Background and Purpose
Sphingosine1‐phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 ...receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non‐selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases.
Experimental Approach
The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6‐trinitrobenzenesulfonic acid colitis and CD4+CD45RBhi T cell adoptive transfer colitis) was assessed.
Key Results
RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7+ T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half‐life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models.
Conclusions and Implications
S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.
Ruminant production systems are important contributors to anthropogenic methane (CH4) emissions, but there are large uncertainties in national and global livestock CH4 inventories. Sources of ...uncertainty in enteric CH4 emissions include animal inventories, feed dry matter intake (DMI), ingredient and chemical composition of the diets, and CH4 emission factors. There is also significant uncertainty associated with enteric CH4 measurements. The most widely used techniques are respiration chambers, the sulfur hexafluoride (SF6) tracer technique, and the automated head-chamber system (GreenFeed; C-Lock Inc., Rapid City, SD). All 3 methods have been successfully used in a large number of experiments with dairy or beef cattle in various environmental conditions, although studies that compare techniques have reported inconsistent results. Although different types of models have been developed to predict enteric CH4 emissions, relatively simple empirical (statistical) models have been commonly used for inventory purposes because of their broad applicability and ease of use compared with more detailed empirical and process-based mechanistic models. However, extant empirical models used to predict enteric CH4 emissions suffer from narrow spatial focus, limited observations, and limitations of the statistical technique used. Therefore, prediction models must be developed from robust data sets that can only be generated through collaboration of scientists across the world. To achieve high prediction accuracy, these data sets should encompass a wide range of diets and production systems within regions and globally. Overall, enteric CH4 prediction models are based on various animal or feed characteristic inputs but are dominated by DMI in one form or another. As a result, accurate prediction of DMI is essential for accurate prediction of livestock CH4 emissions. Analysis of a large data set of individual dairy cattle data showed that simplified enteric CH4 prediction models based on DMI alone or DMI and limited feed- or animal-related inputs can predict average CH4 emission with a similar accuracy to more complex empirical models. These simplified models can be reliably used for emission inventory purposes.
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► We evaluated methods of partitioning whole mitogenomes for phylogenetic analyses. ► Commonly used schemes for partitioning mitogenomic data lack explicit justification. ► Optimally ...partitioning animal mitogenomic datasets requires at least six data subgroups. ► Complete mitogenome datasets yield better resolved phylogenies than smaller samples.
Whole mitochondrial genome sequences have been used in studies of animal phylogeny for two decades, and current technologies make them ever more available, but methods for their analysis are lagging and best practices have not been established. Most studies ignore variation in base composition and evolutionary rate within the mitogenome that can bias phylogenetic inference, or attempt to avoid it by excluding parts of the mitogenome from analysis. In contrast, partitioned analyses accommodate heterogeneity, without discarding data, by applying separate evolutionary models to differing portions of the mitogenome. To facilitate use of complete mitogenomic sequences in phylogenetics, we (1) suggest a set of categories for dividing mitogenomic datasets into subsets, (2) explore differences in evolutionary dynamics among those subsets, and (3) apply a method for combining data subsets with similar properties to produce effective and efficient partitioning schemes. We demonstrate these procedures with a case study, using the mitogenomes of species in the grackles and allies clade of New World blackbirds (Icteridae). We found that the most useful categories for partitioning were codon position, RNA secondary structure pairing, and the coding/noncoding distinction, and that a scheme with nine data groups outperformed all of the more complex alternatives (up to 44 data groups) that we tested. As hoped, we found that analyses using whole mitogenomic sequences yielded much better-resolved and more strongly-supported hypotheses of the phylogenetic history of that locus than did a conventional 2-kilobase sample (i.e. sequences of the cytochrome b and ND2 genes). Mitogenomes have much untapped potential for phylogenetics, especially of birds, a taxon for which they have been little exploited except in investigations of ordinal-level relationships.
Assessing the body condition of wild animals is necessary to monitor the health of the population and is critical to defining a framework for conservation actions. Body condition indices (BCIs) are a ...non-invasive and relatively simple means to assess the health of individual animals, useful for addressing a wide variety of ecological, behavioral, and management questions. The Antillean manatee (Trichechus manatus manatus) is an endangered subspecies of the West Indian manatee, facing a wide variety of threats from mostly human-related origins. Our objective was to define specific BCIs for the subspecies that, coupled with additional health, genetic and demographic information, can be valuable to guide management decisions. Biometric measurements of 380 wild Antillean manatees captured in seven different locations within their range of distribution were obtained. From this information, we developed three BCIs (BCI
= UG/SL, BCI
= W/SL
, BCI
= W/(SL*UG
)). Linear models and two-way ANCOVA tests showed significant differences of the BCIs among sexes and locations. Although our three BCIs are suitable for Antillean manatees, BCI
is more practical as it does not require information about weight, which can be a metric logistically difficult to collect under particular circumstances. BCI
was significantly different among environments, revealing that the phenotypic plasticity of the subspecies have originated at least two ecotypes-coastal marine and riverine-of Antillean manatees.
Great-tailed Grackle (Quiscalus mexicanus) and Common Grackle (Q. quiscula) are phylogenetically distant among grackles and were historically allopatric. Northward range expansion of Great-tailed ...Grackle and westward expansion of Common Grackle brought these species into increasing contact over the past century but has not led to notable interactions. Hybrids of Great-tailed Grackle with Boat-tailed Grackle (Q. major), Brewer's Blackbird (Euphagus cyanocephalus), and Red-winged Blackbird (Agelaius phoeniceus) have been reported, whereas hybridization of Common Grackle has never been documented with any species. We report a brood of 2 hybrid offspring of a male Great-tailed Grackle and female Common Grackle in Dillon, Montana, in 2015. For about a week after their discovery, both parents defended and fed the fledglings, the latter behavior extraordinary for a male Great-tailed Grackle. Moreover, whereas the female parent was no longer seen, the male continued to feed the young for at least another 7 weeks after they left the nest tree, during which time the trio moved ∼2 km across town and the young began prebasic molt, growing iridescent blue-black secondary coverts as expected for male Great-tailed Grackle but not for Common Grackle or female Great-tailed Grackle. Analysis of DNA from a feather of one offspring confirmed that it had hybrid nuclear DNA, had Common Grackle mitochondrial DNA, and was male. In 2016, the male Great-tailed Grackle again courted a female Common Grackle that nested in his tree, a nest which he defended, but she was also attended by a male Common Grackle. She produced 5 young, all of which were genetically pure Common Grackles, not hybrids. Also notable in 2016, another male Great-tailed Grackle in the general vicinity was observed feeding young in 1 of 3 nests that he defended, suggesting that male parental care may be more common in that species than has been appreciated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
In this work, we report the discovery and analysis of six new compact triply eclipsing triple star systems found with the TESS mission: TICs 37743815, 42565581, 54060695, 178010808, ...242132789, and 456194776. All of these exhibit distinct third-body eclipses where the inner eclipsing binary (EB) occults the third (‘tertiary’) star, or vice versa. We utilized the TESS photometry, archival photometric data, and available archival spectral energy distribution curves (SED) to solve for the properties of all three stars, as well as many of the orbital elements. We describe in detail our SED fits, search of the archival data for the outer orbital period, and the final global photodynamical analyses. From these analyses, we find that all six systems are coplanar to within 0°−5°, and are viewed nearly edge on (i.e. within a couple of degrees). The outer orbital periods and eccentricities of the six systems are {Pout (days), e}: {68.7, 0.36}, {123, 0.16}, {60.7, 0.01}, {69.0, 0.29}, {41.5, 0.01}, {93.9, 0.29}, respectively, in the order the sources are listed above. The masses of all 12 EB stars were in the range of 0.7–1.8 M⊙ and were situated near the main sequence. By contrast, the masses and radii of the tertiary stars ranged from 1.5 to 2.3 M⊙ and 2.9 to 12 R⊙, respectively. We use this information to estimate the occurrence rate of compact flat triple systems..
A calibration is presented for an activity–composition model for amphiboles in the system Na2O–CaO–FeO–MgO–Al2O3–SiO2–H2O–O (NCFMASHO), formulated in terms of an independent set of six end‐members: ...tremolite, tschermakite, pargasite, glaucophane, ferroactinolite and ferritschermakite. The model uses mixing‐on‐sites for the ideal‐mixing activities, and for the activity coefficients, a macroscopic multicomponent van Laar model. This formulation involves 15 pairwise interaction energies and six asymmetry parameters. Calibration of the model is based on the geometrical constraints imposed by the size and shape of amphibole solvi inherent in a data set of 71 coexisting amphibole pairs from rocks, formed over 400–600 °C and 2–18 kbar. The model parameters are calibrated by combining these geometric constraints with qualitative consideration of parameter relationships, given that the data are insufficient to allow all the model parameters to be determined from a regression of the data. Use of coexisting amphiboles means that amphibole activity–composition relationships are calibrated independently of the thermodynamic properties of the end‐members. For practical applications, in geothermobarometry and the calculation of phase diagrams, the amphibole activity–composition relationships are placed in the context of the stability of other minerals by evaluating the properties of the end‐members in the independent set that are in internally consistent data sets. This has been performed using an extended natural data set for hornblende–garnet–plagioclase–quartz, giving the small adjustments necessary to the enthalpies of formation of tschermakite, pargasite and glaucophane for working with the Holland and Powell data set.
Grazing is the de facto method of habitat management used in much of the Nebraska Sandhills. Ranchers use a variety of grazing systems, and our goal was to evaluate the effects of systems on ...grassland birds. We estimated the species richness and density of grassland birds for three grazing systems used on private ranches: long, medium, and short duration grazing systems. We observed sixty species, and the grazing system with pastures utilizing long duration grazing periods had the highest estimates of species richness as well as the most heterogeneous habitat structure. Differences in species richness among systems were most pronounced in years of limited precipitation. Together, grasshopper sparrows (Ammodramus savannarum), western meadowlarks (Sturnella neglecta), and brown-headed cowbirds (Molothrus ater) accounted for 72% of our observations. We used a model comparison approach to determine the effects of habitat on the densities of six species. Densities of grasshopper sparrows and mourning doves showed effects of the grazing system. More species had higher densities in short duration, rotational systems than other grazing systems. However, species of grassland birds showed responses to a variety of cover types and habitat structures depending on life history needs. Regardless of the grazing system used, managers can use grazing and other tools such as prescribed burning to maintain habitat heterogeneity to support diverse bird communities.
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