Polydactylous limbs in Strong's Luxoid mice result from ectopic polarizing activity

Strong's Luxoid (1st^D) is a semidominant mouse mutation in which heterozygotes show preaxial hindlimb polydactyly, and homozygotes show fore- and hindlimb polydactyly. The digit patterns of these polydactylous limbs resemble those caused by polarizing grafts, since additional digits with posterior character are present at the anterior side of the limb. Such observations suggest that 1st^D limb buds might contain a genetically determined ectopic region of polarizing activity. Accordingly, we show that mutant embryos ectopically express the pattern-determining genes fibroblast growth factor 4 (fgf-4), sonic hedgehog (shh), and Hoxd-12 in the anterior region of the limb. Further, we show that anterior mesoderm from mutant limbs exhibits polarizing activity when grafted into host chicken limbs. In contrast to an experimentally derived polydactylous transgenic mouse, forelimbs of homozygotes show a normal pattern of Hoxb-8 expression, indicating that the duplication of polarizing tissue here occurs downstream or independently of Hoxb-8. We suggest that the 1st gene product is involved in anteroposterior axis formation during normal limb development

Deep homology in the age of next-generation sequencing

The principle of homology is central to conceptualizing the comparative aspects of morphological evolution. The distinctions between homologous or non-homologous structures have become blurred, however, as modern evolutionary developmental biology (evo-devo) has shown that novel features often result from modification of pre-existing developmental modules, rather than arising completely de novo. With this realization in mind, the term 'deep homology' was coined, in recognition of the remarkably conserved gene expression during the development of certain animal structures that would not be considered homologous by previous strict definitions. At its core, it can help to formulate an understanding of deeper layers of ontogenetic conservation for anatomical features that lack any clear phylogenetic continuity. Here, we review deep homology and related concepts in the context of a gene expression-based homology discussion. We then focus on how these conceptual frameworks have profited from the recent rise of high-throughput next-generation sequencing. These techniques have greatly expanded the range of organisms amenable to such studies. Moreover, they helped to elevate the traditional gene-by-gene comparison to a transcriptome-wide level. We will end with an outlook on the next challenges in the field and how technological advances might provide exciting new strategies to tackle these questions.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'

Requérant-e-s d'asile mineur-e-s non accompagné-e-s en Suisse: dispositif institutionnel de prise en charge, réactions au vécu de l'exil et comportement identitaire

L'intérêt pour la problématique des "requérant·e·s d'asile mineur·e·s non accompagné·e·s" (MNA) commence à émerger en Suisse au début des années 90. Malgré une première directive (sommaire) de l'Office des réfugiés en 1989, les organismes d'entraide soulignaient à cette époque les carences de leur prise en charge institutionnelle et juridique, contribuant par la même occasion à donner une certaine visibilité à cette catégorie d'exilé·e·s et à la constituer en "problème social" spécifique. La dénonciation d’octobre 1991 au Conseil fédéral, suite à la décision de renvoi de deux mineurs hébergés dans le canton de Vaud, révélait les principales lacunes du traitement des MNA, qui ont constitué – avec d'autres par la suite – les points d'achoppement majeurs entre les institutions de défense du droit d’asile et les autorités compétentes. De manière générale, les discussions se sont concentrées autour de l'opposition entre la protection des mineur·e·s et le droit d'asile (les autorités doivent notamment tenir compte de la Convention des droits de l'enfant de 1989, signée par la Suisse en 1991 et entrée en vigueur en 1997). Le nombre de demandes déposées en Suisse par des MNA oscille, depuis 1996, entre quelques centaines et environ 2000 par année. A Genève, l'arrivée de MNA est un problème auquel les institutions d'accueil ont été confrontées dès la fin des années 80 : un foyer spécifiquement destiné à cette population fut même ouvert durant plus de deux ans entre 1986 et 1988 ; en 1995 une Coordination des mandats tutélaires a été ouverte, qui dépend aujourd'hui de l'Office cantonal du tuteur général. Dans le canton de Vaud aussi, un foyer (Karibu) a été ouvert à leur intention entre 1991 et 1994, et un poste de tuteur des MNA a été ouvert à l'Office cantonal du tuteur général en 1993. Les informations dont nous disposons au sujet des MNA proviennent de sources éparses, notamment de documents internes diffusés dans les institutions de travail social ; elles se concentrent principalement sur l'aspect juridique de la problématique, leur but essentiel étant de donner aux assistant·e·s sociaux/sociales et aux juristes les moyens techniques de défendre les droits de ces jeunes exilé·e·s. Mais qu'en est-il des besoins de ces adolescent·e·s et enfants ? Comment ressentent-ils/elles leur situation ? Avec quelles attentes sont-ils/elles arrivé·e·s en Europe, et comment ces attentes évoluent-elles durant leur séjour ? Quelles valeurs attribuent-ils/elles à l'école, à la formation professionnelle, au travail ? Comment pensent-ils/elles les relations avec les autorités en général, et avec les autorités de tutelle en particulier ? Une connaissance de la trajectoire des MNA et une perception de leur vécu de l'exil et de l'accueil en Suisse sont indispensables à la mise en oeuvre d'une action sociale réfléchie, mais, jusqu’à ce jour, cette connaissance est essentiellement pratique : seul·e·s les professionnel·le·s en contact régulier avec les MNA possèdent ce savoir pratique. Sans prétendre apporter des réponses à toutes les questions évoquées, cette recherche a pour but principal de synthétiser et de conceptualiser ce savoir pratique, de manière à pouvoir le transmettre. Elle vise également à mieux connaître la manière dont les MNA eux-mêmes perçoivent leur situation et leurs perspectives afin d'en tenir compte dans le travail qui est fait avec eux

Multiple Phases of Chondrocyte Enlargement Underlie Differences in Skeletal Proportions

Even a casual pass through the great halls of mammals in the world’s natural history museums highlights the wide diversity of skeletal proportions that allow us to distinguish between species even when reduced to their calcified components. Similarly each individual is comprised of a variety of bones of differing lengths. The largest contribution to the lengthening of a skeletal element, and to the differential elongation of elements, comes from a dramatic increase in the volume of hypertrophic chondrocytes in the growth plate as they undergo terminal differentiation1–7. Despite this recognized importance, the mechanisms of chondrocyte volume enlargement have remained a mystery8–11. Here we use quantitative phase microscopy12 to show that chondrocytes undergo three distinct phases of volume increase, including a phase of massive cell swelling in which the cellular dry mass is significantly diluted. In light of the tight fluid regulatory mechanisms known to control volume in many cell types13, this stands as a remarkable mechanism for increasing cell size and regulating growth rate. It is, however, the duration of the final phase of volume enlargement by proportional dry mass increase at low density that varies most between rapidly and slowly elongating growth plates. Moreover, we find that this third phase is locally regulated through an Insulin-like Growth Factor-dependent mechanism. This study provides a framework for understanding how skeletal size is regulated and for exploring how cells sense, modify, and establish a volume set point

Sodium intake and blood pressure in children and adolescents: protocol for a systematic review and meta-analysis.

Hypertension is a major risk factor for cardiovascular diseases. In adults, high sodium intake is associated with elevated blood pressure. In children, experimental studies have shown that reducing sodium intake can reduce blood pressure. However, their external validity is limited, notably because the sodium reduction was substantial and not applicable in a real-life setting. Observational studies, on the other hand, allow assess the association between blood pressure and sodium intake across usual levels of consumption. There is also evidence that the association differs between subgroups of children according to age and body weight. Our objective is to conduct a systematic review and meta-analysis of experimental and observational studies on the association between sodium intake and blood pressure in children and adolescents and to assess whether the association differs according to age and body weight. A systematic search of the MEDLINE, EMBASE, CINAHL and CENTRAL databases will be conducted and supplemented by a manual search of bibliographies and unpublished studies. Experimental and observational studies involving children or adolescents between 0 and 18 years of age will be included. The exposure will be dietary sodium intake, estimated using different methods including urinary sodium excretion. The outcomes will be systolic and diastolic blood pressure, elevated blood pressure and hypertension. If appropriate, meta-analyses will be performed by pooling data across all studies together and separately for experimental and observational studies. Subgroup meta-analyses by age and body weight will be also conducted. Moreover, separate meta-analyses for different sodium intake levels will be conducted to investigate the dose-response relationship. This systematic review and meta-analysis will be published in a peer-reviewed journal. A report will be prepared for national authorities and other stakeholders in the domains of nutrition, public health, and child health in Switzerland. CRD42016038245

Adapting the "Chester step test" to predict peak oxygen uptake in children.

Maximal exercise testing may be difficult to perform in clinical practice, especially in obese children who have low cardiorespiratory fitness and exercise tolerance. We aimed to elaborate a model predicting peak oxygen consumption (VO2) in lean and obese children with use of the submaximal Chester step test. We performed a maximal step test, which consisted of 2-minute stages with increasing intensity to exhaustion, in 169 lean and obese children (age range: 7-16 years). VO2 was measured with indirect calorimetry. A statistical Tobit model was used to predict VO2 from age, gender, body mass index (BMI) z-score and intensity levels. Estimated VO2peak was then determined from the heart rate-VO2 linear relationship extrapolated to maximal heart rate (220 minus age, in beats.min-1). VO2 (ml/kg/min) can be predicted using the following equation: VO2 = 22.82 - [0.68*BMI z-score] - [0.46*age (years)] - [0.93*gender (male = 0; female = 1)] + [4.07*intensity level (stage 1, 2, 3 etc.)] - [0.24*BMI z-score *intensity level] - [0.34*gender*intensity level]. VO2 was lower in participants with high BMI z-scores and in female subjects. The Chester step test can assess cardiorespiratory fitness in lean and obese children in clinical settings. Our adapted equation allows the Chester step test to be used to estimate peak aerobic capacity in children

SOX11 contributes to the regulation of GDF5 in joint maintenance

Background: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. Results: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5’ UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. Conclusions: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis

Cryptic Variation in Morphological Evolution: HSP90 as a Capacitor for Loss of Eyes in Cavefish

In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution in a natural setting