Linked 3-D modelling of megathrust earthquake-tsunami events: from subduction to tsunami run up

How does megathrust earthquake rupture govern tsunami behaviour? Recent modelling advances permit evaluation of the influence of 3-D earthquake dynamics on tsunami genesis, propagation, and coastal inundation. Here, we present and explore a virtual laboratory in which the tsunami source arises from 3-D coseismic seafloor displacements generated by a dynamic earthquake rupture model. This is achieved by linking open-source earthquake and tsunami computational models that follow discontinuous Galerkin schemes and are facilitated by highly optimized parallel algorithms and software. We present three scenarios demonstrating the flexibility and capabilities of linked modelling. In the first two scenarios, we use a dynamic earthquake source including time-dependent spontaneous failure along a 3-D planar fault surrounded by homogeneous rock and depth-dependent, near-lithostatic stresses. We investigate how slip to the trench influences tsunami behaviour by simulating one blind and one surface-breaching rupture. The blind rupture scenario exhibits distinct earthquake characteristics (lower slip, shorter rupture duration, lower stress drop, lower rupture speed), but the tsunami is similar to that from the surface-breaching rupture in run-up and length of impacted coastline. The higher tsunami-generating efficiency of the blind rupture may explain how there are differences in earthquake characteristics between the scenarios, but similarities in tsunami inundation patterns. However, the lower seafloor displacements in the blind rupture result in a smaller displaced volume of water leading to a narrower inundation corridor inland from the coast and a 15 per cent smaller inundation area overall. In the third scenario, the 3-D earthquake model is initialized using a seismo-thermo-mechanical geodynamic model simulating both subduction dynamics and seismic cycles. This ensures that the curved fault geometry, heterogeneous stresses and strength and material structure are consistent with each other and with millions of years of modelled deformation in the subduction channel. These conditions lead to a realistic rupture in terms of velocity and stress drop that is blind, but efficiently generates a tsunami. In all scenarios, comparison with the tsunamis sourced by the time-dependent seafloor displacements, using only the time-independent displacements alters tsunami temporal behaviour, resulting in later tsunami arrival at the coast, but faster coastal inundation. In the scenarios with the surface-breaching and subduction-initialized earthquakes, using the time-independent displacements also overpredicts run-up. In the future, the here presented scenarios may be useful for comparison of alternative dynamic earthquake-tsunami modelling approaches or linking choices, and can be readily developed into more complex applications to study how earthquake source dynamics influence tsunami genesis, propagation and inundation

GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma

The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes, encoding proteins involved in microtubule dynamics, such as MAP2, MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53. These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability

Coupled, Physics-Based Modeling Reveals Earthquake Displacements are Critical to the 2018 Palu, Sulawesi Tsunami

The September 2018, Mw 7.5 Sulawesi earthquake occurring on the Palu-Koro strike-slip fault system was followed by an unexpected localized tsunami. We show that direct earthquake-induced uplift and subsidence could have sourced the observed tsunami within Palu Bay. To this end, we use a physics-based, coupled earthquake–tsunami modeling framework tightly constrained by observations. The model combines rupture dynamics, seismic wave propagation, tsunami propagation and inundation. The earthquake scenario, featuring sustained supershear rupture propagation, matches key observed earthquake characteristics, including the moment magnitude, rupture duration, fault plane solution, teleseismic waveforms and inferred horizontal ground displacements. The remote stress regime reflecting regional transtension applied in the model produces a combination of up to 6 m left-lateral slip and up to 2 m normal slip on the straight fault segment dipping 65∘ East beneath Palu Bay. The time-dependent, 3D seafloor displacements are translated into bathymetry perturbations with a mean vertical offset of 1.5 m across the submarine fault segment. This sources a tsunami with wave amplitudes and periods that match those measured at the Pantoloan wave gauge and inundation that reproduces observations from field surveys. We conclude that a source related to earthquake displacements is probable and that landsliding may not have been the primary source of the tsunami. These results have important implications for submarine strike-slip fault systems worldwide. Physics-based modeling offers rapid response specifically in tectonic settings that are currently underrepresented in operational tsunami hazard assessment

Flow-cytometric monitoring of disease-associated expression of 9-O-acetylated sialoglycoproteins in combination with known CD antigens, as an index for MRD in children with acute lymphoblastic leukaemia: a two-year longitudinal follow-up study

<p>Abstract</p> <p>Background</p> <p>Over expression of 9-<it>O-</it>acetylated sialoglycoproteins (Neu5,9Ac₂-GPs, abbreviated as <it>O</it>AcSGP) has been demonstrated as a disease-associated antigen on the lymphoblasts of childhood acute lymphoblastic leukaemia (ALL). Achatinin-H, a lectin, has selective affinity towards terminal 9-<it>O-</it>acetylated sialic acids-α2-6-<it>N</it>acetylated galactosamine. Exploring this affinity, enhanced expression of <it>O</it>AcSGP was observed, at the onset of disease, followed by its decrease with chemotherapy and reappearance with relapse. In spite of treatment, patients retain the diseased cells referred to as minimal residual disease (MRD) responsible for relapse. Our aim was to select a suitable template by using the differential expression of <it>O</it>AcSGP along with other known CD antigens to monitor MRD in peripheral blood (PB) and bone marrow (BM) of Indian patients with B- or T-ALL during treatment and correlate it with the disease status.</p> <p>Methods</p> <p>A two-year longitudinal follow-up study was done with 109 patients from the onset of the disease till the end of chemotherapy, treated under MCP841protocol. Paired samples of PB (n = 1667) and BM (n = 999) were monitored by flow cytometry. Three templates selected for this investigation were <it>O</it>AcSGP⁺CD10⁺CD19⁺or <it>O</it>AcSGP⁺CD34⁺CD19⁺for B-ALL and <it>O</it>AcSGP⁺CD7⁺CD3⁺for T-ALL.</p> <p>Results</p> <p>Using each template the level of MRD detection reached 0.01% for a patient in clinical remission (CR). 81.65% of the patients were in CR during these two years while the remaining relapsed. Failure in early clearance of lymphoblasts, as indicated by higher MRD, implied an elevated risk of relapse. Soaring MRD during the chemotherapeutic regimen predicted clinical relapse, at least a month before medical manifestation. Irrespective of B- or T-lineage ALL, the MRD in PB and BM correlated well.</p> <p>Conclusion</p> <p>A range of MRD values can be predicted for the patients in CR, irrespective of their lineage, being 0.03 ± 0.01% (PB) and 0.05 ± 0.015% (BM). These patients may not be stated as normal with respect to the presence of MRD. Hence, MRD study beyond two-years follow-up is necessary to investigate further reduction in MRD, thereby ensuring their disease-free survival. Therefore, we suggest use of these templates for MRD detection, during and post-chemotherapy for proper patient management strategies, thereby helping in personalizing the treatment.</p

Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence

Background: Smoke-free ordinances (SFO) have been shown to be effective public health interventions, but there is limited data on the impact SFO on lung cancer outcomes. We explored the effect of county-level SFO strength with smoking prevalence and lung cancer incidence in Indiana. Methods: We obtained county-level lung cancer incidence from the Indiana State Cancer Registry and county-level characteristics from the Indiana Tobacco Prevention and Cessation Commission's policy database between 1995 and 2016. Using generalized estimating equations, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. Results: Of Indiana's 92 counties, 24 had a SFO by 2011. In 2012, Indiana enacted a state-wide SFO enforcing at least moderate level SFO protection. Mean age-adjusted lung cancer incidence per year was 76.8 per 100,000 population and mean smoking prevalence per year was 25% during the study period. Counties with comprehensive or moderate SFO had a smoking prevalence 1.2% (95% CI [-1.88, -0.52]) lower compared with counties with weak or no SFO. Counties that had comprehensive or moderate SFO also had an 8.4 (95% CI [-11.5, -5.3]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. Conclusion: Counties with stronger smoke-free air ordinances were associated with decreased smoking prevalence and fewer new lung cancer cases per year. Strengthening SFO is paramount to decreasing lung cancer incidence

Differentiation-Dependent Secretion of Proangiogenic Factors by Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are a promising cell population for cell-based bone repair due to their proliferative potential, ability to differentiate into bone-forming osteoblasts, and their secretion of potent trophic factors that stimulate angiogenesis and neovascularization. To promote bone healing, autogenous or allogeneic MSCs are transplanted into bone defects after differentiation to varying degrees down the osteogenic lineage. However, the contribution of the stage of osteogenic differentiation upon angiogenic factor secretion is unclear. We hypothesized that the proangiogenic potential of MSCs was dependent upon their stage of osteogenic differentiation. After 7 days of culture, we observed the greatest osteogenic differentiation of MSCs when cells were cultured with dexamethasone (OM+). Conversely, VEGF protein secretion and upregulation of angiogenic genes were greatest in MSCs cultured in growth media (GM). Using conditioned media from MSCs in each culture condition, GM-conditioned media maximized proliferation and enhanced chemotactic migration and tubule formation of endothelial colony forming cells (ECFCs). The addition of a neutralizing VEGF165/121 antibody to conditioned media attenuated ECFC proliferation and chemotactic migration. ECFCs seeded on microcarrier beads and co-cultured with MSCs previously cultured in GM in a fibrin gel exhibited superior sprouting compared to MSCs previously cultured in OM+. These results confirm that MSCs induced farther down the osteogenic lineage possess reduced proangiogenic potential, thereby providing important findings for consideration when using MSCs for bone repair

Polyamine Sharing between Tubulin Dimers Favours Microtubule Nucleation and Elongation via Facilitated Diffusion

We suggest for the first time that the action of multivalent cations on microtubule dynamics can result from facilitated diffusion of GTP-tubulin to the microtubule ends. Facilitated diffusion can promote microtubule assembly, because, upon encountering a growing nucleus or the microtubule wall, random GTP-tubulin sliding on their surfaces will increase the probability of association to the target sites (nucleation sites or MT ends). This is an original explanation for understanding the apparent discrepancy between the high rate of microtubule elongation and the low rate of tubulin association at the microtubule ends in the viscous cytoplasm. The mechanism of facilitated diffusion requires an attraction force between two tubulins, which can result from the sharing of multivalent counterions. Natural polyamines (putrescine, spermidine, and spermine) are present in all living cells and are potent agents to trigger tubulin self-attraction. By using an analytical model, we analyze the implication of facilitated diffusion mediated by polyamines on nucleation and elongation of microtubules. In vitro experiments using pure tubulin indicate that the promotion of microtubule assembly by polyamines is typical of facilitated diffusion. The results presented here show that polyamines can be of particular importance for the regulation of the microtubule network in vivo and provide the basis for further investigations into the effects of facilitated diffusion on cytoskeleton dynamics

Chimeric aptamers in cancer cell-targeted drug delivery

Aptamers are single-stranded structured oligonucleotides (DNA or RNA) that can bind to a wide range of targets ("apatopes") with high affinity and specificity. These nucleic acid ligands, generated from pools of random-sequence by an in vitro selection process referred to as systematic evolution of ligands by exponential enrichment (SELEX), have now been identified as excellent tools for chemical biology, therapeutic delivery, diagnosis, research, and monitoring therapy in real-time imaging. Today, aptamers represent an interesting class of modern Pharmaceuticals which with their low immunogenic potential mimic extend many of the properties of monoclonal antibodies in diagnostics, research, and therapeutics. More recently, chimeric aptamer approach employing many different possible types of chimerization strategies has generated more stable and efficient chimeric aptamers with aptamer-aptamer, aptamer-nonaptamer biomacromolecules (siRNAs, proteins) and aptamer-nanoparticle chimeras. These chimeric aptamers when conjugated with various biomacromolecules like locked nucleic acid (LNA) to potentiate their stability, biodistribution, and targeting efficiency, have facilitated the accurate targeting in preclinical trials. We developed LNA-aptamer (anti-nucleolin and EpCAM) complexes which were loaded in iron-saturated bovine lactofeerin (Fe-blf)-coated dopamine modified surface of superparamagnetic iron oxide (Fe3O4) nanoparticles (SPIONs). This complex was used to deliver the specific aptamers in tumor cells in a co-culture model of normal and cancer cells. This review focuses on the chimeric aptamers, currently in development that are likely to find future practical applications in concert with other therapeutic molecules and modalities