Current therapeutic approaches to equine protozoal myeloencephalitis

Equine protozoal myeloencephalitis is the most important infectious neurologic disease of horses in the Western Hemisphere. Equine protozoal myeloencephalitis can interfere with a horse\u27s ability to race, work, and perform; untreated, EPM can be lethal. Antemortem diagnosis of EPM is challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Therapeutic approaches to EPM are evolving. First-generation therapeutic approaches for EPM were based on the classic anti–Toxoplasma gondii pyrimethamine–sulfonamide combinations; treatment is prolonged and can be associated with a considerable relapse rate, which may be associated with the difficulty in maintaining effective CNS concentrations of pyrimethamine. Second-generation therapeutic approaches are based on diclazuril and related triazine agentsa; in 2001, toltrazuril sulfoneb (ponazuril) became the first FDA-approved treatment for EPM. Triazine agents may have prolonged plasma half-lives, and their therapeutic efficacy would likely be enhanced by application of loading-dose schedules. A pyrimethamine-sulfonamide combination formulationc received FDA approval in 2004 for the treatment of EPM. Additionally, a diclazuril-based topical feed dressing formulationd received FDA approval in 2011. The ideal therapeutic agents for use against EPM would be effective when administered orally, with high efficacy against Sarcocystis neurona and minimal toxicity for horses. This article reviews the current information available for EPM, including the clinical pharmacology and efficacy of FDA-approved and nonapproved investigational medications for the treatment or prophylaxis of EPM. Equine protozoal myeloencephalitis is caused by 2 apicomplexan protozoal parasites: S neurona and, much less commonly, Neospora hughesi. Location of the causative organism in the CNS is random, so clinical signs of EPM are highly variable. Any combination of neurologic signs is possible, although spinal cord involvement is most common. Onset may be gradual or acute, with the usual pattern being mild clinical signs that progress with time. Furthermore, the intracellular localization of the causative organisms in the CNS creates difficulties for chemotherapeutic approaches and may also interfere with host-based immunologic defenses. Antemortem diagnosis of EPM is particularly challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Definitive diagnosis of EPM is dependent on necropsy detection of typical CNS lesions of the disease or presence of the appropriate causative organisms. Although careful clinical examination remains the most important antemortem diagnostic technique for EPM, laboratory methods have been developed to assist clinical diagnosis. As such, for horses with clinical signs consistent with EPM, it is optimal to perform immunoblotting, an indirect florescent antibody test, or ELISA analyses on blood and CSF samples prior to diagnosis and initiation of treatment. Preventative approaches to EPM are not well defined. Prevention of EPM with daily pyrantel tartratee administration at the current labeled dose has not been effective in immunocompetent horses1 or in interferon-γ knockout mice,2 even though the compound is active against S neurona in vitro.3 An EPM vaccine based on homogenates of S neurona merozoites with conditional licensure has been marketed for prevention of EPM, but this vaccine was removed from the market due to lack of efficacy data in prospective studies

Spatiotemporal Variability in Allee Effects of Invading Gypsy Moth Populations

The Allee threshold, the critical population density separating growth from decline in populations experiencing strong Allee effects, can vary over space and time but few empirical studies have examined this variation. A lack of geographically extensive, long-term studies on low density population dynamics makes studying variability in Allee effects difficult. We used North American gypsy moth population data from 1996-2016 to quantify Allee thresholds in 11 regions of the invasion front. Allee thresholds spanned a continuum from being undetectable due to strong population growth at all densities, to being unmeasurable because populations declined across all densities. The lag-1 temporal autocorrelation in Allee thresholds tended to be negative and spatial synchrony in Allee thresholds extended no further than adjacent regions. This work furthers understanding of spatiotemporal variation in Allee effects using extensive empirical data at the range edge of an invasive insect

The ALMA Early Science View of FUor/EXor Objects - V. Continuum Disc Masses and Sizes

Low-mass stars build a significant fraction of their total mass during short outbursts of enhanced accretion known as FUor and EXor outbursts. FUor objects are characterized by a sudden brightening of ∼5 mag at visible wavelengths within 1 yr and remain bright for decades. EXor objects have lower amplitude outbursts on shorter time-scales. Here we discuss a 1.3 mm Atacama Large Millimeter/submillimeter Array (ALMA) mini-survey of eight outbursting sources (three FUors, four EXors, and the borderline object V1647 Ori) in the Orion Molecular Cloud. While previous papers in this series discuss the remarkable molecular outflows observed in the three FUor objects and V1647 Ori, here we focus on the continuum data and the differences and similarities between the FUor and EXor populations. We find that FUor discs are significantly more massive (∼80–600 MJup) than the EXor objects (∼0.5–40 MJup). We also report that the EXor sources lack the prominent outflows seen in the FUor population. Even though our sample is small, the large differences in disc masses and outflow activity suggest that the two types of objects represent different evolutionary stages. The FUor sources seem to be rather compact (Rc \u3c 20–40 au) and to have a smaller characteristic radius for a given disc mass when compared to T Tauri stars. V1118 Ori, the only known close binary system in our sample, is shown to host a disc around each one of the stellar components. The disc around HBC 494 is asymmetric, hinting at a structure in the outer disc or the presence of a second disc

Physicochemical properties of whole milk powder derived from cows fed pasture or total mixed ration diets

peer-reviewedThis study examined the effect of dietary factors on compositional and functional properties of whole milk powder (WMP) produced from bovine milk. Raw milk samples were obtained from 3 groups of 18 Holstein Friesian spring-calving cows randomly assigned to diets based on perennial ryegrass (GRS), perennial ryegrass/white clover sward (CLV), and total mixed ration (TMR). Raw milks obtained in late lactation were subsequently standardized for fat, heat-treated (90°C for 30 s), evaporated, and homogenized before spray drying. The WMP produced from each diet were analyzed to determine differences in color, particle size distribution, heat coagulation time, yogurt gelation, texture profile, and protein profile due to each diet. Significant differences in heat coagulation time were observed between the CLV and TMR samples, whereas color values were significantly different between GRS and TMR samples. No significant differences in gross composition, protein profile, or whey protein nitrogen index were found between the 3 WMP samples. Average D90 values (the particle size at which 90% of the particles were smaller than the specified size) for fat globules were significantly lower in the TMR sample compared with the GRS and CLV samples. Yogurts produced from GRS- and CLV-derived WMP had significantly higher elastic moduli (G′) than those produced from TMR-derived WMP. Similarly, texture profile analysis revealed significantly higher firmness values in yogurt samples derived from CLV compared with TMR samples. Our data characterize the effect of these diets on the composition and functional properties of fat-standardized WMP, suggesting better yogurt functionality and thermal stability in WMP derived from pasture-based bovine diets

IN-SYNC. V. Stellar kinematics and dynamics in the Orion A Molecular Cloud

The kinematics and dynamics of young stellar populations enable us to test theories of star formation. With this aim, we continue our analysis of the SDSS-III/APOGEE IN-SYNC survey, a high resolution near infrared spectroscopic survey of young clusters. We focus on the Orion A star-forming region, for which IN-SYNC obtained spectra of $\sim2700$ stars. In Paper IV we used these data to study the young stellar population. Here we study the kinematic properties through radial velocities ($v_r$). The young stellar population remains kinematically associated with the molecular gas, following a $\sim10\:{\rm{km\:s}}^{-1}$ gradient along filament. However, near the center of the region, the $v_r$ distribution is slightly blueshifted and asymmetric; we suggest that this population, which is older, is slightly in foreground. We find evidence for kinematic subclustering, detecting statistically significant groupings of co-located stars with coherent motions. These are mostly in the lower-density regions of the cloud, while the ONC radial velocities are smoothly distributed, consistent with it being an older, more dynamically evolved cluster. The velocity dispersion $\sigma_v$ varies along the filament. The ONC appears virialized, or just slightly supervirial, consistent with an old dynamical age. Here there is also some evidence for on-going expansion, from a $v_r$--extinction correlation. In the southern filament, $\sigma_v$ is $\sim2$--$3$ times larger than virial in the L1641N region, where we infer a superposition along the line of sight of stellar sub-populations, detached from the gas. On the contrary, $\sigma_v$ decreases towards L1641S, where the population is again in agreement with a virial state.Comment: 14 pages, 13 figures, ApJ accepte

Developing a weighted measure of speech sound accuracy

Purpose: To develop a system for numerically quantifying a speaker's phonetic accuracy through transcription-based measures. With a focus on normal and disordered speech in children, the authors describe a system for differentially weighting speech sound errors on the basis of various levels of phonetic accuracy using a Weighted Speech Sound Accuracy ( WSSA) score. The authors then evaluate the reliability and validity of this measure. Method: Phonetic transcriptions were analyzed from several samples of child speech, including preschoolers and young adolescents with and without speech sound disorders and typically developing toddlers. The new measure of phonetic accuracy was validated against existing measures, was used to discriminate typical and disordered speech production, and was evaluated to examine sensitivity to changes in phonetic accuracy over time. Reliability between transcribers and consistency of scores among different word sets and testing points are compared. Results: Initial psychometric data indicate that WSSA scores correlate with other measures of phonetic accuracy as well as listeners' judgments of the severity of a child's speech disorder. The measure separates children with and without speech sound disorders and captures growth in phonetic accuracy in toddlers' speech over time. The measure correlates highly across transcribers, word lists, and testing points. Conclusion: Results provide preliminary support for the WSSA as a valid and reliable measure of phonetic accuracy in children's speech. O ne of the continuing needs in the fields of developmental phonology and speech-language pathology is for accurate, sensitive, and viable measures of speech production for research and clinical practice Measurement issues are not trivial. A recent study of "independent measures" used to describe the productive phonology of toddlers withou

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Lifetime Racial/Ethnic Discrimination and Ambulatory Blood Pressure: The Moderating Effect of Age

Objective To determine if the relationships of lifetime discrimination to ambulatory blood pressure (ABP) varied as a function of age in a sample of Black and Latino(a) adults ages 19 – 65. Methods Participants were 607 Black (n = 318) and Latino(a) (n = 289) adults (49% female) who completed the Perceived Ethnic Discrimination Questionnaire-Community Version (PEDQ-CV), which assesses lifetime exposure to racism/ethnic discrimination. They were outfitted with an ABP monitor to assess systolic and diastolic blood pressure (SBP, DBP) across a 24-hour period. Mixed-level modeling was conducted to examine potential interactive effects of lifetime discrimination and age to 24-hour, daytime, and nighttime ABP after adjustment for demographic, socioeconomic, personality and life stress characteristics, and substance consumption covariates (e.g., smoking, alcohol). Results There were significant interactions of Age × Lifetime Discrimination on 24-hour and daytime DBP (ps ≤ .04), and in particular significant interactions for the Social Exclusion component of Lifetime Discrimination. Post-hoc probing of the interactions revealed the effects of Lifetime Discrimination on DBP were seen for older, but not younger participants. Lifetime discrimination was significantly positively associated with nocturnal SBP, and these effects were not moderated by age. All associations of Lifetime Discrimination to ABP remained significant controlling for recent exposure to discrimination as well as all other covariates. Conclusions Exposure to racial/ethnic discrimination across the life course is associated with elevated ABP in middle to older aged Black and Latino(a) adults. Further research is needed to understand the mechanisms linking discrimination to ABP over the life course

Next Generation Very Large Array Memo No. 6, Science Working Group 1: The Cradle of Life

This paper discusses compelling science cases for a future long-baseline interferometer operating at millimeter and centimeter wavelengths, like the proposed Next Generation Vary Large Array (ngVLA). We report on the activities of the Cradle of Life science working group, which focused on the formation of low- and high-mass stars, the formation of planets and evolution of protoplanetary disks, the physical and compositional study of Solar System bodies, and the possible detection of radio signals from extraterrestrial civilizations. We propose 19 scientific projects based on the current specification of the ngVLA. Five of them are highlighted as possible Key Science Projects: (1) Resolving the density structure and dynamics of the youngest HII regions and high-mass protostellar jets, (2) Unveiling binary/multiple protostars at higher resolution, (3) Mapping planet formation regions in nearby disks on scales down to 1 AU, (4) Studying the formation of complex molecules, and (5) Deep atmospheric mapping of giant planets in the Solar System. For each of these projects, we discuss the scientific importance and feasibility. The results presented here should be considered as the beginning of a more in-depth analysis of the science enabled by such a facility, and are by no means complete or exhaustive.Comment: 51 pages, 12 figures, 1 table. For more information visit https://science.nrao.edu/futures/ngvl