Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size.

OBJECTIVES: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood. SUBJECTS AND METHODS: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32). RESULTS: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (β from -0.294 to -0.371; R2 from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (β from -0.428 to -0.552; R2 from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR. CONCLUSIONS: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.This study was supported by grants from the Ministerio de Ciencia e Innovación, Instituto de 10 Salud Carlos III (ISCIII), Madrid, Spain (PI17/00557 to JB, and PI13/01257 and PI16/01335 to AL-B), projects co-funded by FEDER (Fondo Europeo de Desarrollo Regional). RF and MG acknowledge grant funding from the Fondation pour la Recherche Médicale (Equipes FRM, 13 grant number DEQ31703)

Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy.

Background NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target. Methods Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo. Results Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL. Conclusion DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients

Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications

An experimental study on the post-cracking behaviour of Hybrid Industrial/Recycled Steel Fibre-Reinforced Concrete

This paper investigates the mechanical behaviour of FRC made with both Industrial and Recycled Steel Fibres recovered from waste tyres. Specimens of various mixtures, characterised by the same volume fraction of fibres, but different proportions of industrial and recycled reinforcement were tested both in compression and bending. The results highlighted a fairly negligible influence of fibres in terms of compressive strength, whereas a significant decay in the post-cracking behaviour was observed in specimens with higher fractions of recycled fibres. However, a significant enhancement in the bending response was observed with respect to the case of plain concrete, even for specimens reinforced by recycled fibres only

Coordinated Path Following of Multiple UAVs for Time-Critical Missions in the Presence of Time-Varying Communication Topologies

We address the problem of steering multiple unmanned air vehicles (UAVs) along given paths (path-following) under strict temporal coordination constraints requiring, for example, that the vehicles arrive at their final destinations at exactly the same time. Pathfollowing relies on a nonlinear Lyapunov based control strategy derived at the kinematic level with the augmentation of existing autopilots with L1 adaptive output feedback control laws to obtain inner-outer loop control structures with guaranteed performance. Multiple vehicle timecritical coordination is achieved by enforcing temporal constraints on the speed profiles of the vehicles along their paths in response to information exchanged over a dynamic communication network. We consider that each vehicle transmits its coordination state to only a subset of the other vehicles, as determined by the communications topology adopted. We address explicitly the case where the communication graph that captures the underlying communication network topology may be disconnected during some interval of time (or may even fail to be connected at any instant of time) and provide conditions under which the closed-loop system is stable. Flight test results obtained at Camp Roberts, CA in 2008 and hardware-in-the-loop (HITL) simulations demonstrate the benefits of the algorithms developed

Time-Critical Cooperative Path Following of Multiple UAVs over Time-Varying Networks

submitted to AIAA Journal of Guidance, Control and Dynamic

Time-Critical Cooperative Path Following of Multiple UAVs: Case Studies

This paper describes a multi-vehicle motion control framework for time-critical cooperative missions and evaluates its performance by considering two case stud- ies: a simultaneous arrival mission scenario and a sequential auto-landing of a fleet of UAVs. In the adopted setup, the UAVs are assigned nominal spatial paths and speed profiles along those, and the vehicles are then tasked to execute co- operative path following, rather than “open-loop” trajectory-tracking maneuvers. This cooperative strategy yields robust behavior against external disturbances by allowing the UAVs to negotiate their speeds along the paths in response to coordi- nation information exchanged over the supporting communications network. The approach applies to teams of heterogeneous vehicles and does not necessarily lead to swarming behavior