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Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts (1,2), mediated primarily by proliferation of pre-existing cardiomyocytes (3-5). However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers (6). In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function (7-10). Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific a myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals., It was recently reported that new cardiomyocytes in the adult heart are derived from pre-existing cardiomyocytes (3-5), although the identity of cycling cardiomyoctes, and the mechanism of their proliferative competency [...]

Glass fiber reinforced polymer (GFRP) materials are gaining increasing use in geotechnical engineering applications in recent years. The long-term performance of reinforced geostructures may be influenced by the rheological properties of GFRP soil nails or anchors. However, a clear understanding of this effect is lacking. This work aims to investigate the interaction between GFRP soil nail and sand under pullout conditions considering the time-dependent effect. A time-dependent model was proposed to describe the load-deformation characteristics of a GFRP soil nail during pullout. Laboratory pullout tests were performed using a load-controlled pullout apparatus to verify the effectiveness of the proposed model. Quasi-distributed fiber Bragg grating (FBG) optical fiber sensors were adhered on the pre-grooved GFRP soil nail to capture the variations of axial strain during testing. The test results are presented, interpreted, and discussed. It is shown that there is good agreement between the simulation results and the experimental data under low stress levels. Additionally, the impacts of model parameters on the predicted time-dependent pullout behavior of a GFRP soil nail were examined through parametric studies. The results indicate that the distributions of tensile force and GFRP-sand interfacial shear stress along the nail length are highly time dependent. The creep displacement of a GFRP soil nail is significantly influenced by the rheological parameters of the proposed model. Key words: glass fiber reinforced polymer (GFRP), soil nail, pullout, rheology, fiber Bragg grating (FBG). Les materiaux en polymere renforce a la fibre de verre (PRFV) sont de plus en plus utilises en ingenierie geotechnique depuis quelques annees. La performance a long terme des geostructures renforcees peut etre influencee par les proprietes rheologiques des ancrages ou clous d'ancrage au sol en PRFV. Cependant, il reste fi comprendre de maniere precise les effets de ces proprietes. La presente etude a pour but d'analyser les interactions entre un clou d'ancrage en PRFV et du sable sous l'effet de l'arrachement en tenant compte du facteur temps. Un modele dependant du temps a ete propose pour decrire les caracteristiques du couple charge-deformation d'un clou d'ancrage en PRFV lors d'un arrachement. Des essais d'arrachement ont ete effectues en laboratoire au moyen d'un dispositif d'arrachement a controle de charge afin de verifier l'efficacite du modele propose. Des capteurs a fibres optiques a reseaux de Bragg (<< FBG >>) quasi distribues ont ete fixes au clou d'ancrage en PRFV prefilete pour mesurer les variations de contrainte axiale durant les essais. Les resultats des essais sont presentes, interpretes et analyses dans le present article. On montre qu'il y a une bonne concordance entre les essais de simulation et les donnees experimentales pour des niveaux faibles de contraintes. En outre, on s'est interesse, par le biais d'etudes parametriques, a l'influence des parametres de modele sur le l'arrachement predit et dependant du temps du clou d'ancrage en PRFV. Les resultats montrent que les distributions de l'effort de traction et de la contrainte de cisaillement a l'interface PRFV-sable sur toute la longueur du clou sont largement fonction du temps. Le deplacement progressif du clou en PRFV depend beaucoup des parametres rheologiques du modele propose. [Traduit par la Redaction] Mots-cles: polymere renforce a la fibre de verre (PRFV), clou d'ancrage au sol, arrachement, rheologie, reseaux de Bragg (<< FBG >>)., Introduction Glass fiber reinforced polymer (GFRP) materials are potentially suitable alternatives to conventional steel materials owing to their outstanding properties, such as better corrosion resistance, higher strength-to-weight ratio, and easier [...]

How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo (1-10). ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified (3,11,12). Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development., We used multiple approaches, including expression cloning, to identify the receptor(s) for ANGPTLs. Human LILRB2, when ectopically expressed on Baf3 cells, enabled the cells to specifically bind glutathione S-transferase (GST)-ANGPTL5 [...]

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants. Recent studies have reported that oncoprotein YAP can function as tumour suppressor in certain contexts. Here the authors show that inhibition of Hippo signalling or YAP activation blocks ERα transcriptional program and ER + breast cancer growth and mechanistically this is through YAP interfering with TEAD-ERα signalling axis. [ABSTRACT FROM AUTHOR]

Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of crucial questions of stem cell biology. Here we show, using microarray studies, that the HSC-supportive mouse fetal liver CD3[sup.+] cells specifically express the proteins angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). We observed a 24- or 30-fold net expansion of long-term HSCs by reconstitution analysis when we cultured highly enriched HSCs for 10 days in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors. The coiled-coil domain of Angptl2 was capable of stimulating expansion of HSCs. Furthermore, angiopoietin-like 5, angiopoietin-like 7 and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture., Author(s): Cheng Cheng Zhang [1]; Megan Kaba [1]; Guangtao Ge [1]; Kathleen Xie [1]; Wei Tong [1]; Christopher Hug [1, 2, 3]; Harvey F Lodish (corresponding author) [1, 4] HSCs, [...]