A Survey of Interplanetary Small Flux Ropes at Mercury

Interplanetary magnetic flux ropes with durations from a few minutes to a few hours have been termed small flux ropes (SFRs). We have built a comprehensive catalog of SFRs at Mercury using magnetometer data from the orbital phase of the MESSENGER mission (2011–2015). In the absence of solar wind plasma measurements, we developed strict identification criteria for SFRs in the magnetometer observations, including force-free field fits for each flux rope. We identified a total of 48 events that met our strict criteria, with events ranging in duration from 2.5 minutes to 4 hr. Using superposed epoch analysis, we obtained the generic SFR magnetic field profile at Mercury. Due to its eccentric orbit, Mercury\u27s heliospheric distance varies between 0.31 and 0.47 au, a range of ∼0.16 au. This distance is potentially large enough for the SFRs to undergo measurable changes due to distance. Thus, we split the data into two distance bins to look for such changes. We found that the average SFR profile is more symmetric farther from the Sun, in line with the idea that SFRs form closer to the Sun and undergo a relaxation process in the solar wind. Based on this result, as well as the SFR durations and the magnetic field strength fall-off with heliocentric distance, we infer that the SFRs observed at Mercury are expanding as they propagate with the solar wind. We also determined that the SFR occurrence frequency is nearly four times as high at Mercury as for similarly detected events at 1 au. Most interestingly, we found two SFR populations in our data set, one likely generated in a quasi-periodic formation process near the heliospheric current sheet, and the other formed away from the current sheet in isolated events

Fall prevention and bathroom safety in the epilepsy monitoring unit.

Falls are one of the most common adverse events occurring in the epilepsy monitoring unit (EMU) and can result in significant injury. Protocols and procedures to reduce falls vary significantly between institutions as it is not yet known what interventions are effective in the EMU setting. This study retrospectively examined the frequency of falls and the impact of serial changes in fall prevention strategies utilized in the EMU between 2001 and 2014 at a single institution. Overall fall rate was 2.81 per 1000 patient days and varied annually from 0 to 9.02 per 1000 patient days. Both seizures and psychogenic nonepileptic events occurring in the bathroom were more likely to result in falls compared with events occurring elsewhere in the room. With initiation of increased patient education, hourly nurse rounding, nocturnal bed alarms, having two persons assisting for high fall risk patients when out of bed, and immediate postfall team review between 2001 and 2013, there was a trend of decreasing fall frequency; however, no specific intervention could be identified as having a particular high impact. In late 2013, a ceiling lift system extending into the bathroom was put in place for use in all EMU patients when out of bed. In the subsequent 15 months, there have been zero falls. The results reinforce both the need for diligent safety standards to prevent falls in the EMU as well as the challenges in identifying the most effective practices to achieve this goal

Development of a Novel Class of Agents Targeting the RNA-Splicing Machinery in Myeloid Malignancies

Abstract SF3B1 is a splicing factor gene whose mutations are pathognomonic of MDS with ring sideroblasts. Because of the ubiquitous importance of splicing, a major barrier in targeting cells with spliceosomal mutations is the discovery of agents decreasing the competitiveness of mutant cells while preserving the integrity of wild type cells. To date no specific therapies are FDA approved for SF3B1 mutant (SF3B1MT) MDS and few agents are in early clinical testing. We describe a novel targeted approach to drug development for SF3B1MT malignancies. Our investigative strategy started with a high throughput drug screen. We introduced K700E mutation into myeloid cells using CRISPR/Cas9. We then subjected K562+/K700E and matched-parental K562 cells to high throughput drug screen of a library of 3,000 mechanistically annotated, non-redundant, bioactive compounds. Top hits were validated by dose response testing (8 concentrations in half-log dilutions). Our interest focused on compounds with cytostatic activity towards K562+/K700E cells. Among these, a 4-pyridyl-2-anilinothiazole (PAT) showed preferential inhibition of growth in K562+/K700E cells with an IC50 of 3uM. Dose response showed that K562+/K700E cells were significantly sensitive to PAT with a growth inhibition of 20%, 32%, 51%, 65%, 95% at .3uM (P=.01), 1uM (P=.002), 3uM (P<.0001), 10uM (P<.0001), and 20uM (P=.01). High doses (10, 20uM) were toxic to parental cells. PAT treatment did not induce growth arrest in other myeloid cells (THP1, MOLM13FLT3, OCI-AML3DNMT3A, SIG-M5TET2/DNMT3A, K562PHF6) including cells with mutations in other splicing factors (K562U2AF1, K562LUC7L2). PAT induced similar effects in primary SF3B1MT MDS cells at 3uM while it did not induce significant growth inhibition in primary MDS cells with other mutations, including other spliceosomal mutations (e.g.,U2AF1) (N=6). In normal bone marrow cells (N=6), complete growth arrest of erythroid and myeloid cells was observed at high doses (20uM). Using PAT as our lead, we employed a fragment based reiterative medicinal chemistry approach to synthesize selective compounds and improve therapeutic index. Libraries were constructed following Lipinski rules with ease of synthetic construction in mind. Pilot libraries were constructed via the classic Hantsch thiazole synthesis which involves condensation of α-halo ketones with substituted thioureas. This enterprise investigated SAR modifications of PAT by considering features such as regiochemistry and basicity of the nitrogen of the pyridine ring in the head region; replacement of the spacer 2,4-disubstituted thiazole ring with heteroatom containing rings (5,6,7 membered aromatic or aliphatic ring structures); alternatives for the aniline of the tail region e.g., sulfonamide, amide, and substituted amine linkers and substituted aromatic and aliphatic ring structures for the phenyl substituent. A major challenge in drug development of agents targeting spliceosomal mutations is the identification of key clusters of aberrantly spliced genes restored by drug treatment, e.g., identification of a pharmacodynamic endpoint that could be used to prove that that the drug reached its target. SF3B1 mutations induce aberrant 3′-ss selection by promoting use of alternative branch points. To identify biomarkers of splicing changes to screen our libraries, K562+/K700E and parental cells were treated with PAT (3uM) and RNA libraries were subjected to RNA Seq. The splicing pattern of parental cells was used as reference. We identified 328 cassette exons (±25% splicing inclusion difference, pFDR<.05) in K562+/K700E cells of whom the splicing of 22 exons was partially or completely restored upon treatment. Among these, PAT treatment restored the splicing of exons in sensitive 3′-ss sequences (ENOSF1), RNA binding SR-related factors (ACIN1), zing fingers (ZC3H7A) already associated with SF3B1 downregulation, histone modifiers (HMGN3), mitochondrial genes (TMEM126B), proto-oncogenes (CREB1) and heat shock proteins (DNAJC24). Ongoing experiments include tests of the ability of PATs to restore the splicing of misspliced exons and its efficacy in reducing the percentage of SF3B1MT cells in xenografts of K562+/K700E and primary SF3B1MT cells and Sf3b1+/K700E mice. In sum, we described novel classes of compounds that inhibit the expansion of SF3B1MT cells by restoring the splicing defects intrinsically associated with SF3B1. Disclosures Carraway: Novartis: Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy

DNA vaccination before conception protects Zika virus-exposed pregnant macaques against prolonged viremia and improves fetal outcomes.

Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes