Discrete element modeling of the influences of density and confining pressure on the compression and shear behavior of granular materials

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 1998.Includes bibliographical references (leaves 94-95).by Andrew J. Walsh.M.S

An efficient numerical approach to modeling the effects of particle shape on rubble-pile dynamics

We present an approach for the inclusion of non-spherical constituents in high-resolution N-body discrete element method (DEM) simulations. We use aggregates composed of bonded spheres to model non-spherical components. Though the method may be applied more generally, we detail our implementation in the existing N-body code pkdgrav. It has long been acknowledged that non-spherical grains confer additional shear strength and resistance to flow when compared with spheres. As a result, we expect that rubble-pile asteroids will also exhibit these properties and may behave differently than comparable rubble piles composed of idealized spheres. Since spherical particles avoid some significant technical challenges, most DEM gravity codes have used only spherical particles, or have been confined to relatively low resolutions. We also discuss the work that has gone into improving performance with non-spherical grains, building on pkdgrav's existing leading-edge computational efficiency among DEM gravity codes. This allows for the addition of non-spherical shapes while maintaining the efficiencies afforded by pkdgrav's tree implementation and parallelization. As a test, we simulated the gravitational collapse of 25,000 non-spherical bodies in parallel. In this case, the efficiency improvements allowed for an increase in speed by nearly a factor of three when compared with the naive implementation. Without these enhancements, large runs with non-spherical components would remain prohibitively expensive. Finally, we present the results of several small-scale tests: spinup due to the YORP effect, tidal encounters, and the Brazil-nut Effect. In all cases, we find that the inclusion of non-spherical constituents has a measurable impact on simulation outcomes.Comment: 35 pages, 8 figure

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

The amyloid precursor protein of Alzheimer’s disease clusters at the organelle/microtubule interface on organelles that bind microtubules in an ATP dependent manner

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 11 (2016): e0147808, doi:10.1371/journal.pone.0147808.The amyloid precursor protein (APP) is a causal agent in the pathogenesis of Alzheimer’s disease and is a transmembrane protein that associates with membrane-limited organelles. APP has been shown to co-purify through immunoprecipitation with a kinesin light chain suggesting that APP may act as a trailer hitch linking kinesin to its intercellular cargo, however this hypothesis has been challenged. Previously, we identified an mRNA transcript that encodes a squid homolog of human APP770. The human and squid isoforms share 60% sequence identity and 76% sequence similarity within the cytoplasmic domain and share 15 of the final 19 amino acids at the C-terminus establishing this highly conserved domain as a functionally import segment of the APP molecule. Here, we study the distribution of squid APP in extruded axoplasm as well as in a well-characterized reconstituted organelle/microtubule preparation from the squid giant axon in which organelles bind microtubules and move towards the microtubule plus-ends. We find that APP associates with microtubules by confocal microscopy and co-purifies with KI-washed axoplasmic organelles by sucrose density gradient fractionation. By electron microscopy, APP clusters at a single focal point on the surfaces of organelles and localizes to the organelle/microtubule interface. In addition, the association of APP-organelles with microtubules is an ATP dependent process suggesting that the APP-organelles contain a microtubule-based motor protein. Although a direct kinesin/APP association remains controversial, the distribution of APP at the organelle/microtubule interface strongly suggests that APP-organelles have an orientation and that APP like the Alzheimer’s protein tau has a microtubule-based function.Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103430

COVID-19: Beyond Washing Your Hands and Social Distancing

A pandemic due to the outbreak of the COVID-19 virus was declared as of March 2020. The authors provide perspective towards preventing and/or mitigating the impact of contracting the virus known as COVID-19. The authors posit straightforward strategies that an individual could implement that may decrease the likelihood of developing COVID-19, help lessen the severity of the symptoms related to the COVID-19 and potentially mitigate the transmission of the virus. The authors consider their comments as food for thought and not as professional medical advice. If you believe you have contracted the COVID-19 virus seek the advice of your healthcare provider

Antifungal prophylaxis in chemotherapy-associated neutropenia: a retrospective, observational study

<p>Abstract</p> <p>Background</p> <p>In August 2002, the antifungal prophylaxis algorithm for neutropenic hematology/oncology (NHO) patients at the Medical Center was changed from conventional amphotericin (AMB) to an azole (AZ) based regimen (fluconazole [FLU] in low-risk and voriconazole [VOR] in high-risk patients). The aim of our study was to compare outcomes associated with the two regimens, including breakthrough fungal infection, adverse drug events, and costs.</p> <p>Methods</p> <p>Adult, non-febrile, NHO patients who received prophylactic AMB from 8/01/01-7/30/02 or AZ from 8/01/02-7/30/03 were retrospectively evaluated.</p> <p>Results</p> <p>A total of 370 patients (AMB: n = 181; AZ: n = 216) associated with 580 hospitalizations (AMB: n = 259; AZ: n = 321) were included. The incidence of probable/definite breakthrough Aspergillus infections was similar among regimens (AMB: 1.9% vs AZ: 0.6%; p=0.19). A greater incidence of mild/moderate (24.7% vs. 5.3%; p < 0.0001) and severe renal dysfunction (13.5% vs. 4.4%; p < 0.0012) was observed with AMB. In contrast, patients treated with VOR were found to have an increased rate of severe hepatic toxicity (32.5%) compared with patients treated with either AMB (22.6%) or FLU (21.4%) (p = 0.05). While the AZ period was associated with a >$9,000 increase in mean total costs/hospitalization, the mean acquisition cost associated with AZ was only$947/hospitalization more than AMB.</p> <p>Conclusion</p> <p>While an AZ-based regimen is associated with increased cost, the reduced rate of nephrotoxicity and availability of oral dosage forms, suggests that azoles be used preferentially over AMB. However, an increased rate of severe hepatic toxicity may be associated with VOR.</p

Multicenter Collaborative Study of the Interaction of Antifungal Combinations against BrowZine Journal Cover Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5−4, indicating no significant pharmacodynamic interactions for all of the strain−combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p \u3c 0.0001). Using a narrower additivity range of 1−2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found