide a useful model to study the contribution of this MHC class I molecule in the disease development. Of particular interest was the observation of absence of arthritis in B27 rats grown in germ-free conditions and a recent theory suggests that microbial dysbiosis and gut inflammation might play a key role in initiating the HLA-B27-associated diseases. Studies in our laboratory have previously demonstrated that HLA-B27 expression alters the development of the myeloid compartment within the bone marrow (BM) in B27 rat and causes loss of a specific dendritic cell (DC) population involved in self-tolerance mechanisms within the gut. The aim of this thesis was to further analyse the myeloid compartment in B27 rats with a particular focus on the osteoclast progenitors and the bone phenotype and to link this to the gut inflammation. In addition, translational studies analysed peripheral monocyte/pre-osteoclasts in AS patients and teased apart the role of cytokines in in vitro human osteoclast differentiation. To understand the dynamics of the myeloid/monocyte compartment within the B27-associated inflammation, monocytes within the bloodstream and BM of B27 rats were characterised via flow cytometry and their ability to differentiate into osteoclast was assessed in vitro. Moreover, an antibiotic regime was used to reduce the B27 ileitis and to evaluate whether this could affect the migration, the phenotype, and the osteoclastogenic potential of B27 monocytes. B27 animals display a systemic and central increase of “inflammatory” CD43low MOs, which are the main contributors to osteoclastogenesis in vitro. Antibiotic treatment reduced ileitis and also reverted the B27 monocyte phenotype. This was also associated with the reduction of the previous described TNFα-enhancement of osteoclast differentiation from B27 BM precursors. These evidences support the idea that in genetically susceptible individuals inflammation in the gut might influence the myeloid compartment within the BM; in other terms, pre-emptively educate precursor cells to acquire specific phenotype end functions after being recruited into the tissue. This might explain the enhanced differentiation of osteoclast from B27 BM progenitors and thus the HLA-B27-associated bone loss. The data shown in this thesis suggest a link between the immunity within the gut and BM haematopoiesis. This provides an attractive and novel research prospective that could help not only to increase the understanding of the HLA-B27-associated aetiopathogenesis but also to unravel the cellular crosstalk that allows the mucosal immunity to program central cell differentiation. Human translational studies on monocyte subsets, cytokines and cytokine network in AS osteoclastogenesis evidenced altered osteoclast differentiation in the presence of IL-22 although no differences in the phenotype and functions of circulating CD14+ monocytes were observed. In addition, studies on the role of TNFα and TNFRs showed a dual role of this inflammatory cytokine in the human OC differentiation. In particular, the activation of TNFR1 in monocytes in early osteoclastogenesis inhibits OC differentiation while TNFα-biasing for TNFR2 on osteoclast precursors mediates the osteoclastogenic effect. Whether similar mechanisms are involved in the TNFα-mediated joint destruction in human rheumatic diseases needs further investigations. This could contribute to the development of novel and more specific anti-TNFα agents for the treatment of bone erosion. In conclusion, taken together my studies support the idea of a crosstalk between the periphery and the central system during the inflammatory response and provide new insights to the mechanisms behind the enhancement of osteoclastogenesis in B27-associated disorders.

PPARα regulates endothelial progenitor cell maturation and myeloid lineage differentiation through a NADPH oxidase-dependent mechanism in mice

International audience

Epigenetic regulation in neural crest development : role of DNA methyltransferases 3A and 3B

The neural crest is a group of migratory, multipotent stem cells that play a crucial role in many aspects of embryonic development. This uniquely vertebrate cell population forms within the dorsal neural tube but then emigrates out and migrates long distances to different regions of the body. These cells contribute to formation of many structures such as the peripheral nervous system, craniofacial skeleton, and pigmentation of the skin. Why some neural tube cells undergo a change from neural to neural crest cell fate is unknown as is the timing of both onset and cessation of their emigration from the neural tube. In recent years, growing evidence supports an important role for epigenetic regulation as a new mechanism for controlling aspects of neural crest development. In this thesis, I dissect the roles of the de novo DNA methyltransferases (DNMTs) 3A and 3B in neural crest specification, migration and differentiation. First, I show that DNMT3A limits the spatial boundary between neural crest versus neural tube progenitors within the neuroepithelium. DNMT3A promotes neural crest specification by directly mediating repression of neural genes, like Sox2 and Sox3. Its knockdown causes ectopic Sox2 and Sox3 expression at the expense of neural crest territory. Thus, DNMT3A functions as a molecular switch, repressing neural to favor neural crest cell fate. Second, I find that DNMT3B restricts the temporal window during which the neural crest cells emigrate from the dorsal neural tube. Knockdown of DNMT3B causes an excess of neural crest emigration, by extending the time that the neural tube is competent to generate emigrating neural crest cells. In older embryos, this resulted in premature neuronal differentiation. Thus, DNMT3B regulates the duration of neural crest production by the neural tube and the timing of their differentiation. My results in avian embryos suggest that de novo DNA methylation, exerted by both DNMT3A and DNMT3B, plays a dual role in neural crest development, with each individual paralogue apparently functioning during a distinct temporal window. The results suggest that de novo DNA methylation is a critical epigenetic mark used for cell fate restriction of progenitor cells during neural crest cell fate specification. Our discovery provides important insights into the mechanisms that determine whether a cell becomes part of the central nervous system or peripheral cell lineages.