The cell cycle is a highly conserved, continuous process which controls faithful replication and division of cells. Single-cell technologies have enabled increasingly precise measurements of the cell ...cycle both as a biological process of interest and as a possible confounding factor. Despite its importance and conservation, there is no universally applicable approach to infer position in the cell cycle with high-resolution from single-cell RNA-seq data.
Here, we present tricycle, an R/Bioconductor package, to address this challenge by leveraging key features of the biology of the cell cycle, the mathematical properties of principal component analysis of periodic functions, and the use of transfer learning. We estimate a cell-cycle embedding using a fixed reference dataset and project new data into this reference embedding, an approach that overcomes key limitations of learning a dataset-dependent embedding. Tricycle then predicts a cell-specific position in the cell cycle based on the data projection. The accuracy of tricycle compares favorably to gold-standard experimental assays, which generally require specialized measurements in specifically constructed in vitro systems. Using internal controls which are available for any dataset, we show that tricycle predictions generalize to datasets with multiple cell types, across tissues, species, and even sequencing assays.
Tricycle generalizes across datasets and is highly scalable and applicable to atlas-level single-cell RNA-seq data.
Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of ...Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/βGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.
Cholestatic drug-induced liver injury is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline ...phosphatase (ALP). A number of competing etiologies need to be ruled out, such as hepatobilary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis and right sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Check point inhibitors (CPIs) are one of the types of drugs shown to lead to SSC. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade and the pathogenesis behind cholestatic injury better defined. In this review, the focus is on diagnostic approach, description of new clinical phenotypes such as SSC and vanishing bile duct syndrome. Furthermore, the review provides an overview on the risk factors, genetic determinants and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty and future direction are also presented.Cholestatic drug-induced liver injury is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline phosphatase (ALP). A number of competing etiologies need to be ruled out, such as hepatobilary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis and right sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Check point inhibitors (CPIs) are one of the types of drugs shown to lead to SSC. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade and the pathogenesis behind cholestatic injury better defined. In this review, the focus is on diagnostic approach, description of new clinical phenotypes such as SSC and vanishing bile duct syndrome. Furthermore, the review provides an overview on the risk factors, genetic determinants and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty and future direction are also presented.
Idiosyncratic drug‐induced liver injury (DILI) is traditionally thought not to be dose‐related. However, it has been pointed out that most medicines that were withdrawn from marketing or received a ...black‐box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day. To examine the relationship between daily dose of medications and idiosyncratic DILI, we conducted a study with two aims. First, using two pharmaceutical databases, we examined the relationship between daily dose of commonly prescribed medicines in the United States and reported frequency of their selected hepatic adverse events. Second, we examined serious DILI cases reported to the Swedish Adverse Drug Reactions Advisory Committee (1970‐2004) for any signals supporting the relationship between daily dose and idiosyncratic DILI. Medications were categorized into ≤10 mg/day, 11‐49 mg/day, and ≥50 mg/day groups. Among US prescription medicines, a statistically significant relationship was observed between daily dose of oral medicines and reports of liver failure (P = 0.009), liver transplantation (P < 0.001), and death caused by DILI (P = 0.004) but not alanine aminotransferase (ALT) > 3 × upper limit of normal (P = 0.10) or jaundice (P = 0.16). Of 598 eligible Swedish DILI cases, 9% belonged to the ≤10 mg/day group, 14.2% to the 11‐49 mg/day group, and 77% of cases were caused by medications given at dose ≥50 mg/day. A statistically significant relationship was noted between daily dose and poor outcome (death or liver transplantation) of Swedish DILI cases (2%, 9.4%, and 13.2% in ≤10, 11‐49, and ≥50 mg/day groups, respectively, P = 0.03). Conclusion: These data suggest a relationship between daily doses of oral prescription medications and idiosyncratic DILI. More studies are needed to validate these observations and to explore their implications. (HEPATOLOGY 2008.)
ABSTRACT We present high spatial resolution optical imaging and polarization observations of the PSRB0540-69.3 and its highly dynamical pulsar wind nebula (PWN) performed with Hubble Space Telescope, ...and compare them with X-ray data obtained with the Chandra X-ray Observatory. In particular, we have studied the bright region south-west of the pulsar where a bright 'blob' is seen in 1999. In a recent paper by De Luca et al. it was argued that the 'blob' moves away from the pulsar at high speed. We show that it may instead be a result of local energy deposition around 1999, and that the emission from this then faded away rather than moved outward. Polarization data from 2007 show that the polarization properties show dramatic spatial variations at the 1999 blob position arguing for a local process. Several other positions along the pulsar-'blob' orientation show similar changes in polarization, indicating previous recent local energy depositions. In X-rays, the spectrum steepens away from the 'blob' position, faster orthogonal to the pulsar-'blob' direction than along this axis of orientation. This could indicate that the pulsar-'blob' orientation is an axis along where energy in the PWN is mainly injected, and that this is then mediated to the filaments in the PWN by shocks. We highlight this by constructing an Sii-to-Oiii-ratio map, and comparing this to optical continuum and X-ray emission maps. We argue, through modelling, that the high Sii/Oiii ratio is not due to time-dependent photoionization caused by possible rapid X-ray emission variations in the 'blob' region. We have also created a multiwavelength energy spectrum for the 'blob' position showing that one can, to within 2σ, connect the optical and X-ray emission by a single power law. The slope of that power law (defined from ) would be αν= 0.74 ± 0.03, which is marginally different from the X-ray spectral slope alone with αν= 0.65 ± 0.03. A single power law for most of the PWN is, however, not be possible. We obtain best power-law fits for the X-ray spectrum if we include 'extra' oxygen, in addition to the oxygen column density in the interstellar gas of the Large Magellanic Cloud and the Milky Way. This oxygen is most naturally explained by the oxygen-rich ejecta of the supernova remnant. The oxygen needed likely places the progenitor mass in the 20-25M range, i.e. in the upper mass range for progenitors of Type IIP supernovae. PUBLICATION ABSTRACT
Measurements of polarization play a crucial role in the understanding of the dominant emission mechanism of astronomical sources. Polarized Gamma-ray Observer-Light version (PoGOLite) is a ...balloon-borne astronomical soft gamma-ray polarimeter at the 25–80
keV band. The PoGOLite detector consists of a hexagonal close-packed array of 217 Phoswich detector cells (PDCs) and side anti-coincidence shields (SASs) made of BGO crystals surrounding PDCs. Each PDC consists of a slow hollow scintillator, a fast scintillator and a BGO crystal that connects to a photomultiplier tube at the end. To examine the PoGOLite's capability and estimate the performance, we conducted experiments with the PDC using radioisotope
241Am. In addition, we compared this result with performance expected by Monte Carlo simulation with Geant4. As a result, we found that the actual PDC has the capability to detect a 100
m Crab source until 80
keV.
Linear polarization in X- and γ-rays is an important diagnostic of many astrophysical sources, foremost giving information about their geometry, magnetic fields, and radiation mechanisms. However, ...very few X-ray polarization measurements have been made, and then only mono-energetic detections, whilst several objects are assumed to have energy dependent polarization signatures.
In this paper, we investigate whether detection of energy dependent polarization from cosmic sources is possible using the Compton technique, in particular with the proposed PoGOLite balloon-experiment, in the 25–100
keV range. We use Geant4 simulations of a PoGOLite model and input photon spectra based on Cygnus X-1 and accreting magnetic pulsars (100
mCrab). Effective observing times of 6 and 35
h were simulated, corresponding to a standard and a long duration flight, respectively. Both smooth and sharp energy variations of the polarization are investigated and compared to constant polarization signals using chi-square statistics.
We can reject constant polarization, with energy, for the Cygnus X-1 spectrum (in the hard state), if the reflected component is assumed to be completely polarized, whereas the distinction cannot be made for weaker polarization. For the accreting pulsar, constant polarization can be rejected in the case of polarization in a narrow energy band with at least 50% polarization, and similarly for a negative step distribution from 30% to 0% polarization.
Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating ...that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (r
= 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
We describe a new balloon-borne instrument (PoGOLite) capable of detecting 10% polarisation from 200
mCrab point-like sources between 25 and 80
keV in one 6-h flight. Polarisation measurements in the ...soft gamma-ray band are expected to provide a powerful probe into high energy emission mechanisms as well as the distribution of magnetic fields, radiation fields and interstellar matter. Synchrotron radiation, inverse Compton scattering and propagation through high magnetic fields are likely to produce high degrees of polarisation in the energy band of the instrument. We demonstrate, through tests at accelerators, with radioactive sources and through computer simulations, that PoGOLite will be able to detect degrees of polarisation as predicted by models for several classes of high energy sources. At present, only exploratory polarisation measurements have been carried out in the soft gamma-ray band. Reduction of the large background produced by cosmic-ray particles while securing a large effective area has been the greatest challenge. PoGOLite uses Compton scattering and photo-absorption in an array of 217 well-type phoswich detector cells made of plastic and BGO scintillators surrounded by a BGO anticoincidence shield and a thick polyethylene neutron shield. The narrow field of view (FWHM
=
1.25
msr, 2.0
deg
×
2.0
deg) obtained with detector cells and the use of thick background shields warrant a large effective area for polarisation measurements (∼228
cm
2 at
E
=
40
keV) without sacrificing the signal-to-noise ratio. Simulation studies for an atmospheric overburden of 3–4
g/cm
2 indicate that neutrons and gamma-rays entering the PDC assembly through the shields are dominant backgrounds. Off-line event selection based on recorded phototube waveforms and Compton kinematics reduce the background to that expected for a ∼100
mCrab source between 25 and 50
keV. A 6-h observation of the Crab pulsar will differentiate between the Polar Cap/Slot Gap, Outer Gap, and Caustic models with greater than 5
σ significance; and also cleanly identify the Compton reflection component in the Cygnus X-1 hard state. Long-duration flights will measure the dependence of the polarisation across the cyclotron absorption line in Hercules X-1. A scaled-down instrument will be flown as a pathfinder mission from the north of Sweden in 2010. The first science flight is planned to take place shortly thereafter.
AIMS: The primary aim of this study was to investigate the capacity of a microalga, Scenedesmus sp. AMDD, to remediate nutrients from municipal wastewater, either as the sole nutrient source or after ...blending with wastewater obtained from the anaerobic digestion of swine manure. A complimentary aim was to study and define the effects of these wastewaters on microalgal growth, biomass productivity and composition which have important implications for a commercial biofuels production system. METHODS AND RESULTS: A microalga, Scenedesmus sp. AMDD, was grown in continuous chemostats in municipal wastewater or wastewater supplemented with 1·6× or 2·4× higher levels of nitrogen (N) obtained through supplementation with anaerobic digestates. Biomass productivity increased with increasing nutrient supplementation, but was limited by light at high cell densities. Cellular quotas of carbon (C), nitrogen and phosphorus (P) all increased in direct proportion to their concentrations in the combined wastewaters. At higher cell densities, total carbohydrate decreased while protein increased. Fatty acid content remained relatively constant. Under high nutrient levels, the fatty acid profiles contained a higher concentration of polyunsaturated fatty acids at the expense of monounsaturated fatty acids. Chlorophyll a was 2·5 times greater in the treatment of greatest nutrient supplementation compared to the treatment with the least. Ammonium (NH₄⁺) and phosphate (PO₄³‐) were completely removed by algal growth in all treatments and with maximal removal rates of 41·2 mg N l⁻¹ d⁻¹and 6·7 mg P l⁻¹ d⁻¹observed in wastewater amended with 2·4× higher N level. SIGNIFICANCE AND IMPACT OF THE STUDY: The study is the first to report stable, long‐term continuous algal growth and productivity obtained by combining wastewaters of different sources. The study is supported by detailed analyses of the composition of the cultivated biomass and links composition to the nutrient and light availabilities in the cultures. Simultaneous remediation of these wastes by algal growth is discussed as a strategy for the valorization of the biomass.
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