Bostonia: The Boston University Alumni Magazine. Volume 29

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs

BUMC Annual Report

Annual report of the Boston University Medical Center

DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs

We present drug force-field recalibration (DFFR), a new method for refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast and flexible and can be easily automatized for a high-throughput regime, making it useful in drug-design projects. We tested the performance of the method in a few model systems and also in a variety of druglike molecules using reference data derived from: (i) density functional theory coupled to a self-consistent reaction field (DFT/SCRF) calculations on highly populated conformers and (ii) enhanced sampling quantum mechanical/molecular mechanics (QM/MM) where the drug is reproduced at the QM level, while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed

KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure

Capability of common SNPs to tag rare variants

Genome-wide association studies are based on the linkage disequilibrium pattern between common tagging single-nucleotide polymorphisms (SNPs) (i.e., SNPs having only common alleles) and true causal variants, and association studies with rare SNP alleles aim to detect rare causal variants. To better understand and explain the findings from both types of studies and to provide clues to improve the power of an association study with only common SNPs genotyped, we study the correlation between common SNPs and the presence of rare alleles within a region in the genome and look at the capability of common SNPs in strong linkage disequilibrium with each other to capture single rare alleles. Our results indicate that common SNPs can, to some extent, tag the presence of rare alleles and that including SNPs in strong linkage disequilibrium with each other among the tagging SNPs helps to detect rare alleles

Observations of Energetic-particle Population Enhancements along Intermittent Structures near the Sun from the Parker Solar Probe

Observations at 1 au have confirmed that enhancements in measured energetic-particle (EP) fluxes are statistically associated with "rough" magnetic fields, i.e., fields with atypically large spatial derivatives or increments, as measured by the Partial Variance of Increments (PVI) method. One way to interpret this observation is as an association of the EPs with trapping or channeling within magnetic flux tubes, possibly near their boundaries. However, it remains unclear whether this association is a transport or local effect; i.e., the particles might have been energized at a distant location, perhaps by shocks or reconnection, or they might experience local energization or re-acceleration. The Parker Solar Probe (PSP), even in its first two orbits, offers a unique opportunity to study this statistical correlation closer to the corona. As a first step, we analyze the separate correlation properties of the EPs measured by the Integrated Science Investigation of the Sun (IS⊙IS) instruments during the first solar encounter. The distribution of time intervals between a specific type of event, i.e., the waiting time, can indicate the nature of the underlying process. We find that the IS⊙IS observations show a power-law distribution of waiting times, indicating a correlated (non-Poisson) distribution. Analysis of low-energy (~15 – 200 keV/nuc) IS⊙IS data suggests that the results are consistent with the 1 au studies, although we find hints of some unexpected behavior. A more complete understanding of these statistical distributions will provide valuable insights into the origin and propagation of solar EPs, a picture that should become clear with future PSP orbits

DC-SIGN and DC-SIGNR Bind Ebola Glycoproteins and Enhance Infection of Macrophages and Endothelial Cells

AbstractEbola virus exhibits a broad cellular tropism in vitro. In humans and animal models, virus is found in most tissues and organs during the latter stages of infection. In contrast, a more restricted cell and tissue tropism is exhibited early in infection where macrophages, liver, lymph node, and spleen are major initial targets. This indicates that cellular factors other than the broadly expressed virus receptor(s) modulate Ebola virus tropism. Here we demonstrate that the C-type lectins DC-SIGN and DC-SIGNR avidly bind Ebola glycoproteins and greatly enhance transduction of primary cells by Ebola virus pseudotypes and infection by replication-competent Ebola virus. DC-SIGN and DC-SIGNR are expressed in several early targets for Ebola virus infection, including dendritic cells, alveolar macrophages, and sinusoidal endothelial cells in the liver and lymph node. While DC-SIGN and DC-SIGNR do not directly mediate Ebola virus entry, their pattern of expression in vivo and their ability to efficiently capture virus and to enhance infection indicate that these attachment factors can play an important role in Ebola transmission, tissue tropism, and pathogenesis