Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells [preprint]

The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While toll-like receptor ligation relies on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNγ). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in macrophages to identify the regulators of IFNγ-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNγ signaling pathway. We report that the IFNγ response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNγ and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity

Weakly-semi-supervised object detection in remotely sensed imagery

Deep learning for detecting objects in remotely sensed imagery can enable new technologies for important applications including mitigating climate change. However, these models often require large datasets labeled with bounding box annotations which are expensive to curate, prohibiting the development of models for new tasks and geographies. To address this challenge, we develop weakly-semi-supervised object detection (WSSOD) models on remotely sensed imagery which can leverage a small amount of bounding boxes together with a large amount of point labels that are easy to acquire at scale in geospatial data. We train WSSOD models which use large amounts of point-labeled images with varying fractions of bounding box labeled images in FAIR1M and a wind turbine detection dataset, and demonstrate that they substantially outperform fully supervised models trained with the same amount of bounding box labeled images on both datasets. Furthermore, we find that the WSSOD models trained with 2-10x fewer bounding box labeled images can perform similarly to or outperform fully supervised models trained on the full set of bounding-box labeled images. We believe that the approach can be extended to other remote sensing tasks to reduce reliance on bounding box labels and increase development of models for impactful applications.Comment: Tackling Climate Change with Machine Learning at NeurIPS 202

Redshifted iron emission and absorption lines in the Chandra X-ray spectrum of Centaurus A

Cen A hosts the closest active galactic nucleus to the Milky Way, which makes it an ideal target for investigating the dynamical processes in the vicinity of accreting supermassive black holes. In this paper, we present 14 Chandra HETGS spectra of the nucleus of Cen A that were observed throughout 2022. We compared them with each other, and contrasted them against the two previous Chandra HETGS spectra from 2001. This enabled an investigation into the spectral changes occurring on timescales of months and 21 years. All Chandra spectra could be well fitted by an absorbed power law with a strong and narrow Fe K$\alpha$ line, a leaked power law feature at low energies, and Si and S K$\alpha$ lines that could not be associated with the central engine. The flux of the continuum varied by a factor of $2.74\pm0.05$ over the course of the observations, whereas the Fe line only varied by $18.8\pm8.8\%$. The photon index increased over 21 years, and the Hydrogen column density varied significantly within a few months as well. The Fe K$\alpha$ line was found at a lower energy than expected from the Cen A redshift, amounting to an excess velocity of $326^{+84}_{-94}~\mathrm{km}~\mathrm{s}^{-1}$ relative to Cen A. We investigated warped accretion disks, bulk motion, and outflows as possible explanations of this shift. The spectra also featured ionized absorption lines from Fe XXV and Fe XXVI, describing a variable inflow.Comment: 19 pages, 9 figures, went through peer review, and was accepted for publication by the The Astrophysical Journa

Successful Recanalization of Chronic Total Occlusions Is Associated With Improved Long-Term Survival

ObjectivesThis study investigated the impact of procedural success on mortality following chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a large cohort of patients in the drug-eluting stent era.BackgroundDespite advances in expertise and technologies, many patients with CTO are not offered PCI.MethodsA total of 6,996 patients underwent elective PCI for stable angina at a single center (2003 to 2010), 836 (11.9%) for CTO. All-cause mortality was obtained to 5 years (median: 3.8 years; interquartile range: 2.0 to 5.4 years) and stratified according to successful chronic total occlusion (sCTO) or unsuccessful chronic total occlusion (uCTO) recanalization. Major adverse cardiac events (MACE) included myocardial infarction (MI), urgent revascularization, stroke, or death.ResultsA total of 582 (69.6%) procedures were successful. Stents were implanted in 97.0% of successful procedures (mean: 2.3 ± 0.1 stents per patient, 73% drug-eluting). Prior revascularization was more frequent among uCTO patients: coronary artery bypass grafting (CABG) (16.5% vs. 7.4%; p < 0.0001), PCI (36.0% vs. 21.2%; p < 0.0001). Baseline characteristics were otherwise similar. Intraprocedural complications, including coronary dissection, were more frequent in unsuccessful cases (20.5% vs. 4.9%; p < 0.0001), but did not affect in-hospital MACE (3% vs. 2.1%; p = NS). All-cause mortality was 17.2% for uCTO and 4.5% for sCTO at 5 years (p < 0.0001). The need for CABG was reduced following sCTO (3.1% vs. 22.1%; p < 0.0001). Multivariate analysis demonstrated that procedural success was independently predictive of mortality (hazard ratio [HR]: 0.32 [95% confidence interval (CI): 0.18 to 0.58]), which persisted when incorporating a propensity score (HR: 0.28 [95% CI: 0.15 to 0.52]).ConclusionsSuccessful CTO PCI is associated with improved survival out to 5 years. Adoption of techniques and technologies to improve procedural success may have an impact on prognosis

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines. IMPORTANCE Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.This work, including the efforts of Hardy Kornfeld, was funded by HHS | National Institutes of Health (NIH) (HL081149). This work, including the efforts of Sam Behar, was funded by HHS | National Institutes of Health (NIH) (AI123286-01). This work, including the efforts of Clare Margaret Smith and Christopher Sassetti, was funded by Howard Hughes Medical Institute (HHMI)

SNR 1E 0102.2-7219 as an X-ray calibration standard in the 0.5−1.0 keV bandpass and its application to the CCD instruments aboard Chandra , Suzaku , Swift and XMM-Newton

Context. The flight calibration of the spectral response of charge-coupled device (CCD) instruments below 1.5 keV is difficult in general because of the lack of strong lines in the on-board calibration sources typically available. This calibration is also a function of time due to the effects of radiation damage on the CCDs and/or the accumulation of a contamination layer on the filters or CCDs. Aims. We desire a simple comparison of the absolute effective areas of the current generation of CCD instruments onboard the following observatories: Chandra ACIS-S3, XMM-Newton (EPIC-MOS and EPIC-pn), Suzaku XIS, and Swift XRT and a straightforward comparison of the time-dependent response of these instruments across their respective mission lifetimes. Methods. We have been using 1E 0102.2-7219, the brightest supernova remnant in the Small Magellanic Cloud, to evaluate and modify the response models of these instruments. 1E 0102.2-7219 has strong lines of O, Ne, and Mg below 1.5 keV and little or no Fe emission to complicate the spectrum. The spectrum of 1E 0102.2-7219 has been well-characterized using the RGS gratings instrument on XMM-Newton and the HETG gratings instrument on Chandra. As part of the activities of the International Astronomical Consortium for High Energy Calibration (IACHEC), we have developed a standard spectral model for 1E 0102.2-7219 and fit this model to the spectra extracted from the CCD instruments. The model is empirical in that it includes Gaussians for the identified lines, an absorption component in the Galaxy, another absorption component in the SMC, and two thermal continuum components with different temperatures. In our fits, the model is highly constrained in that only the normalizations of the four brightest lines/line complexes (the O vii Heα triplet, O viii Lyα line, the Ne ix Heα triplet, and the Ne x Lyα line) and an overall normalization are allowed to vary, while all other components are fixed. We adopted this approach to provide a straightforward comparison of the measured line fluxes at these four energies. We have examined these measured line fluxes as a function of time for each instrument after applying the most recent calibrations that account for the time-dependent response of each instrument. Results. We performed our effective area comparison with representative, early mission data when the radiation damage and contamination layers were at a minimum, except for the XMM-Newton EPIC-pn instrument which is stable in time. We found that the measured fluxes of the O vii Heαr line, the O viii Lyα line, the Ne ix Heαr line, and the Ne x Lyα line generally agree to within ±10% for all instruments, with 38 of our 48 fitted normalizations within ± 10% of the IACHEC model value. We then fit all available observations of 1E 0102.2-7219 for the CCD instruments close to the on-axis position to characterize the time dependence in the 0.5−1.0 keV band. We present the measured line normalizations as a function of time for each CCD instrument so that the users may estimate the uncertainty in their measured line fluxes for the epoch of their observations

Instrument for Analysis of Greenland's Glacier Mills

A new instrument is used to study the inner workings of Greenland s glacier mills by riding the currents inside a glacier s moulin. The West Greenland Moulin Explorer instrument was deployed into a tubular shaft to autonomously record temperature, pressure, 3D acceleration, and location. It is built with a slightly positive buoyancy in order to assist in recovery. The unit is made up of several components. A 3-axis MEMS (microelectromechanical systems) accelerometer with 0.001-g resolution forms the base of the unit. A pressure transducer is added that is capable of withstanding 500 psi (=3.4 MPa), and surviving down to -40 C. An Iridium modem sends out data every 10 minutes. The location is traced by a GPS (Global Positioning System) unit. This GPS unit is also used for recovery after the mission. Power is provided by a high-capacity lithium thionyl chloride D-sized battery. The accelerometer is housed inside a cylindrical, foot-long (=30 cm) polyvinyl chloride (PVC) shell sealed at each end with acrylic. The pressure transducer is attached to one of these lids and a MEMS accelerometer to the other, recording 100 samples per second per axis

Using smart pumps to help deliver universal access to safe and affordable drinking water

It is estimated that broken water pumps impact 62 million people in sub-Saharan Africa. Over the last 20 years, broken handpumps have represented US$1·2–1·5 billion of lost investment in this region, with 30–40% of rural water systems failing prematurely. While the contributory factors are complex and multi-faceted, the authors consider that improved post-construction monitoring strategies for remote water projects, which rely on smart pumps to monitor operational performance in place of physical site visits, may address some of these problems and help reduce the heavy time and resource demands on stakeholders associated with traditional monitoring strategies. As such, smart pumps could play a significant role in improving project monitoring and might subsequently help deliver universal access to safe and affordable drinking water by 2030, which constitutes one of the key targets of United Nations sustainable development goal 6 and is embedded in some national constitutions

Transient Astrophysics Probe: White Paper

The Transient Astrophysics Probe (TAP) is a wide-field multi-wavelength transient mission proposed for flight starting in the late 2020s. The mission instruments include unique ``Lobster-eye'' imaging soft X-ray optics that allow an approximately 1600-degrees-squared Field of View (FoV); a high sensitivity, 1-degree-squared FoV soft X-ray telescope; a 1-degree-squared FoV Infrared telescope with bandpass 0.6 to 3 microns; and a set of 8 NaI gamma-ray detectors. TAP's most exciting capability will be the observation of tens per year of X-ray and Infrared counterparts of gravitational waves (GWs) involving stellar-mass black holes and neutron stars detected by LIGO (Laser Interferometer Gravitational-Wave Observatory ) / Virgo / KAGRA (Kamioka (Japan) Gravitational Wave Detector) / LIGO-India, and possibly several per year X-ray counterparts of GWs from supermassive black holes, detected by LISA (Laser Interferometer Space Antenna) and Pulsar Timing Arrays. TAP will also discover hundreds of X-ray transients related to compact objects, including tidal disruption events, supernova shock breakouts, and Gamma-Ray Bursts from the epoch of reionization