Deformation-Induced Mechanical Instabilities at the Core-Mantle Boundary

Post-Perovskite: The Last Mantle Phase Transition Our understanding of the core-mantle boundary (CMB) region has improved significantly over the past several years due, in part, to the discovery of the post-perovskite phase. Sesimic data suggest that the CMB region is highly heterogeneous, possibly reflecting chemical and physical interaction between outer core material and the lowermost mantle. In this contribution we present the results of a new mechanism of mass transfer across the CMB and comment on possible repercussions that include the initiation of deep, siderophile-enriched mantle plumes. We view the nature of core-mantle interaction, and the geodynamic and geochemical ramifications, as multiscale processes, both spatially and temporally. Three lengthscales are defined. On the microscale (1-50 km), we describe the effect of loading and subsequent shearing of the CMB region and show how this may drive local flow of outer core fluid upwards into D". We propose that larger scale processes operating on a mesoscale (50-300 km) and macroscale regimes (> 300 km) are linked to the microscale, and suggest ways in which these processes may impact on global mantle dynamics

Case Management of Diabetes in the Virgin Islands

No abstract available

Shear-induced material transfer across the core-mantle boundary aided by the post-perovskite phase transition

We present a novel mechanical model for the extraction of outer core material upwards across the CMB into the mantle side region of D" and subsequent interaction with the post-perovskite (ppv) phase transition. A strong requirement of the model is that the D" region behaves as a poro-viscoelastic granular material with dilatant properties. Using new ab-initio estimates of the ppv shear modulus, we show how shear-enhanced dilation promoted by downwelling mantle sets up an instability that drives local fluid flow. If loading rates locally exceed c. 10-12 s-1 , calculated core metal upwelling rates are >10-4 m/s, far in excess of previous estimates based on static percolation or capillary flow. Associated mass flux rates are sufficient to deliver 0.5% outer core mass to D" in <10 6 yr, provided the minimum required loading rate is maintained. Core metal transported upwards into D" may cause local rapid changes in electrical and thermal conductivity and rheology that if preserved, may account for some of the observed small wavelength heterogeneties (e.g. PKP scattering) there

Alleviating poverty in Hong Kong : the evolution of policy decisions and instruments

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.

Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions

Role of activin receptors in driving central nervous system regeneration of myelin

Myelin damage in central nervous system white matter disorders such as multiple sclerosis (MS) leads to axonal dysfunction/degeneration and clinical disability. Regeneration of myelin (termed remyelination) can occur and requires oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes, which are then able to make contact with axons and ensheath them. However, this process fails in progressive MS. The lack of approved therapies aimed at promoting remyelination highlight the need to identify mechanisms driving this regenerative process to develop novel therapeutic strategies. Previous work in the lab identified the TGF-β superfamily member activin-A as being increased during remyelination in vivo and sufficient in stimulating activin receptor-driven OPC differentiation into mature oligodendrocytes in vitro. Here, these studies were followed up by undertaking a comprehensive assessment of the role of activin receptors and their ligands during remyelination. Using an ex vivo brain explant model of demyelination, the stimulation of activin receptors using activin-A was sufficient to enhance remyelination. Blocking activin receptors using an endogenous inhibitor (Inhibin) hindered remyelination, demonstrating the requirement of activin receptor signalling for this process. Surprisingly, blocking the binding of endogenous activin-A to activin receptors using follistatin did not impact remyelination, suggesting that other activin receptor ligands are involved in driving remyelination. As activin receptors may bind other ligands in the TGF-β superfamily, the expression and function of alternative ligands was investigated, and each was found to be important for remyelination (albeit with distinct timing/ effects). Both activin receptors and their ligands were expressed on microglia/macrophages in mouse and human disease tissue. Finally, analysis of activin receptor expression on oligodendrocytes in human tissue revealed potential functional differences between receptor subtypes. Together, these results demonstrate previously undefined roles of a subset of TGF-β superfamily members in regulating remyelination, and have implications for the development of novel approaches to enhancing remyelination in disease