Geophysical Exploration of Vesta

Dawn’s year-long stay at Vesta allows comprehensive mapping of the shape, topography, geology, mineralogy, elemental abundances, and gravity field using it’s three instruments and highprecision spacecraft navigation. In the current Low Altitude Mapping Orbit (LAMO), tracking data is being acquired to develop a gravity field expected to be accurate to degree and order ~20 [1, 2]. Multi-angle imaging in the Survey and High Altitude Mapping Orbit (HAMO) has provided adequate stereo coverage to develop a shape model accurate to ~10 m at 100 m horizontal spatial resolution. Accurate mass determination combined with the shape yields a more precise value of bulk density, albeit with some uncertainty resulting from the unmeasured seasonally-dark north polar region. The shape and gravity of Vesta can be used to infer the interior density structure and investigate the nature of the crust, informing models for Vesta’s formation and evolution

Antigiardial activity of novel guanidine compounds

From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter-screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC50<5 μM, seven with IC50<1.0 μM. Most active were 2,2′-bis{[4-(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride (30), 2,2′-bis{[4-(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride (32), and 2,2′-bis[(2-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride (41) with IC50=0.2 μM. The maximal observed activity was a 5 h IC50 value of 0.2 μM for 41. The clinically used metronidazole was inactive at this timepoint at a concentration of 25 μM. Robenidine off-target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41, no Giardia regrowth was noted after 48 h

Bound states between dark matter particles and emission of gravitational radiation

Bound states of two weakly interactive massive particles are studied. It is assumed that the WIMPonium is formed due to the gravitational interaction, since the weak interaction can sometimes be repulsive. The lifetimes of the spontaneous emission of gravitational radiation and of the WIMPs annihilation into a pair of gravitons are computed, and are shown to be many orders of magnitude larger than the age of the universe.Comment: Accepted for publication in GER

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens

Published: 23 September 2022Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs &gt; 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.Hongfei Pi, Henrietta Venter, Cecilia C. Russell, Kelly A. Young, Adam McCluskey, Stephen W. Page, Abiodun D. Ogunniyi and Darren J. Trot

K-ras Mutation Targeted to Gastric Tissue Progenitor Cells Results in Chronic Inflammation, an Altered Microenvironment, and Progression to Intraepithelial

Chronic infectious diseases, such as Helicobacter pylori infection, can promote cancer in a large part through induction of chronic inflammation. Oncogenic K-ras mutation in epithelial cells activates inflammatory pathways, which could compensate for a lack of infectious stimulus. Gastric histopathology and putative progenitor markers [doublecortin and calcium/calmodulin-dependent protein kinase-like 1 (Dcamkl1) and keratin 19 (K19)] in K19-K-ras-V12 (K19-kras) transgenic mice were assessed at 3, 6, 12, and 18 months of age, in comparison with Helicobacter felis–infected wild-type littermates. Inflammation was evaluated by reverse transcription–PCR of proinflammatory cytokines, and K19-kras mice were transplanted with green fluorescent protein (GFP)–labeled bone marrow. Both H. felis infection and K-ras mutation induced upregulation of proinflammatory cytokines, expansion of Dcamkl1+ cells, and progression to oxyntic atrophy, metaplasia, hyperplasia, and high-grade dysplasia. K19-kras transgenic mice uniquely displayed mucous metaplasia as early as 3 months and progressed to high-grade dysplasia and invasive intramucosal carcinoma by 20 months. In bone marrow–transplanted K19-kras mice that progressed to dysplasia, a large proportion of stromal cells were GFP+ and bone marrow–derived, but only rare GFP+ epithelial cells were observed. GFP+ bone marrow–derived cells included leukocytes and CD45− stromal cells that expressed vimentin or α smooth muscle actin and were often found surrounding clusters of Dcamkl1+ cells at the base of gastric glands. In conclusion, the expression of mutant K-ras in K19+ gastric epithelial cells can induce chronic inflammation and promote the development of dysplasia.National Institutes of Health (U.S.) (Grant NIH 5R01 CA120979-02)National Institutes of Health (U.S.) (Grant R01 DK060694)National Institutes of Health (U.S.) (Grant U01 CA143056)National Institutes of Health (U.S.) (Grant P30 DK050306)Uehara Memorial Foundatio

Affleck-Dine dynamics and the dark sector of pangenesis

Pangenesis is the mechanism for jointly producing the visible and dark matter asymmetries via Affleck-Dine dynamics in a baryon-symmetric universe. The baryon-symmetric feature means that the dark asymmetry cancels the visible baryon asymmetry and thus enforces a tight relationship between the visible and dark matter number densities. The purpose of this paper is to analyse the general dynamics of this scenario in more detail and to construct specific models. After reviewing the simple symmetry structure that underpins all baryon-symmetric models, we turn to a detailed analysis of the required Affleck-Dine dynamics. Both gravity-mediated and gauge-mediated supersymmetry breaking are considered, with the messenger scale left arbitrary in the latter, and the viable regions of parameter space are determined. In the gauge-mediated case where gravitinos are light and stable, the regime where they constitute a small fraction of the dark matter density is identified. We discuss the formation of Q-balls, and delineate various regimes in the parameter space of the Affleck-Dine potential with respect to their stability or lifetime and their decay modes. We outline the regions in which Q-ball formation and decay is consistent with successful pangenesis. Examples of viable dark sectors are presented, and constraints are derived from big bang nucleosynthesis, large scale structure formation and the Bullet cluster. Collider signatures and implications for direct dark matter detection experiments are briefly discussed. The following would constitute evidence for pangenesis: supersymmetry, GeV-scale dark matter mass(es) and a Z' boson with a significant invisible width into the dark sector.Comment: 51 pages, 7 figures; v2: minor modifications, comments and references added; v3: minor changes, matches published versio

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi

Discovery of 4,6-bis(2-((E)-benzylidene)hydrazinyl)pyrimidin-2-Amine with antibiotic activity

Robenidine (E)-N'-((E)-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant Staphyoccoccus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL-1. Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2-NH2 triazine moiety saw a 10-fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4-BrPh and 4-CH3Ph with MIC values of 2 and 4 μg mL-1, against MRSA and VRE respectively, are promising candidates for future development.Cecilia C. Russe, Andrew Stevens, Kelly A. Young, Jennifer R. Baker ... Manouchehr Khazandi ... Abiodun Ogunniyi ... et al

Implementation of a transitional care model for stroke: Perspectives from frontline clinicians, administrators, and COMPASS-TC implementation staff

Background and Objectives: Stroke is a chronic, complex condition that disproportionally affects older adults. Health systems are evaluating innovative transitional care (TC) models to improve outcomes in these patients. The Comprehensive Post-Acute Stroke Services (COMPASS) Study, a large cluster-randomized pragmatic trial, tested a TC model for patients with stroke or transient ischemic attack discharged home from the hospital. The implementation of COMPASS-TC in complex real-world settings was evaluated to identify successes and challenges with integration into the clinical workflow. Research Design and Methods: We conducted a concurrent process evaluation of COMPASS-TC implementation during the first year of the trial. Qualitative data were collected from 4 sources across 19 intervention hospitals. We analyzed transcripts from 43 conference calls with hospital clinicians, individual and group interviews with leaders and clinicians from 9 hospitals, and 2 interviews with the COMPASS-TC Director of Implementation using iterative thematic analysis. Themes were compared to the domains of the RE-AIM framework. Results: Organizational, individual, and community factors related to Reach, Adoption, and Implementation were identified. Organizational readiness was an additional key factor to successful implementation, in that hospitals that were not "organizationally ready" had more difficulty addressing implementation challenges. Discussion and Implications: Multifaceted TC models are challenging to implement. Facilitators of implementation were organizational commitment and capacity, prioritizing implementation of innovative delivery models to provide comprehensive care, being able to address challenges quickly, implementing systems for tracking patients throughout the intervention, providing clinicians with autonomy and support to address challenges, and adequately resourcing the intervention. Clinical Trial Registration: NCT02588664

Observation of a Complex Solar Wind Reconnection Exhaust from Spacecraft Separated by over 1800 R E

We analyze Wind, ACE, and STEREO (ST-A and ST-B) plasma and magnetic field data in the vicinity of the heliospheric current sheet (HCS) crossed by all spacecraft between 22:15 UT on 31 March and 01:25 UT on 1 April 2007 corresponding to its observation at ST-A and ST-B, which were separated by over 1800 R E (or over 1200 R E across the Sun – Earth line). Although only Wind and ACE provided good ion flow data in accord with a solar wind magnetic reconnection exhaust at the HCS, the magnetic field bifurcation typical of such exhausts was clearly observed at all spacecraft. They also all observed unambiguous strahl mixing within the exhaust, consistent with the sunward flow deflection observed at Wind and ACE and thus with the formation of closed magnetic field lines within the exhaust with both ends attached to the Sun. The strong dawnward flow deflection in the exhaust is consistent with the exhaust and X-line orientations obtained from minimum variance analysis at each spacecraft so that the X-line is almost along the GSE Z-axis and duskward of all the spacecraft. The observation of strahl mixing in extended and intermittent layers outside the exhaust by ST-A and ST-B is consistent with the formation of electron separatrix layers surrounding the exhaust. This event also provides further evidence that balanced parallel and antiparallel suprathermal electron fluxes are not a necessary condition for identification of closed field lines in the solar wind. In the present case the origin of the imbalance simply is the mixing of strahls of substantially different strengths from a different solar source each side of the HCS. The inferred exhaust orientations and distances of each spacecraft relative to the X-line show that the exhaust was likely nonplanar, following the Parker spiral orientation. Finally, the separatrix layers and exhausts properties at each spacecraft suggest that the magnetic reconnection X-line location and/or reconnection rate were variable in both space and time at such large scales