Affordance realization in climbing: learning and transfer

The aim of this study was to investigate how the affordances of an indoor climbing wall changed for intermediate climbers following a period of practice during which hold orientation was manipulated within a learning and transfer protocol. The learning protocol consisted of four sessions, in which eight climbers randomly ascended three different routes of fixed absolute difficulty (5c on the French scale), as fluently as possible. All three routes were 10.3 m in height and composed of 20 hand-holds at the same locations on an artificial climbing wall; only hold orientations were altered: (i) a horizontal-edge route (H) was designed to afford horizontal hold grasping, (ii) a vertical-edge route (V) afforded vertical hold grasping, and (iii), a double-edge route (D) was designed to afford both horizontal and vertical hold grasping. Five inertial measurement units (IMU) (3D accelerometer, 3D gyroscope, 3D magnetometer) were attached to the hip, feet and forearms to analyze the vertical acceleration and direction (3D unitary vector) of each limb and hip in ambient space during the entire ascent. Segmentation and classification processes supported detection of movement and stationary phases for each IMU. Depending on whether limbs and/or hip were moving, a decision tree distinguished four states of behavior: stationary (absence of limb and hip motion), hold exploration (absence of hip motion but at least one limb in motion), hip movement (hip in motion but absence of limb motion) and global motion (hip in motion and at least one limb in motion). Results showed that with practice, the learners decreased the relative duration of hold exploration, suggesting that they improved affordance perception of hold grasp-ability. The number of performatory movements also decreased as performance increased during learning sessions, confirming that participants' climbing efficacy improved as a function of practice. Last, the results were more marked for the H route, while the D route led to longer relative stationary duration and a shorter relative duration of performatory states. Together, these findings emphasized the benefit of manipulating task constraints to promote safe exploration during learning, which is particularly relevant in extreme sports involving climbing tasks

Constructivist approach to intercultural education

U radu se interkulturalno obrazovanje sagledava iz pozicije konstruktivizma, sa namerom da se pokaže kako se u konstruktivističkom pristupu interkulturalnom obrazovanju shvataju dispozicije nastavnika za bavljenje kulturnom heterogenošću. Odgovor na pitanje kako nastavnici sagledavaju i razumeju interkulturalno obrazovanje predstavlja polaznu osnovu u obezbeđivanju uslova za razvoj interkulturalnih kompetencija nastavnika, pre svega njihove interkulturalne osetljivosti. Zbog toga se u drugom delu rada naglašava značaj istraživanja uverenja nastavnika o interkulturalnom obrazovanju i njihovoj interkulturalnoj osetljivosti za potrebe efikasnijeg koncipiranja programa interkulturalnog obrazovanja. Otkrivanja uverenja nastavnika o interkulturalnom obrazovanju relevantno je za razne kontekste, što se u radu ilustrije primerom Švajcarske i Srbije. U završnom delu rada obrazložen je i značaj istraživanja nastavničkih uverenja o interkulturalnom obrazovanju kako za teoriju obrazovanja, tako i za obrazovnu praksu.In this paper intercultural education is examined from the position of constructivism with the intention to show how the constructivist approach to intercultural education takes into account the teacher's dispositions for dealing with cultural heterogeneity. The answer to the question how teachers perceive and understand intercultural education is the starting point in providing conditions for the development of intercultural competences of teachers, primarily their intercultural sensitivity. Therefore, the second part of the paper emphasizes the importance of researching teachers' beliefs about intercultural education and their intercultural sensitivity in order to conceive efficiently intercultural education programs. Revealing teachers' beliefs about intercultural education is relevant for various contexts, which is in this paper illustrated by examples from Switzerland and Serbia. Final part of the paper outlines the importance of researching teachers' beliefs about intercultural education both for the educational theory and practice

Runx proteins regulate Foxp3 expression

Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor β to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes

Étudier l’occupation d’une ville : les enjeux du PCR « Topographie générale et insertion territoriale de l’agglomération antique de Briga »

Les fouilles conduites depuis 2006 sur le site du « Bois-l’Abbé », situé sur la commune d’Eu (Seine-Maritime), ont permis de mettre en évidence que ce dernier ne consistait non pas en un sanctuaire isolé, comme l’évoquaient les précédents chercheurs, mais comme une agglomération nommée Briga, dont la superficie atteignait au moins 65 hectares à son apogée au début du iiie siècle. À la suite de ces découvertes, le Programme Collectif de Recherche « Topographie générale et insertion territoriale de l’agglomération antique de Briga », coordonné par Étienne Mantel (DRAC – SRA de Normandie), a été initié en 2018. Interdisciplinaire par nature, ce programme a pour objectif de fédérer des intervenants venant de différentes institutions (DRAC, Universités, INRAP et bénévoles) afin d’accroître les connaissances sur l’urbanisme, les origines, le développement et le déclin de cette agglomération encore inconnue jusqu’en 2006

Kisspeptin Restores Pulsatile LH Secretion in Patients with Neurokinin B Signaling Deficiencies:Physiological, Pathophysiological and Therapeutic Implications

Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.Publisher PDFPeer reviewe

Association between Thymic Function and Allogeneic Hematopoietic Stem Cell Transplantation Outcome: Results of a Pediatric Study

Abstract Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities

Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-β–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-β signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b–deficient T cells, and Foxo3a deficiency results in defective TGF-β–driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation

Familial Glucocorticoid Receptor Haploinsufficiency by Non-Sense Mediated mRNA Decay, Adrenal Hyperplasia and Apparent Mineralocorticoid Excess

Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension

From stability to dynamics: understanding molecular mechanisms of regulatory T cells through Foxp3 transcriptional dynamics

Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor forkhead box protein 3 (Foxp3). This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesize a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3. In particular, we introduce a recent advancement in the study of Foxp3‐mediated T cell regulation through the development of the Timer of cell kinetics and activity (Tocky) system, and show that the investigation of Foxp3 transcriptional dynamics can reveal temporal changes in the differentiation and function of Treg in vivo. We highlight the role of Foxp3 as a gene downstream of T cell receptor (TCR) signalling and show that temporally persistent TCR signals initiate Foxp3 transcription in self‐reactive thymocytes. In addition, we feature the autoregulatory transcriptional circuit for the Foxp3 gene as a mechanism for consolidating Treg differentiation and activating their suppressive functions. Furthermore, we explore the potential mechanisms behind the dynamic regulation of epigenetic modifications and chromatin architecture for Foxp3 transcription. Lastly, we discuss the clinical relevance of temporal changes in the differentiation and activation of Treg