GHOSTS I: A New Faint very Isolated Dwarf Galaxy at D = 12 +/- 2 Mpc

We report the discovery of a new faint dwarf galaxy, GHOSTS I, using HST/ACS data from one of our GHOSTS (Galaxy Halos, Outer disks, Substructure, Thick disk, and Star clusters) fields. Its detected individual stars populate an approximately one magnitude range of its luminosity function (LF). Using synthetic color-magnitude diagrams (CMDs) to compare with the galaxy's CMD, we find that the colors and magnitudes of GHOSTS I's individual stars are most consistent with being young helium-burning and asymptotic giant branch stars at a distance of 12 +/- 2 Mpc. Morphologically, GHOSTS I appears to be actively forming stars, so we tentatively classify it as a dwarf irregular (dIrr) galaxy, although future HST observations deep enough to resolve a larger magnitude range in its LF are required to make a more secure classification. GHOSTS I's absolute magnitude is $M_V = -9.85^{+ 0.40}_{- 0.33}$, making it one of the least luminous dIrr galaxies known, and its metallicity is lower than [Fe/H] =-1.5 dex. The half-light radius of GHOSTS I is 226 +/- 38 pc and its ellipticity is 0.47 +/- 0.07, similar to Milky Way and M31 dwarf satellites at comparable luminosity. There are no luminous massive galaxies or galaxy clusters within ~ 4 Mpc from GHOSTS I that could be considered as its host, making it a very isolated dwarf galaxy in the Local Universe.Comment: 8 pages, 7 figures. Accepted for publication in Ap

An Interaction of a Magellanic Leading Arm High Velocity Cloud with the Milky Way Disk

The Leading Arm of the Magellanic System is a tidally formed HI feature extending \sim 60\arcdeg from the Magellanic Clouds ahead of their direction of motion. Using atomic hydrogen (HI) data from the Galactic All Sky-Survey (GASS), supplemented with data from the Australia Telescope Compact Array, we have found evidence for an interaction between a cloud in the Leading Arm and the Galactic disk where the Leading Arm crosses the Galactic plane. The interaction occurs at velocities permitted by Galactic rotation, which allows us to derive a kinematic distance to the cloud of 21 kpc, suggesting that the Leading Arm crosses the Galactic Plane at a Galactic radius of $R\approx 17$ kpc.Comment: 14 pages, 5 figures, accepted to Astrophysical Journal Letters. Full resolution version available at ftp://ftp.atnf.csiro.au/pub/people/nmcclure/papers/LeadingArm_apjl.pd

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

Coxiella burnetii in domestic doe goats in the United States, 2019–2020

Coxiella burnetii is a bacterial pathogen capable of causing serious disease in humans and abortions in goats. Infected goats can shed C. burnetii through urine, feces, and parturient byproducts, which can lead to infections in humans when the bacteria are inhaled. Goats are important C. burnetii reservoirs as evidenced by goat-related outbreaks across the world. To better understand the current landscape of C. burnetii infection in the domestic goat population, 4,121 vaginal swabs from 388 operations across the United States were analyzed for the presence of C. burnetii by IS1111 PCR as part of the United States Department of Agriculture, Animal Plant Health Inspection Service, Veterinary Services’ National Animal Health Monitoring System Goats 2019 Study. In total, 1.5% (61/4121) of swabs representing 10.3% (40/388) (weighted estimate of 7.8, 95% CI 4.4–13.5) of operations were positive for C. burnetii DNA. The quantity of C. burnetii on positive swabs was low with an average Ct of 37.9. Factors associated with greater odds of testing positive included suspected Q fever in the herd in the previous 3 years, the presence of wild deer or elk on the operation, and the utilization of hormones for estrus synchronization. Factors associated with reduced odds of testing positive include the presence of kittens and treatment of herds with high tannin concentrate plants, diatomaceous earth, and tetrahydropyrimidines. In vitro analysis demonstrated an inhibitory effect of the tetrahydropyrimidine, pyrantel pamoate, on the growth of C. burnetii in axenic media as low as 1 μg per mL. The final multivariable logistic regression modeling identified the presence of wild predators on the operation or adjacent property (OR = 9.0, 95% CI 1.3–61.6, p value = 0.0248) as a risk factor for C. burnetii infection

Integration of genomic and other epidemiologic data to investigate and control a cross-institutional outbreak of Streptococcus pyogenes outbrea

Single-strain outbreaks of Streptococcus pyogenes infections are common and often go undetected. In 2013, two clusters of invasive group A Streptococcus (iGAS) infection were identified in independent but closely located care homes in Oxfordshire, United Kingdom. Investigation included visits to each home, chart review, staff survey, microbiologic sampling, and genome sequencing. S. pyogenes emm type 1.0, the most common circulating type nationally, was identified from all cases yielding GAS isolates. A tailored whole-genome reference population comprising epidemiologically relevant contemporaneous isolates and published isolates was assembled. Data were analyzed independently using whole-genome multilocus sequencing and single-nucleotide polymorphism analyses. Six isolates from staff and residents of the homes formed a single cluster that was separated from the reference population by both analytical approaches. No further cases occurred after mass chemoprophylaxis and enhanced infection control. Our findings demonstrate the ability of 2 independent analytical approaches to enable robust conclusions from nonstandardized whole-genome analysis to support public health practice

Assessing nonresponse bias at follow-up in a large prospective cohort of relatively young and mobile military service members

<p>Abstract</p> <p>Background</p> <p>Nonresponse bias in a longitudinal study could affect the magnitude and direction of measures of association. We identified sociodemographic, behavioral, military, and health-related predictors of response to the first follow-up questionnaire in a large military cohort and assessed the extent to which nonresponse biased measures of association.</p> <p>Methods</p> <p>Data are from the baseline and first follow-up survey of the Millennium Cohort Study. Seventy-six thousand, seven hundred and seventy-five eligible individuals completed the baseline survey and were presumed alive at the time of follow-up; of these, 54,960 (71.6%) completed the first follow-up survey. Logistic regression models were used to calculate inverse probability weights using propensity scores.</p> <p>Results</p> <p>Characteristics associated with a greater probability of response included female gender, older age, higher education level, officer rank, active-duty status, and a self-reported history of military exposures. Ever smokers, those with a history of chronic alcohol consumption or a major depressive disorder, and those separated from the military at follow-up had a lower probability of response. Nonresponse to the follow-up questionnaire did not result in appreciable bias; bias was greatest in subgroups with small numbers.</p> <p>Conclusions</p> <p>These findings suggest that prospective analyses from this cohort are not substantially biased by non-response at the first follow-up assessment.</p

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

HI Clouds in the Lower Halo: I. The Galactic All-Sky Survey Pilot Region

We have detected over 400 HI clouds in the lower halo of the Galaxy within the pilot region of the Galactic All-Sky Survey (GASS), a region of the fourth quadrant that spans 18 degrees in longitude, 40 degrees in latitude and is centered on the Galactic equator. These clouds have a median peak brightness temperature of 0.6 K, a median velocity width of 12.8 km/s, and angular sizes <1 degree. The motion of these clouds is dominated by Galactic rotation with a random cloud-to-cloud velocity dispersion of 18 km/s. A sample of clouds likely to be near tangent points was analyzed in detail. These clouds have radii on the order of 30 pc and a median HI mass of 630 Msun. The population has a vertical scale height of 400 pc and is concentrated in Galactocentric radius, peaking at R=3.8 kpc. This confined structure suggests that the clouds are linked to spiral features, while morphological evidence that many clouds are aligned with loops and filaments is suggestive of a relationship with star formation. The clouds might result from supernovae and stellar winds in the form of fragmenting shells and gas that has been pushed into the halo rather than from a galactic fountain.Comment: 16 pages. Accepted for publication in Ap

Species-Specific Structural Requirements of Alpha-Branched Trehalose Diester Mincle Agonists

Despite the ever present need for an effective Mycobacterium tuberculosis (Mtb) vaccine, efforts for development have been largely unsuccessful. Correlates of immune protection against Mtb are not wholly defined, but Th1 and likely Th17 adaptive immune responses have been demonstrated to be necessary for vaccine-mediated protection. Unfortunately, no approved adjuvants are able to drive a Th17 response, though recent clinical trials with CAF01 have demonstrated proof of concept. Herein we present the discovery and characterization of a new class of potential Th17-inducing vaccine adjuvants, alpha-branched trehalose diester molecules (αTDE). Based off the Mtb immunostimulatory component trehalose dimycolate (TDM), we synthesized and evaluated the immunostimulatory capacity of a library of structural derivatives. We evaluated the structure activity relationship of the compounds in relation to chain length and engagement of the Mincle receptor, production of innate cytokines from human and murine cells, and a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells. Murine cells displayed more structural tolerance, engaging and responding to a wide array of compound chain lengths. Interestingly, human cells displayed a unique specificity for ester chains between 5 and 14 carbons for maximal immune stimulating activity. Evaluation of two distinct αTDEs, B16 and B42, in concert with a recombinant Mtb antigen demonstrated their ability to augment a Th17 immune response against a Mtb antigen in vivo. Collectively this data describes the species-specific structural requirements for maximal human activity of alpha-branched trehalose diester compounds and demonstrates their capacity to serve as potent Th17-inducing adjuvants