Attenuation of Acute Rejection in a Rat Liver Transplantation Model by a Liver-Targeted Dextran Prodrug of Methylprednisolone

Background. The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in nontarget tissues. Therefore, selective delivery of NIP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model. Methods. The model consisted of a high responder rejection strain combination (Dark Agouti donors and Lewis recipients). Liver recipients were intravenously administered saline or a single subtherapeutic dose of MP (5 mg/kg) as the parent drug (MP) or its prodrug (DMP). Different groups were then monitored for graft survival or euthanized 5 or 9 days posttransplantation. Plasma chemistry, including alkaline phosphatase and bilirubin, allograft histology, and survival duration were determined. Results. Untreated recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allografts, and a mean graft survival time (MST) of 10.5 days. MP treatment did not alter any of these parameters. In contrast, a single dose of DMP resulted in a decrease in plasma levels of liver injury markers, a decrease in histological grade of rejection on day 5, and a substantial increase in MST (27.5 days). Conclusions. These results demonstrate attenuation of acute rejection following local (allograft) immunosuppression with a single subtherapeutic dose of NIP delivered as a liver-targeted prodrug. Dextran prodrugs may be useful for selective delivery of immunosuppressants to the liver following liver transplantation

Reproductive Capacity Evolves in Response to Ecology through Common Changes in Cell Number in Hawaiian Drosophila

© 2019 Elsevier Ltd Lifetime reproductive capacity is a critical fitness component. In insects, female reproductive capacity is largely determined by the number of ovarioles, the egg-producing subunits of the ovary [e.g., 1]. Recent work has provided insights into ovariole number regulation in Drosophila melanogaster. However, whether mechanisms discovered under laboratory conditions explain evolutionary variation in natural populations is an outstanding question. We investigated potential effects of ecology on the developmental processes underlying ovariole number evolution among Hawaiian Drosophila, a large adaptive radiation wherein the highest and lowest ovariole numbers of the family have evolved within 25 million years. Previous studies proposed that ovariole number correlated with oviposition substrate [2–4] but sampled largely one clade of these flies and were limited by a provisional phylogeny and the available comparative methods. We test this hypothesis by applying phylogenetic modeling to an expanded sampling of ovariole numbers and substrate types and show support for these predictions across all major groups of Hawaiian Drosophila, wherein ovariole number variation is best explained by adaptation to specific substrates. Furthermore, we show that oviposition substrate evolution is linked to changes in the allometric relationship between body size and ovariole number. Finally, we provide evidence that the major changes in ovarian cell number that regulate D. melanogaster ovariole number also regulate ovariole number in Hawaiian drosophilids. Thus, we provide evidence that this remarkable adaptive radiation is linked to evolutionary changes in a key reproductive trait regulated at least partly by variation in the same developmental parameters that operate in the model species D. melanogaster. Organisms leaving more offspring likely have higher fitness. Sarikaya et al. use the adaptive radiation of Hawaiian Drosophila to investigate the evolution of fecundity. They find that habitat shifts played a strong role and identify a developmental process that underlies evolutionary change in ovarian development and impacts egg-laying capacity

Kepler and TESS observations of PG 1159-035

PG 1159-035 is the prototype of the PG 1159 hot (pre-)white dwarf pulsators. This important object was observed during the Kepler satellite K2 mission for 69 days in 59 s cadence mode and by the TESS satellite for 25 days in 20 s cadence mode. We present a detailed asteroseismic analysis of those data. We identify a total of 107 frequencies representing 32 ℓ = 1 modes, 27 frequencies representing 12 ℓ = 2 modes, and eight combination frequencies. The combination frequencies and the modes with very high k values represent new detections. The multiplet structure reveals an average splitting of 4.0 ± 0.4 μHz for ℓ = 1 and 6.8 ± 0.2 μHz for ℓ = 2, indicating a rotation period of 1.4 ± 0.1 days in the region of period formation. In the Fourier transform of the light curve, we find a significant peak at 8.904 ± 0.003 μHz suggesting a surface rotation period of 1.299 ± 0.002 days. We also present evidence that the observed periods change on timescales shorter than those predicted by current evolutionary models. Our asteroseismic analysis finds an average period spacing for ℓ = 1 of 21.28 ± 0.02 s. The ℓ = 2 modes have a mean spacing of 12.97 ± 0.4 s. We performed a detailed asteroseismic fit by comparing the observed periods with those of evolutionary models. The best-fit model has Teff = 129, 600 ± 11 100 K, M* = 0.565 ± 0.024M⊙, and $\mathrm{log}g={7.41}_{-0.54}^{+0.38}$, within the uncertainties of the spectroscopic determinations. We argue for future improvements in the current models, e.g., on the overshooting in the He-burning stage, as the best-fit model does not predict excitation for all of the pulsations detected in PG 1159-035

Attenuation of Acute Rejection in a Rat Liver Transplantation Model by a Liver-Targeted Dextran Prodrug of Methylprednisolone

The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in non-target tissues. Therefore, selective delivery of MP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model

Pulsating hydrogen-deficient white dwarfs and pre-white dwarfs observed with TESS : III. Asteroseismology of the DBV star GD 358

Context. The collection of high-quality photometric data by space telescopes, such as the completed Kepler mission and the ongoing TESS program, is revolutionizing the area of white-dwarf asteroseismology. Among the different kinds of pulsating white dwarfs, there are those that have He-rich atmospheres, and they are called DBVs or V777 Her variable stars. The archetype of these pulsating white dwarfs, GD 358, is the focus of the present paper. Aims. We report a thorough asteroseismological analysis of the DBV star GD 358 (TIC 219074038) based on new high-precision photometric data gathered by the TESS space mission combined with data taken from the Earth. Methods. We reduced TESS observations of the DBV star GD 358 and performed a detailed asteroseismological analysis using fully evolutionary DB white-dwarf models computed accounting for the complete prior evolution of their progenitors. We assessed the mass of this star by comparing the measured mean period separation with the theoretical averaged period spacings of the models, and we used the observed individual periods to look for a seismological stellar model. We detected potential frequency multiplets for GD 358, which we used to identify the harmonic degree (`) of the pulsation modes and rotation period. Results. In total, we detected 26 periodicities from the TESS light curve of this DBV star using standard pre-whitening. The oscillation frequencies are associated with nonradial g(gravity)-mode pulsations with periods from ∼422 s to ∼1087 s. Moreover, we detected eight combination frequencies between ∼543 s and ∼295 s. We combined these data with a huge amount of observations from the ground. We found a constant period spacing of 39.25 ± 0.17 s, which helped us to infer its mass (M? = 0.588 ± 0.024 M ) and constrain the harmonic degree ` of the modes. We carried out a period-fit analysis on GD 358, and we were successful in finding an asteroseismological model with a stellar mass (M? = 0.584+0.025 −0.019 M ), compatible with the stellar mass derived from the period spacing, and in line with the spectroscopic mass (M? = 0.560 ± 0.028M ). In agreement with previous works, we found that the frequency splittings vary according to the radial order of the modes, suggesting differential rotation. Obtaining a seismological model made it possible to estimate the seismological distance (dseis = 42.85 ± 0.73 pc) of GD 358, which is in very good accordance with the precise astrometric distance measured by Gaia EDR3 (π = 23.244 ± 0.024, dGaia = 43.02 ± 0.04 pc). Conclusions. The high-quality data measured with the TESS space telescope, used in combination with data taken from ground-based observatories, provides invaluable information for conducting asteroseismological studies of DBV stars, analogously to what happens with other types of pulsating white-dwarf stars. The currently operating TESS mission, together with the advent of other similar space missions and new stellar surveys, will give an unprecedented boost to white dwarf asteroseismology

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

Background: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LT alpha) may be important for the development of cerebral malaria (CM) and other SM syndromes

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Development of a New Tacaribe Arenavirus Infection Model and Its Use to Explore Antiviral Activity of a Novel Aristeromycin Analog

Background A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice. Methodology/Principal Findings Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD50 of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4–8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P\u3c0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality. Conclusions/Significance MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses