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A genome-wide DNA-methylation profiling on familial breast cancer is performed to identify patterns of methylation which are particular to the different mutation groups or intrinsic types of breast cancer. Data obtained using a support vector machine classification algorithm, gene-expression profiling and SNP CGH array identify distinct methylation profiles defined by the mutation status, which are different from the intrinsic subtypes.

We study water flows and wave dissipation within near-bed pneumatophore canopies at the wave-exposed fringe of a mangrove forest on Cù Lao Dung Island, in the Mekong Delta. To evaluate canopy drag, the three-dimensional geometry of pneumatophore stems growing upward from the buried lateral roots of Sonneratia caseolaris mangroves was reconstructed from photogrammetric surveys. In cases where hydrodynamic measurements were obtained, up to 84 stems per square meter were observed, with stem heights < 0.6 m, and basal diameters 0.01–0.02 m. The parameter a = (frontal area of pneumatophores blocking the flow)/(canopy volume) ranged from zero to 1.8 m −1 . Within-canopy water velocity displayed a phase lead and slight attenuation relative to above-canopy flows. The phase lead was frequency-dependent, ranging from 0 to 30 degrees at the frequencies of energetic waves ( > 0.1 Hz), and up to 90 degrees at lower frequencies. A model is developed for wave-induced flows within the vertically variable canopy. Scaling suggests that acceleration-induced forces and vertical mixing were negligible at wave frequencies. Consistent with theory, drag-induced vertical variability in velocity scaled with Λ = T w / ( 2 π T f ) , where T w = wave period, T f = 2 / ( C D a | u | ) is the frictional time scale, C D ≈ 2 is the drag coefficient, and | u | is a typical flow speed. For fixed wave conditions ( | u | and T w ), theory predicts increasing dissipation with increasing vegetation density (i.e. increasing a ), until a maximum is reached for order-one Λ . For larger Λ , within-canopy flow is so inhibited by drag that further increases in a reduce within-canopy dissipation. For observed cases, Λ ⩽ 0.38 at energetic wave frequencies, so wave dissipation near the forest edge is expected to increase with increasing pneumatophore canopy density. However, under different wave conditions, the most dense canopies may occasionally approach the dissipation maximum ( Λ ≈ 1 ). Predicted dissipation by the pneumatophore canopy was sufficient to attenuate most wave energy over distances slightly less (more) than 100 m into the marsh in 1 m (2 m) water depth. [ABSTRACT FROM AUTHOR]

Mangroves have been shown to protect shorelines against damage from the combined hydrodynamic forces of waves and tides, owing to the presence of roots (pneumatophores) and tree trunks that enhance vegetative drag. However, field measurements within these environments are limited. We present field observations of flows from the seaward coast of Cù Lao Dung Island (Sóc Trăng Province) in the Mekong Delta, Vietnam. Measurements were made in two different seasons along a transect that crosses from mudflats to mangrove forest. Flows are also explored using an idealised numerical model. Both the data and model capture the flow transitions from mudflat across the fringing region to the forest interior. We observe a rotation of the obliquely incident flows toward an orientation nearly perpendicular to the vegetated/unvegetated boundary. The momentum balances governing the large-scale flow are assessed and indicate the relative importance of friction, winds and depth-averaged pressure forces. In the forest, drag coefficients were 10–30 times greater than values usually observed for bottom friction, with particularly effective friction in the regions of dense pneumatophores at the fringe and when water depths were lower than the height of the pneumatophores. Pressure gradient balances suggest that the drag induced by bottom friction from pneumatophores was dominant relative to drag from the larger, but sparser, tree trunks. [ABSTRACT FROM AUTHOR]

The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Recent advances in cancer genomics, together with biochemical characterization of the APOBEC3 enzymes, have now implicated at least two family members in somatic mutagenesis during tumor development. We review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. [ABSTRACT FROM AUTHOR]

Summary Topological domains are key architectural building blocks of chromosomes, but their functional importance and evolutionary dynamics are not well defined. We performed comparative high-throughput chromosome conformation capture (Hi-C) in four mammals and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions and that this is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, are enriched at strong topological domain borders, and bind to DNA motifs with orientations that define the directionality of CTCF’s long-range interactions. Conversely, divergent CTCF binding between species is correlated with divergence of internal domain structure, likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked to a continuous flux of local conformation changes. We also show that large-scale domains are reorganized during genome evolution as intact modules. [ABSTRACT FROM AUTHOR]

T cell pathology in the skin leads to monocyte influx, but we have little understanding of the fate of recruited cells within the diseased niche, or the long-term impact on cutaneous immune homeostasis. By combining a murine model of acute graft-versus-host disease (aGVHD) with analysis of patient samples, we demonstrate that pathology initiates dermis-specific macrophage differentiation and show that aGVHD-primed macrophages continue to dominate the dermal compartment at the relative expense of quiescent MHCIIint cells. Exposure of the altered dermal niche to topical haptens after disease resolution results in hyper-activation of regulatory T cells (Treg), but local breakdown in tolerance. Disease-imprinted macrophages express increased IL-1β and are predicted to elicit altered TNF superfamily interactions with cutaneous Treg, and we demonstrate the direct loss of T cell regulation within the resolved skin. Thus, T cell pathology leaves an immunological scar in the skin marked by failure to re-set immune homeostasis. [Display omitted] • Skin immune pathology drives dermis-specific monocyte differentiation • GVHD-primed macrophages dominate the dermis after disease • T cell tolerance to topical haptens fails despite recovery from GVHD • Tregs are dysfunctional within the altered dermal niche The impact of T cell pathology on cutaneous immunity is not well understood. Here, West et al. combine a model of graft-versus-host-disease with patient data to reveal prolonged dysregulation of dermal macrophage differentiation, and breakdown in Treg function, leading to a failure to re-set the skin immune balance after disease. [ABSTRACT FROM AUTHOR]

Summary: APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV− HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation. [Copyright &y& Elsevier]

Abstract: Around high tide over a flooded tidal flat, vertical shear measured 0.13–0.4m beneath the sea surface by upward-looking Acoustic Doppler Profilers (ADPs) was usually aligned with the wind. However, shear did not increase with increasing windspeed, likely owing to an increase in wave heights and wave-generated mixing with increasing windspeed. The associated increase in water-side drag coefficient with windspeed was predicted, with substantial scatter, by a model for near-surface mixing by breaking waves. A depth-independent eddy-viscosity model yielded only slightly less skill than a fitted depth-dependent model. Farther (0.3–0.6m) from the surface, model skill was low, suggesting that shear at depth was often determined by factors other than wind. Wave heights tended to increase with increasing water depth. Consequently, the simulated wave-generated surface eddy viscosity tended to increase with increasing depth. [Copyright &y& Elsevier]

Secondary lymphedema is a debilitating condition, and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene (adrenomedullin gene). AM and its putative receptor calcitonin receptor-like receptor (CLR) are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene-knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (AdmAM+/Δ animals). After hind limb skin incision, Adm messenger RNA expression was upregulated in wounded tissue of both AdmAM+/+ and AdmAM+/Δ mice. However, only AdmAM+/Δ animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density, and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in AdmAM+/Δ mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics, and blood vessels. Our study identified a previously unrecognized role for endogenous AM as a key factor in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder. [ABSTRACT FROM AUTHOR]

This paper examines the role of mangrove pneumatophore roots as a spatial control over the turbulent kinetic energy (TKE) dissipation rate within a natural mangrove forest. Measurements of turbulence at millimeter scales were compared with vegetation geometries reconstructed using a novel photogrammetric technique. These small-scale relationships were then averaged to show larger-scale patterns in turbulence across the mudflat and mangrove fringe-forest transition. Although turbulence estimates varied with across-shore position, TKE dissipation was always elevated in the fringe relative to mudflat and forest interior sample sites. The largest dissipation rates (4.5 × 10 −3 W kg −1 ) were measured as breaking waves propagated over canopies in very shallow water. Dissipation was reduced, but often remained intense (10 −5 –10 −4 W kg −1 ) under non-breaking waves at the fringe, likely indicating turbulent generation in pneumatophore wakes. Pneumatophore density was positively correlated with the spatial distribution of TKE dissipation. Turbulence was also correlated positively with wave height and negatively with water depth. Fringe sediments were more sandy and less muddy than sediments onshore and offshore, suggesting that the intense turbulence may lead to winnowing of fine-grained sediments at the fringe. [ABSTRACT FROM AUTHOR]

Summary Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha ( PDGFRA ) amplification. Here, we describe a somatic mouse model wherein H3.3 K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero . H3.3 K27M -driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3 K27M -tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3 K27M -pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies. [ABSTRACT FROM AUTHOR]