'Non-Mendelian' genetics of fetal growth

International audienceMendelian genetics showed that a few mutated genes, or errors in parental imprinting, can lead to major phenotypic changes (diseases) in pre-natal growth. Mendelian genetics, however, do not explain the individual subtle variability of size at birth within the normal range. Fetal growth is a complex multifactorial, multigenic trait made of various sub-traits, such as body mass, fat and muscle, brain mass, head circumference, skeletal growth of the spine and limbs. It is likely that multiple genetic factors and genomic variants are responsible for the variations of these sub-traits. A study has been launched to investigate the genetics of the variation of human birth weight, with the ultimate aim of identifying genomic variations that are within or near certain genes and are associated with variations of human height and weight at birth

A criterion for homeomorphism between closed Haken manifolds

In this paper we consider two connected closed Haken manifolds denoted by M^3 and N^3, with the same Gromov simplicial volume. We give a simple homological criterion to decide when a given map f: M^3-->N^3 between M^3 and N^3 can be changed by a homotopy to a homeomorphism. We then give a convenient process for constructing maps between M^3 and N^3 satisfying the homological hypothesis of the map f.Comment: Published by Algebraic and Geometric Topology at http://www.maths.warwick.ac.uk/agt/AGTVol3/agt-3-12.abs.htm

Hydrogen production by the hyperthermophilic bacterium Thermotoga maritima part I: effects of sulfured nutriments, with thiosulfate as model, on hydrogen production and growth

International audienceBackground: Thermotoga maritima and T. neapolitana are hyperthermophile bacteria chosen by many research teams to produce bio-hydrogen because of their potential to ferment a wide variety of sugars with the highest theoretical H-2/glucose yields. However, to develop economically sustainable bio-processes, the culture medium formulation remained to be optimized. The main aim of this study was to quantify accurately and specifically the effect of thiosulfate, used as sulfured nutriment model, on T. maritima growth, yields and productivities of hydrogen. The results were obtained from batch cultures, performed into a bioreactor, carefully controlled, and specifically designed to prevent the back-inhibition by hydrogen. Results: Among sulfured nutriments tested, thiosulfate, cysteine, and sulfide were found to be the most efficient to stimulate T. maritima growth and hydrogen production. In particular, under our experimental conditions (glucose 60 mmol L-1 and yeast extract 1 g L-1), the cellular growth was limited by thiosulfate concentrations lower than 0.06 mmol L-1. Under these conditions, the cellular yield on thiosulfate (Y X/Thio) could be determined at 3617 mg mmol(-1). In addition, it has been shown that the limitations of T. maritima growth by thiosulfate lead to metabolic stress marked by a significant metabolic shift of glucose towards the production of extracellular polysaccharides (EPS). Finally, it has been estimated that the presence of thiosulfate in the T. maritima culture medium significantly increased the cellular and hydrogen productivities by a factor 6 without detectable sulfide production. Conclusions: The stimulant effects of thiosulfate at very low concentrations on T. maritima growth have forced us to reconsider its role in this species and more probably also in all thiosulfato-reducer hyperthermophiles. Henceforth, thiosulfate should be considered in T. maritima as (1) an essential sulfur source for cellular materials when it is present at low concentrations (about 0.3 mmol g(-1) of cells), and (2) as both sulfur source and detoxifying agent for H-2 when thiosulfate is present at higher concentrations and, when, simultaneously, the pH(2) is high. Finally, to improve the hydrogen production in bio-processes using Thermotoga species, it should be recommended to incorporate thiosulfate in the culture medium

Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study

Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors. PARs are activated by a serine-dependent cleavage generating a tethered activating ligand. PAR-2 was shown to be involved in inflammatory pathways. We investigated the in situ levels and modulation of PAR-2 in human normal and osteoarthritis (OA) cartilage/chondrocytes. Furthermore, we evaluated the role of PAR-2 on the synthesis of the major catabolic factors in OA cartilage, including metalloproteinase (MMP)-1 and MMP-13 and the inflammatory mediator cyclooxygenase 2 (COX-2), as well as the PAR-2-activated signalling pathways in OA chondrocytes. PAR-2 expression was determined using real-time reverse transcription-polymerase chain reaction and protein levels by immunohistochemistry in normal and OA cartilage. Protein modulation was investigated in OA cartilage explants treated with a specific PAR-2-activating peptide (PAR-2-AP), SLIGKV-NH2 (1 to 400 μM), interleukin 1 beta (IL-1β) (100 pg/mL), tumor necrosis factor-alpha (TNF-α) (5 ng/mL), transforming growth factor-beta-1 (TGF-β1) (10 ng/mL), or the signalling pathway inhibitors of p38 (SB202190), MEK1/2 (mitogen-activated protein kinase kinase) (PD98059), and nuclear factor-kappa B (NF-κB) (SN50), and PAR-2 levels were determined by immunohistochemistry. Signalling pathways were analyzed on OA chondrocytes by Western blot using specific phospho-antibodies against extracellular signal-regulated kinase 1/2 (Erk1/2), p38, JNK (c-jun N-terminal kinase), and NF-κB in the presence or absence of the PAR-2-AP and/or IL-1β. PAR-2-induced MMP and COX-2 levels in cartilage were determined by immunohistochemistry. PAR-2 is produced by human chondrocytes and is significantly upregulated in OA compared with normal chondrocytes (p < 0.04 and p < 0.03, respectively). The receptor levels were significantly upregulated by IL-1β (p < 0.006) and TNF-α (p < 0.002) as well as by the PAR-2-AP at 10, 100, and 400 μM (p < 0.02) and were downregulated by the inhibition of p38. After 48 hours of incubation, PAR-2 activation significantly induced MMP-1 and COX-2 starting at 10 μM (both p < 0.005) and MMP-13 at 100 μM (p < 0.02) as well as the phosphorylation of Erk1/2 and p38 within 5 minutes of incubation (p < 0.03). Though not statistically significant, IL-1β produced an additional effect on the activation of Erk1/2 and p38. This study documents, for the first time, functional consequences of PAR-2 activation in human OA cartilage, identifies p38 as the major signalling pathway regulating its synthesis, and demonstrates that specific PAR-2 activation induces Erk1/2 and p38 in OA chondrocytes. These results suggest PAR-2 as a potential new therapeutic target for the treatment of OA

Rat endopeptidase-24.18 α subunit is secreted into the culture medium as a zymogen when expressed by COS-1 cells

AbstractEndopeptidase-24.18 (EC 3.4.24.18, E-24.18) is an oligomeric Zn-ectoenzyme. The α and β submits have been cloned from both rat and mouse kidneys. The primary structure of these subunits revealed that they both contain the consensus Zn binding site and that they are members of the astacin family. Analysis of the hydropathy plot also suggested that they are anchored by a C-terminal hydrophobic domain. In order to verify the mode of anchoring of the rat E-24.18 α subunit and to test the functionality of the astacin-like domain in the α subunit when expressed alone, COS-1 cells were transfected with a cloned cDNA for rat α subunit. Despite the presence of its putative transmembrane domain, the α subunit was not anchored in the plasma membrane but rather secreted as a dimer into the culture medium. When the enzymatic activity of the secreted recombinant protein was tested in the azocasein degradation assay, the α subunit was found to be inactive. Activity could, however, be revealed after mild trypsin digestion. This activity was abolished by replacing the Glu-157 in the active site by Val. Taken together our results suggest that the α subunit of Endopeptidase-24.18 contains a latent astacin-like Zn metallopeptidase activity which could be secreted as a soluble enzyme by kidney and intestine

Analyses of biodynamic responses of seated occupants to uncorrelated fore-aft and vertical whole-body vibration

The apparent mass and seat-to-head-transmissibility response functions of the seated human body were investigated under exposures to fore-aft (x), vertical (z), and combined fore-aft and vertical (x and z) axis whole-body vibration. The coupling effects of dual-axis vibration were investigated using two different frequency response function estimators based upon the cross- and auto-spectral densities of the response and excitation signals, denoted as H1 and Hv estimators, respectively. The experiments were performed to measure the biodynamic responses to single and uncorrelated dual-axis vibration, and to study the effects of hands support, back support and vibration magnitude on the body interactions with the seatpan and the backrest, characterized in terms of apparent masses and the vibration transmitted to the head. The data were acquired with 9 subjects exposed to two different magnitudes of vibration applied along the individual x- and z-axis (0.25 and 0.4 m/s2 rms), and along both the axis (0.28 and 0.4 m/s2 rms along each axis) in the 0.5–20 Hz frequency range. The two methods resulted in identical single-axis responses but considerably different dual-axis responses. The dual-axis responses derived from the Hv estimator revealed notable effects of dual-axis vibration, as they comprised both the direct and cross-axis responses observed under single axis vibration. Such effect, termed as the coupling effect, was not evident in the dual-axis responses derived using the commonly used H1 estimator. The results also revealed significant effects of hands and back support conditions on the coupling effects and the measured responses. The back support constrained the upper body movements and thus showed relatively weaker coupling compared to that observed in the responses without the back support. The effect of hand support was also pronounced under the fore-aft vibration. The results suggest that a better understanding of the seated human body responses to uncorrelated multi-axis whole-body vibration could be developed using the power-spectral-density based Hv estimator

Fibulin-2: genetic mapping and exclusion as a candidate gene in Marfan syndrome type 2.

International audienceFibulin-2 (FBLN2) is a new extracellular matrix protein that has been considered a candidate gene for Marfan syndrome type 2 (locus MFS2) based on chromosomal colocation at 3p24.2-p25 and disease phenotype. In the absence of polymorphic markers reported for FBLN2, direct sequencing of the gene was performed and two intragenic polymorphisms were identified. Linkage was excluded between FBLN2 and the MFS2 gene. Furthermore, two-point lod scores were generated between these markers and anonymous markers arrayed on the genetic map of 3p and closely linked to MFS2. These analyses placed FBLN2 at marker D3S1585

Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc