H2AX Deficiency is Associated with Erythroid Dysplasia and Compromised Haematopoietic Stem Cell Function

Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of terminal erythropoiesis, enucleation was decreased. H2AX deficiency also led to the loss of quiescence of hematopoietic stem and progenitor cells, which dramatically compromised their bone marrow engraftment. These results reveal important roles of H2AX in late-stage terminal erythropoiesis and hematopoietic stem cell function

Precise Masses and Orbits for Nine Radial Velocity Exoplanets

Radial velocity (RV) surveys have discovered hundreds of exoplanetary systems but suffer from a fundamental degeneracy between planet mass $M_p$ and orbital inclination $i$. In this paper we break this degeneracy by combining RVs with complementary absolute astrometry taken from the Gaia EDR3 version of the cross-calibrated Hipparcos-Gaia Catalog of Accelerations (HGCA). We use the Markov Chain Monte Carlo orbit code $\tt orvara$ to simultaneously fit literature RVs and absolute astrometry from the HGCA. We constrain the orbits, masses, and inclinations of nine single and massive RV companions orbiting nearby G and K stars. We confirm the planetary nature of six companions: HD 29021 b ($4.47_{-0.65}^{+0.67}\,M_{\rm Jup}$), HD 81040 b ($7.24_{-0.37}^{+1.0}\,M_{\rm Jup}$), HD 87883 b ($6.31_{-0.32}^{+0.31}\,M_{\rm Jup}$), HD 98649 b ($9.7_{-1.9}^{+2.3}\,M_{\rm Jup}$), HD 106252 b ($10.00_{-0.73}^{+0.78}\,M_{\rm Jup}$), and HD 171238 b ($8.8_{-1.3}^{+3.6}\,M_{\rm Jup}$). We place one companion, HD 196067 b ($12.5_{-1.8}^{+2.5}\,M_{\rm Jup}$) on the planet-brown dwarf boundary, and two companions in the low mass brown dwarf regime: HD 106515 Ab ($18.9_{-1.4}^{+1.5}\,M_{\rm Jup}$), and HD 221420 b (${20.6}_{-1.6}^{+2.0}\,M_{\rm Jup}$). The brown dwarf HD 221420 b, with a semi-major axis of ${9.99}_{-0.70}^{+0.74}$ AU, a period of ${27.7}_{-2.5}^{+3.0}$ years, and an eccentricity of $0.162_{-0.030}^{+0.035}$ represents a promising target for high-contrast imaging. The RV orbits of HD 87883 b, HD 98649 b, HD 171238 b, and HD 196067 b are not fully constrained yet because of insufficient RV data. We find two possible inclinations for each of these orbits due to difficulty in separating prograde from retrograde orbits, but we expect this will change decisively with future Gaia data releases

Modeling the cost of influenza: the impact of missing costs of unreported complications and sick leave

Background Estimating the economic impact of influenza is complicated because the disease may have non-specific symptoms, and many patients with influenza are registered with other diagnoses. Furthermore, in some countries like Norway, employees can be on paid sick leave for a specified number of days without a doctor's certificate ("self-reported sick leave") and these sick leaves are not registered. Both problems result in gaps in the existing literature: costs associated with influenza-related illness and self-reported sick leave are rarely included. The aim of this study was to improve estimates of total influenza-related health-care costs and productivity losses by estimating these missing costs. Methods Using Norwegian data, the weekly numbers of influenza-attributable hospital admissions and certified sick leaves registered with other diagnoses were estimated from influenza-like illness surveillance data using quasi-Poisson regression. The number of self-reported sick leaves was estimated using a Monte-Carlo simulation model of illness recovery curves based on the number of certified sick leaves. A probabilistic sensitivity analysis was conducted on the economic outcomes. Results During the 1998/99 through 2005/06 influenza seasons, the models estimated an annual average of 2700 excess influenza-associated hospitalizations in Norway, of which 16% were registered as influenza, 51% as pneumonia and 33% were registered with other diagnoses. The direct cost of seasonal influenza totaled US$22 million annually, including costs of pharmaceuticals and outpatient services. The annual average number of working days lost was predicted at 793 000, resulting in an estimated productivity loss of US$231 million. Self-reported sick leave accounted for approximately one-third of the total indirect cost. During a pandemic, the total cost could rise to over US$800 million. Conclusions Influenza places a considerable burden on patients and society with indirect costs greatly exceeding direct costs. The cost of influenza-attributable complications and the cost of self-reported sick leave represent a considerable part of the economic burden of influenza

Surveying Nearby Brown Dwarfs with HGCA: Direct Imaging Discovery of a Faint, High-Mass Brown Dwarf Orbiting HD 176535 A

Brown dwarfs with well-measured masses, ages and luminosities provide direct benchmark tests of substellar formation and evolutionary models. We report the first results from a direct imaging survey aiming to find and characterize substellar companions to nearby accelerating stars with the assistance of the Hipparcos-Gaia Catalog of Accelerations (HGCA). In this paper, we present a joint high-contrast imaging and astrometric discovery of a substellar companion to HD 176535 A, a K3.5V main-sequence star aged approximately $3.59_{-1.15}^{+0.87}$ Gyrs at a distance of $36.99 \pm 0.03$ pc. In advance of our high-contrast imaging observations, we combined precision HARPS RVs and HGCA astrometry to predict the potential companion's location and mass. We thereafter acquired two nights of KeckAO/NIRC2 direct imaging observations in the $L'$ band, which revealed a companion with a contrast of $\Delta L'_p = 9.20\pm0.06$ mag at a projected separation of $\approx$0.\!\!''35 ($\approx$13 AU) from the host star. We revise our orbital fit by incorporating our dual-epoch relative astrometry using the open-source MCMC orbit fitting code $\tt orvara$. HD 176535 B is a new benchmark dwarf useful for constraining the evolutionary and atmospheric models of high-mass brown dwarfs. We found a luminosity of $\rm log(L_{bol}/L_{\odot}) = -5.26\pm0.06$ and a model-dependent effective temperature of $980 \pm 35$ K for HD 176535 B. Our dynamical mass suggests that some substellar evolutionary models may be underestimating luminosity for high-mass T dwarfs. Given its angular separation and luminosity, HD 176535 B would make a promising candidate for Aperture Masking Interferometry with JWST and GRAVITY/KPIC, and further spectroscopic characterization with instruments like the CHARIS/SCExAO/Subaru integral field spectrograph

James Webb Space Telescope Near-Infrared Spectrograph: Dark Performance of the First Flight Candidate Detector Arrays

The James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec) incorporates two 5 micron cutoff (lambda(sub co) = 5 micron) 2048x2048 pixel Teledyne HgCdTe HAWAII-2RG sensor chip assemblies. These detector arrays, and the two Teledyne SIDECAR application specific integrated circuits that control them, are operated in space at T approx. 37 K. This article focuses on the measured performance of the first flight-candidate, and near-flight candidate, detector arrays. These are the first flight-packaged detector arrays that meet NIRSpec's challenging 6 e(-) rms total noise requirement

TET1 is a tumor suppressor of hematopoietic malignancy

The methylcytosine dioxygenase TET1 (‘ten-eleven translocation 1’) is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.National Institutes of Health (U.S.) (5RO1HD045022)National Institutes of Health (U.S.) (5R37CA084198

Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression

BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer

A Novel Escherichia coli O157:H7 Clone Causing a Major Hemolytic Uremic Syndrome Outbreak in China

An Escherichia coli O157:H7 outbreak in China in 1999 caused 177 deaths due to hemolytic uremic syndrome. Sixteen outbreak associated isolates were found to belong to a new clone, sequence type 96 (ST96), based on multilocus sequence typing of 15 housekeeping genes. Whole genome sequencing of an outbreak isolate, Xuzhou21, showed that the isolate is phylogenetically closely related to the Japan 1996 outbreak isolate Sakai, both of which share the most recent common ancestor with the US outbreak isolate EDL933. The levels of IL-6 and IL-8 of peripheral blood mononuclear cells induced by Xuzhou21 and Sakai were significantly higher than that induced by EDL933. Xuzhou21 also induced a significantly higher level of IL-8 than Sakai while both induced similar levels of IL-6. The expression level of Shiga toxin 2 in Xuzhou21 induced by mitomycin C was 68.6 times of that under non-inducing conditions, twice of that induced in Sakai (32.7 times) and 15 times higher than that induced in EDL933 (4.5 times). Our study shows that ST96 is a novel clone and provided significant new insights into the evolution of virulence of E. coli O157:H7

Isolation and Characterization of Cytotoxic, Aggregative Citrobacter freundii

Citrobacter freundii is an infrequent but established cause of diarrhea in humans. However, little is known of its genetic diversity and potential for virulence. We analyzed 26 isolates, including 12 from human diarrheal patients, 2 from human fecal samples of unknown diarrheal status, and 12 from animals, insects, and other sources. Pulsed field gel electrophoresis using XbaI allowed us to divide the 26 isolates into 20 pulse types, while multi-locus sequence typing using 7 housekeeping genes allowed us to divide the 26 isolates into 6 sequence types (STs) with the majority belonging to 4 STs. We analyzed adhesion and cytotoxicity to HEp-2 cells in these 26 strains. All were found to adhere to HEp-2 cells. One strain, CF74, which had been isolated from a goat, showed the strongest aggregative adhesion pattern. Lactate dehydrogenase (LDH) released from HEp-2 cells was evaluated as a measure of cytotoxicity, averaging 7.46%. Strain CF74 induced the highest level of LDH, 24.3%, and caused >50% cell rounding, detachment, and death. We named strain CF74 “cytotoxic and aggregative C. freundii.” Genome sequencing of CF74 revealed that it had acquired 7 genomic islands, including 2 fimbriae islands and a type VI secretion system island, all of which are potential virulence factors. Our results show that aggregative adherence and cytotoxicity play an important role in the pathogenesis of C. freundii