Enhancing multi-scale cardiac simulations by coupling electrophysiology and mechanics: a flexible high performance approach to cardiac electromechanics

This work focuses on the development of computational methods for the simulation of the propagation of the electrical potential in the heart and of the resulting mechanical contraction. The interaction of these two physical phenomena is described by an electromechanical model which consists of the monodomain system, which describes the propagation of the action potential in the cardiac tissue, and the equations of incompressible elasticity, which describe its mechanical response. In fully-coupled electromechanical simulations, two main computational challenges are usually identified in literature: the time integration of the monodomain system and the efficient solution of the equations of incompressible elasticity. These two are the actual bottlenecks in the realization of accurate and efficient fully-coupled electromechanical simulations. The first computational challenge arises from the discretization in time of the equations that describe the electrical activation of cardiac tissue. The monodomain system should be discretized employing both fine spatial grids and small time-steps, to capture the spatial steep gradients typical of the action potential and the behavior of the stiff gating variables, respectively. To obtain an accurate and computationally-cheap numerical solution, we propose a novel method based on coupling high-order backward differentiation formulae with high-order exponential time stepping schemes for the time integration of the monodomain system. We propose a novel quasi-Newton approach for the implicit discretization of the monodomain equation. We also compare this latter approach against a complex step differentiation-based approach. As a result, we show by means of numerical tests the accuracy of the developed strategies and how the use of high-order time integration schemes affects the simulation of post- processed quantities of clinical relevance such as the conduction velocity. The second computational challenge is due to the structure the discretization of the equations of incompressible elasticity. Due to the incompressibility constraint, the arising linear system has a saddle point structure for which standard solution methods such as multigrid or domain de- composition do not provide optimal convergence if not properly adapted. In order to overcome this problematic, we propose a segregated multigrid preconditioned solution method. The segregated approach allows to recast the saddle-point problem into two elliptic problems for which multigrid methods are shown to provide optimal convergence. The electromechanical model is employed to evaluate the effects of geometrical changes due to the contraction of the heart on simulated electrocardiograms. Finally, the effect of different electrical activations on the resulting pressure-volume loops is investigated by coupling the electromechanical model with a lumped model of the circulatory system

The monoclonal antibody nBT062 conjugated to maytansinoids has potent and selective cytotoxicity against CD138 positive multiple myeloma cells _in vitro_ and _in vivo_

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives _in vitro_ and _in vivo_. These agents significantly inhibited growth of CD138-positive MM cell lines and primary tumor cells from MM patients, without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2/M cell cycle arrest followed by apoptosis associated with cleavage of PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth _in vivo_ in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM

A Novel Role for CCL3 (MIP-1α) in Myeloma-induced Bone Disease via Osteocalcin Downregulation and Inhibition of Osteoblast Function

Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine whose levels in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. Here, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function and therefore contributes to OB/OC uncoupling in MM

Technical Report Series on Global Modeling and Data Assimilation, Volume 41 : GDIS Workshop Report

The workshop "An International Global Drought Information System Workshop: Next Steps" was held on 10-13 December 2014 in Pasadena, California. The more than 60 participants from 15 countries spanned the drought research community and included select representatives from applications communities as well as providers of regional and global drought information products. The workshop was sponsored and supported by the US National Integrated Drought Information System (NIDIS) program, the World Climate Research Program (WCRP: GEWEX, CLIVAR), the World Meteorological Organization (WMO), the Group on Earth Observations (GEO), the European Commission Joint Research Centre (JRC), the US Climate Variability and Predictability (CLIVAR) program, and the US National Oceanic and Atmospheric Administration (NOAA) programs on Modeling, Analysis, Predictions and Projections (MAPP) and Climate Variability & Predictability (CVP). NASA/JPL hosted the workshop with logistical support provided by the GEWEX program office. The goal of the workshop was to build on past Global Drought Information System (GDIS) progress toward developing an experimental global drought information system. Specific goals were threefold: (i) to review recent research results focused on understanding drought mechanisms and their predictability on a wide range of time scales and to identify gaps in understanding that could be addressed by coordinated research; (ii) to help ensure that WRCP research priorities mesh with efforts to build capacity to address drought at the regional level; and (iii) to produce an implementation plan for a short duration pilot project to demonstrate current GDIS capabilities. See http://www.wcrp-climate.org/gdis-wkshp-2014-objectives for more information

Retraction: Fatty acid synthase is a novel therapeutic target in multiple myeloma

This study investigated the biological significance of the inhibition of fatty acid synthase (FAS) in multiple myeloma (MM) using the small molecule inhibitor Cerulenin. Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of caspase -8, -9, -3 and PARP; moreover, the pan-caspase inhibitor Z-VAD-FMK did not inhibit Cerulenin-induced apoptosis and cell death. In addition, treatment of MM cells with Cerulenin primarily up-regulated apoptosis-inducing factor/endonuclease G, mediators of caspase-independent apoptosis. Importantly, Cerulenin induced endoplasmic reticulum stress response via up-regulation of the Grp78/IRE1α/JNK pathway. Although the C-Jun-NH2-terminal kinase (JNK) inhibitor SP600215 blocked Cerulenin-induced cytotoxicity, it did not inhibit apoptosis and caspase cleavage. Furthermore, Cerulenin showed synergistic cytotoxic effects with various agents including Bortezomib, Melphalan and Doxorubicin. Our results therefore indicate that inhibition of FAS by Cerulenin primarily triggered caspase-independent apoptosis and JNK-dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti-tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM

Ectonucleotidase activity and immunosuppression in astrocyte-CD4 T cell bidirectional signaling

Astrocytes play a crucial role in neuroinflammation as part of the glia limitans, which regulates infiltration of the brain parenchyma by leukocytes. The signaling pathways and molecular events, which result from the interaction of activated T cells with astrocytes are poorly defined. Here we show that astrocytes promote the expression and enzymatic activity of CD39 and CD73 ectonucleotidases in recently activated CD4 cells by a contact dependent mechanism that is independent of T cell receptor interaction with class II major histocompatibility complex (MHC). Transforming growth factor-β (TGF-β) is robustly upregulated and sufficient to promote ectonucleotidases expression. T cell adhesion to astrocyte results in differentiation to an immunosuppressive phenotype defined by expression of the transcription factor Rorγt, which characterizes the CD4 T helper 17 subset. CD39 activity in T cells in turn inhibits spontaneous calcium oscillations in astrocytes that correlated with enhanced and reduced transcription of CCL2 chemokine and Sonic hedgehog (Shh), respectively. We hypothesize this TCR-independent interaction promote an immunosuppressive program in T cells to control possible brain injury by deregulated T cell activation during neuroinflammation. On the other hand, the increased secretion of CCL2 with concomitant reduction of Shh might promote leukocytes extravasation into the brain parenchyma

Obras maestras en la colección del Museo de Sitio de Pachacamac

Importante publicación sobre la colección del museo y de la investigación arqueológica que le dio lugar, así también del sitio arqueológico y su historia. Se establece también una relación de las piezas del museo que se encuentran en el registro nacional, y contribuye a la defensa y protección de nuestro patrimonio cultural

The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020

To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019