S5S^5: Probing the Milky Way and Magellanic Clouds potentials with the 6-D map of the Orphan-Chenab stream

We present a 6-D map of the Orphan-Chenab (OC) stream by combining the data from 5 years of Southern Stellar Stream Spectroscopic Survey $S^5$ observations with Gaia EDR3 data. We reconstruct the proper motion, radial velocity, distance and on-sky track of stream stars with spline models and extract the stellar density along the stream. The stream has a total luminosity of $M_V=-8.2$ and an average metallicity of $[Fe/H]=-1.9$, similar to classical MW satellites like Draco. The stream shows drastic changes in its physical width varying from 200 pc to 1 kpc, a constant line of sight velocity dispersion of 5 km/s, but an increase in the velocity dispersion along the stream near pericenter to $\sim$ 10 km/s. Despite the large apparent variation in the stellar number density along the stream, the flow rate of stars along the stream is remarkably constant. We model the 6-D stream track by a Lagrange-point stripping method with a flexible MW potential in the presence of a moving extended LMC potential. This allows us to constrain the mass profile of the MW within the distance range 15.6 < r < 55.5 kpc, with the best measured enclosed mass of $(2.85\pm 0.1)\times10^{11}\,M_\odot$ within 32.4 kpc. With the OC stream's closest approach distance to the LMC of $\sim 21$ kpc, our stream measurements are highly sensitive to the LMC mass profile with the most precise measurement of the LMC's enclosed mass being at 32.8 kpc with $M=(7.02\pm 0.9)\times10^{10}\, {M}_\odot$. We confidently detect that the LMC DM halo extends to at least 53 kpc. The fitting of the OC stream allows us to constrain the past LMC trajectory and the degree of dynamical friction it experienced. We demonstrate that the stars on the OC stream show large energy and angular momentum spreads caused by the LMC perturbation and revealing the limitations of orbital invariants for substructure identification in the MW halo.Comment: submitted to MNRAS; comments welcome; data released with the paper is available on Zenodo https://zenodo.org/record/722265

Heart failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings

Aims: Viral-induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF)-like syndromes. COVID-19 can lead to myocardial damage and vascular injury. We hypothesised that COVID-19 patients frequently develop a HFpEF-like syndrome, and designed this study to explore this. Methods and results: Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID-19 patients from April-November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56 ± 19 years, females: 31%, severe COVID-19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA-PEFF score. A low (0-1 points), intermediate (2-4 points), and high (5-6 points) HFA-PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID-19 showed these scores in 30%, 66%, and 4%, respectively (between groups: P = 0.0002). High HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, P = 0.001). In COVID-19 patients, the HFA-PEFF score significantly correlated with age, estimated glomerular filtration rate, high-sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H2 FPEF score (all P < 0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA-PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA-PEFF scores [median 5 (interquartile range 3-6) vs. 1 (0-3), P < 0.001] and more often showed left ventricular diastolic dysfunction (75% vs. 27%, P < 0.001). Conclusion: Hospitalized COVID-19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of left ventricular diastolic function and biomarkers should become routine in the care of hospitalized COVID-19 patients

The Cognitive Impact of the ANK3 Risk Variant for Bipolar Disorder: Initial Evidence of Selectivity to Signal Detection during Sustained Attention

BACKGROUND: Abnormalities in cognition have been reported in patients with Bipolar Disorder (BD) and their first degree relatives, suggesting that susceptibility genes for BD may impact on cognitive processes. Recent genome-wide genetic studies have reported a strong association with BD in a single nucleotide polymorphism (SNP) (rs10994336) within ANK3, which codes for Ankyrin 3. This protein is involved in facilitating the propagation of action potentials by regulating the assembly of sodium gated ion channels. Since ANK3 influences the efficiency of transmission of neuronal impulses, allelic variation in this gene may have widespread cognitive effects. Preclinical data suggest that this may principally apply to sequential signal detection, a core process of sustained attention. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and eighty-nine individuals of white British descent were genotyped for the ANK3 rs10994336 polymorphism and received diagnostic interviews and comprehensive neurocognitive assessment of their general intellectual ability, memory, decision making, response inhibition and sustained attention. Participants comprised euthymic BD patients (n = 47), their unaffected first-degree relatives (n = 75) and healthy controls (n = 67). The risk allele T was associated with reduced sensitivity in target detection (p = 0.0004) and increased errors of commission (p = 0.0018) during sustained attention regardless of diagnosis. We found no effect of the ANK3 genotype on general intellectual ability, memory, decision making and response inhibition. CONCLUSIONS/SIGNIFICANCE: Our results suggest that allelic variation in ANK3 impacts cognitive processes associated with signal detection and this mechanism may relate to risk for BD. However, our results require independent replication and confirmation that ANK3 (rs10994336) is a direct functional variant

The effects of melatonin versus placebo on delirium in hip fracture patients: study protocol of a randomised, placebo-controlled, double blind trial

<p>Abstract</p> <p>Background</p> <p>With an ageing population, older persons become a larger part of the hospital population. The incidence of delirium is high in this group, and experiencing delirium has major short- and long-term sequelae, which makes prevention crucial. During delirium, a disruption of the sleep-wake cycle is frequently observed. Melatonin plays an important role in the regulation of the sleep-wake cycle, so this raised the hypothesis that alterations in the metabolism of melatonin might play an important role in the development of delirium. The aim of this article is to describe the design of a randomised, placebo controlled double-blind trial that is currently in progress and that investigates the effects of melatonin versus placebo on delirium in older, postoperative hip fracture patients.</p> <p>Methods/Design</p> <p>Acutely hospitalised patients aged 65 years or older admitted for surgical repair of hip fracture are randomised (n = 452) into a treatment or placebo group. Prophylactic treatment consists of orally administered melatonin (3 mg) at 21:00 h on five consecutive days. The primary outcome is the occurrence of delirium, to be diagnosed according to the Confusion Assessment Method, within eight days after start of the study medication. Secondary outcomes are delirium severity, measured by the Delirium Rating Scale; duration of delirium; differences in subtypes of delirium; differences in total length of hospital stay; total dose of antipsychotics and/or benzodiazepine use during delirium; and in-hospital complications. In the twelve-month follow up visit, cognitive function is measured by a Mini-Mental state examination and the Informant Questionnaire on Cognitive Decline in the Elderly. Functional status is assessed with the Katz ADL index score (patient and family version) and grip strength measurement. The outcomes of these assessments are compared to the outcomes that were obtained during admission.</p> <p>Discussion</p> <p>The proposed study will contribute to our knowledge because studies on the prophylactic treatment of delirium with long term follow up remain scarce. The results may lead to a prophylactic treatment for frail older persons at high risk for delirium that is safe, effective, and easily implementable in daily practice.</p> <p>Trial registration</p> <p>Dutch Clinical Trial Registry: <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1576">NTR1576</a></p

Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape

We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase I hypersensitivity analysis followed by sequencing (DNase-seq) experiment with accuracy comparable to that of chromatin immunoprecipitation followed by sequencing (ChIP-seq). We applied PIQ to analyze DNase-seq data from mouse embryonic stem cells differentiating into prepancreatic and intestinal endoderm. We identified 120 and experimentally validated eight 'pioneer' TF families that dynamically open chromatin. Four pioneer TF families only opened chromatin in one direction from their motifs. Furthermore, we identified 'settler' TFs whose genomic binding is principally governed by proximity to open chromatin. Our results support a model of hierarchical TF binding in which directional and nondirectional pioneer activity shapes the chromatin landscape for population by settler TFs.National Institutes of Health (U.S.) (Common Fund 5UL1DE019581)National Institutes of Health (U.S.) (Common Fund RL1DE019021)National Institutes of Health (U.S.) (Common Fund 5TL1EB008540)National Institutes of Health (U.S.) (Grant 1U01HG007037)National Institutes of Health (U.S.) (Grant 5P01NS055923

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Static and dynamic mechanics of the murine lung after intratracheal bleomycin

<p>Abstract</p> <p>Background</p> <p>Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure.</p> <p>Methods</p> <p>Single intratracheal injections of saline (50 μL) or bleomycin (2 mg/Kg in 50 μL saline) were administered to C57BL/6 (<it>n </it>= 40) and Balb/c (<it>n </it>= 32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (<it>R_N</it>), tissue damping (<it>G</it>) and elastance coefficient (<it>H</it>), hysteresivity (<it>η</it>), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD <it>post hoc </it>tests.</p> <p>Results</p> <p>Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and <it>G </it>and <it>H </it>non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. <it>G </it>and <it>H</it>, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, <it>H </it>and <it>G </it>was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls.</p> <p>Conclusions</p> <p>Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.</p