Regulation of major histocompatibility complex class II gene expression in trophoblast cells

Trophoblast cells are unique because they are one of the few mammalian cell types that do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to IFN-γ. The absence of MHC class II antigen expression on trophoblast cells has been postulated to be one of the essential mechanisms by which the semi-allogeneic fetus evades immune rejection reactions by the maternal immune system. Consistent with this hypothesis, trophoblast cells from the placentas of women suffering from chronic inflammation of unknown etiology and spontaneous recurrent miscarriages have been reported to aberrantly express MHC class II antigens. The lack of MHC class II antigen expression on trophoblast cells is due to silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and IFN-γ-inducible MHC class II gene transcription. Transfection of trophoblast cells with CIITA expression vectors activates both MHC class II and class Ia antigen expression, which confers on trophoblast cells both the ability to activate helper T cells, and sensitivity to lysis by cytotoxic T lymphocytes. Collectively, these studies strongly suggest that stringent silencing of CIITA (and therefore MHC class II) gene expression in trophoblast cells is critical for the prevention of immune rejection responses against the fetus by the maternal immune system. The focus of this review is to summarize studies examining the novel mechanisms by which CIITA is silenced in trophoblast cells. The elucidation of the silencing of CIITA in trophoblast cells may shed light on how the semi-allogeneic fetus evades immune rejection by the maternal immune system during pregnancy

Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates

Influenza virus penetrates cells by fusion of viral and endosomal membranes catalyzed by the viral hemagglutinin (HA). Structures of the initial and final states of the HA trimer define the fusion endpoints, but do not specify intermediates. We have characterized these transitions by analyzing low-pH-induced fusion kinetics of individual virions and validated the analysis by computer simulation. We detect initial engagement with the target membrane of fusion peptides from independently triggered HAs within the larger virus-target contact patch; fusion then requires engagement of three or four neighboring HA trimers. Effects of mutations in HA indicate that withdrawal of the fusion peptide from a pocket in the pre-fusion trimer is rate-limiting for both events, but the requirement for cooperative action of several HAs to bring the fusing membranes together leads to a long-lived intermediate state for single, extended HA trimers. This intermediate is thus a fundamental aspect of the fusion mechanism

The Panchromatic Hubble Andromeda Treasury XI: The Spatially-Resolved Recent Star Formation History of M31

We measure the recent star formation history (SFH) across M31 using optical images taken with the \texit{Hubble Space Telescope} as part of the Panchromatic Hubble Andromeda Treasury (PHAT). We fit the color-magnitude diagrams in ~9000 regions that are ~100 pc $\times$ 100 pc in projected size, covering a 0.5 square degree area (~380 kpc$^2$, deprojected) in the NE quadrant of M31. We show that the SFHs vary significantly on these small spatial scales but that there are also coherent galaxy-wide fluctuations in the SFH back to ~500 Myr, most notably in M31's 10-kpc star-forming ring. We find that the 10-kpc ring is at least 400 Myr old, showing ongoing star formation over the past ~500 Myr. This indicates the presence of molecular gas in the ring over at least 2 dynamical times at this radius. We also find that the ring's position is constant throughout this time, and is stationary at the level of 1 km/s, although there is evidence for broadening of the ring due to diffusion of stars into the disk. Based on existing models of M31's ring features, the lack of evolution in the ring's position makes a purely collisional ring origin highly unlikely. We find that the global SFR has been fairly constant over the last ~500 Myr, though it does show a small increase at 50 Myr that is 1.3 times the average SFR over the past 100 Myr. During the last ~500 Myr, ~60% of all SF occurs in the 10-kpc ring. Finally, we find that in the past 100 Myr, the average SFR over the PHAT survey area is $0.28\pm0.03$ M$_\odot$ yr$^{-1}$ with an average deprojected intensity of $7.3 \times 10^{-4}$ M$_\odot$ yr$^{-1}$ kpc$^{-2}$, which yields a total SFR of ~0.7 M$_\odot$ yr$^{-1}$ when extrapolated to the entire area of M31's disk. This SFR is consistent with measurements from broadband estimates. [abridged]Comment: 23 pages, 17 figures, 2 tables, accepted for publication in Ap

A Forward Genetic Screen for Molecules Involved in Pheromone-Induced Dauer Formation in Caenorhabditis elegans

Animals must constantly assess their surroundings and integrate sensory cues to make appropriate behavioral and developmental decisions. Pheromones produced by conspecific individuals provide critical information regarding environmental conditions. Ascaroside pheromone concentration and composition are instructive in the decision of Caenorhabditis elegans to either develop into a reproductive adult or enter into the stress-resistant alternate dauer developmental stage. Pheromones are sensed by a small set of sensory neurons, and integrated with additional environmental cues, to regulate neuroendocrine signaling and dauer formation. To identify molecules required for pheromone-induced dauer formation, we performed an unbiased forward genetic screen and identified phd (pheromone response-defective dauer) mutants. Here, we describe new roles in dauer formation for previously identified neuronal molecules such as the WD40 domain protein QUI-1 and MACO-1 Macoilin, report new roles for nociceptive neurons in modulating pheromone-induced dauer formation, and identify tau tubulin kinases as new genes involved in dauer formation. Thus, phd mutants define loci required for the detection, transmission, or integration of pheromone signals in the regulation of dauer formation. © 2016 Neal et al.1

Optical Instrument Thermal Control on the Large Ultraviolet/Optical/Infrared Surveyor

The Large Ultraviolet/Optical/Infrared Surveyor (LUVOIR) is a multi-wavelength observatory commissioned by NASA as one of four large mission concept studies for the Astro2020 Decadal Survey. Two concepts are under study which bound a range of cost, risk, and scientific return: an 8-meter diameter unobscured segmented aperture primary mirror and a 15-meter segmented aperture primary mirror. Each concept carries with it an accompanying suite of instruments. The Extreme Coronagraph for Living Planetary Systems (ECLIPS) is a near-ultraviolet (NUV) / optical / near-infrared (NIR) coronagraph; the LUVOIR Ultraviolet Multi-object Spectrograph (LUMOS) provides multi-object imaging spectroscopy in the 100-400 nanometer ultraviolet (UV) range; and the High Definition Imager (HDI) is a wide field-of-view near-UV / optical / near-IR camera that can also perform astrometry. The 15-meter concept also contains an additional instrument, Pollux, which is a high-resolution UV spectro-polarimeter. While the observatory is nominally at a 270 Kelvin operational temperature, the requirements of imaging in both IR and UV require separate detectors operating at different temperature regimes, each with stringent thermal stability requirements. The change in observatory size requires two distinct thermal designs per instrument. In this current work, the thermal architecture is presented for each instrument suite. We describe here the efforts made to achieve the target operational temperatures and stabilities with passive thermal control methods. Additional discussion will focus on how these instrument thermal designs impact the overall system-level architecture of the observatory and indicate the thermal challenges for hardware implementation

Observation-based modeling of ozone chemistry in the Seoul metropolitan area during the Korea-United States Air Quality Study (KORUS-AQ)

The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O3 production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry. Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure

The SPLASH Survey: Kinematics of Andromeda's Inner Spheroid

The combination of large size, high stellar density, high metallicity, and Sersic surface brightness profile of the spheroidal component of the Andromeda galaxy (M31) within R_proj ~ 20 kpc suggest that it is unlike any subcomponent of the Milky Way. In this work we capitalize on our proximity to and external view of M31 to probe the kinematical properties of this "inner spheroid." We employ a Markov chain Monte Carlo (MCMC) analysis of resolved stellar kinematics from Keck/DEIMOS spectra of 5651 red giant branch stars to disentangle M31's inner spheroid from its stellar disk. We measure the mean velocity and dispersion of the spheroid in each of five spatial bins after accounting for a locally cold stellar disk as well as the Giant Southern Stream and associated tidal debris. For the first time, we detect significant spheroid rotation (v_rot ~ 50 km/s) beyond R_proj ~ 5 kpc. The velocity dispersion decreases from about 140 km/s at R_proj = 7 kpc to 120 km/s at R_proj = 14 kpc, consistent to 2 sigma with existing measurements and models. We calculate the probability that a given star is a member of the spheroid and find that the spheroid has a significant presence throughout the spatial extent of our sample. Lastly, we show that the flattening of the spheroid is due to velocity anisotropy in addition to rotation. Though this suggests that the inner spheroid of M31 more closely resembles an elliptical galaxy than a typical spiral galaxy bulge, it should be cautioned that our measurements are much farther out (2 - 14 r_eff) than for the comparison samples.Comment: Accepted for publication in Ap

Seizures in Alzheimer Disease. Who, When, and How Common?

Background: Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established. Objective: To determine the incidence and predictors of new-onset unprovoked seizures. Design: Prospective cohort study. Setting: Three academic centers. Patients: Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992. Main Outcome Measure: Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or “funny” spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, κ = 0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings. Results: Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08-1.41; P = .003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23-16.61). Conclusions: Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD