Single-cell epigenomic variability reveals functional cancer heterogeneity.

BackgroundCell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally.ResultsWe develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity.ConclusionSingle-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution

Loss of Hand2 in a population of Periostin lineage cells results in pronounced bradycardia and neonatal death

The Periostin Cre (Postn-Cre) lineage includes endocardial and neural crest derived mesenchymal cells of the cardiac cushions, neural crest-derived components of the sympathetic and enteric nervous systems, and cardiac fibroblasts. In this study, we use the Postn-Cre transgenic allele to conditionally ablate Hand2 (H2CKO). We find that Postn-Cre H2CKOs die shortly after birth despite a lack of obvious cardiac structural defects. To ascertain the cause of death, we performed a detailed comparison of the Postn-Cre lineage and Hand2 expression at mid and late stages of embryonic development. Gene expression analyses demonstrate that Postn-Cre ablates Hand2 from the adrenal medulla as well as the sphenopalatine ganglia of the head. In both cases, Hand2 loss-of-function dramatically reduces expression of Dopamine Beta Hydroxylase (Dbh), a gene encoding a crucial catecholaminergic biosynthetic enzyme. Expression of the genes Tyrosine Hydroxylase (Th) and Phenylethanolamine N-methyltransferase (Pnmt), which also encode essential catecholaminergic enzymes, were severely reduced in postnatal adrenal glands. Electrocardiograms demonstrate that 3-day postnatal Postn-Cre H2CKO pups exhibit sinus bradycardia. In conjunction with the aforementioned gene expression analyses, these results strongly suggest that the observed postnatal lethality occurs due to a catecholamine deficiency and subsequent heart failure

The role of eddies in the Southern Ocean temperature response to the southern annular mode

© Copyright 2009 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act September 2010 Page 2 or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108, as revised by P.L. 94-553) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form, such as on a web site or in a searchable database, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. Additional details are provided in the AMS Copyright Policy, available on the AMS Web site located at (http://www.ametsoc.org/) or from the AMS at 617-227-2425 or [email protected] role of eddies in modulating the Southern Ocean response to the southern annular mode (SAM) is examined, using an ocean model run at multiple resolutions from coarse to eddy resolving. The high-resolution versions of the model show an increase in eddy kinetic energy that peaks 2–3 yr after a positive anomaly in the SAM index. Previous work has shown that the instantaneous temperature response to the SAM is characterized by predominant cooling south of 45°S and warming to the north. At all resolutions the model captures this temperature response. This response is also evident in the coarse-resolution implementation of the model with no eddy mixing parameterization, showing that eddies do not play an important role in the instantaneous response. On the longer time scales, an intensification of the mesoscale eddy field occurs, which causes enhanced poleward heat flux and drives warming south of the oceanic Polar Front. This warming is of greater magnitude and occurs for a longer period than the initial cooling response. The results demonstrate that this warming is surface intensified and strongest in the mixed layer. Non-eddy-resolving models are unable to capture the delayed eddy-driven temperature response to the SAM. The authors therefore question the ability of coarse-resolution models, such as those commonly used in climate simulations, to accurately represent the full impacts of the SAM on the Southern Ocean

A Master equation approach to modeling an artificial protein motor

Linear bio-molecular motors move unidirectionally along a track by coordinating several different processes, such as fuel (ATP) capture, hydrolysis, conformational changes, binding and unbinding from a track, and center-of-mass diffusion. A better understanding of the interdependencies between these processes, which take place over a wide range of different time scales, would help elucidate the general operational principles of molecular motors. Artificial molecular motors present a unique opportunity for such a study because motor structure and function are a priori known. Here we describe use of a Master equation approach, integrated with input from Langevin and molecular dynamics modeling, to stochastically model a molecular motor across many time scales. We apply this approach to a specific concept for an artificial protein motor, the Tumbleweed.Comment: Submitted to Chemical Physics; 9 pages, 7 figure

TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouse.

The contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand expressed by cells of the innate immune system, to cholestatic liver injury has not been explored. Our aim was to ascertain if TRAIL contributes to liver injury in the bile duct-ligated (BDL) mouse. C57/BL6 wild-type (wt), TRAIL heterozygote (TRAIL(+/-)), and TRAIL knockout (TRAIL(-/-)) mice were used for these studies. Liver injury and fibrosis were examined 7 and 14 days after BDL, respectively. Hepatic TRAIL messenger RNA (mRNA) was 6-fold greater in BDL animals versus sham-operated wt animals (P \u3c 0.01). The increased hepatic TRAIL expression was accompanied by an increase in liver accumulation of natural killer 1.1 (NK 1.1)-positive NK and natural killer T (NKT) cells, the predominant cell types expressing TRAIL. Depletion of NK 1.1-positive cells reduced hepatic TRAIL mRNA expression and serum alanine aminotransferase (ALT) values. Consistent with a role for NK/NKT cells in this model of liver injury, stress ligands necessary for their recognition of target cells were also up-regulated in hepatocytes following BDL. Compared to sham-operated wt mice, BDL mice displayed a 13-fold increase in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and an 11-fold increase in caspase 3/7-positive hepatocytes (P \u3c 0.01). The number of TUNEL and caspase 3/7-positive cells was reduced by \u3e80% in BDL TRAIL knockout animals (P \u3c 0.05). Likewise, liver histology, number of bile infarcts, serum ALT values, hepatic fibrosis, and animal survival were also improved in BDL TRAIL(-/-) animals as compared to wt animals. Conclusion: These observations support a pivotal role for TRAIL in cholestatic liver injury mediated by NK 1.1-positive NK/NKT cells

SPIRITS 15c and SPIRITS 14buu: Two Obscured Supernovae in the Nearby Star-Forming Galaxy IC 2163

SPIRITS---SPitzer InfraRed Intensive Transients Survey---is an ongoing survey of nearby galaxies searching for infrared (IR) transients with Spitzer/IRAC. We present the discovery and follow-up observations of one of our most luminous ($M_{[4.5]} = -17.1\pm0.4$ mag, Vega) and red ($[3.6] - [4.5] = 3.0 \pm 0.2$ mag) transients, SPIRITS 15c. The transient was detected in a dusty spiral arm of IC 2163 ($D\approx35.5$ Mpc). Pre-discovery ground-based imaging revealed an associated, shorter-duration transient in the optical and near-IR (NIR). NIR spectroscopy showed a broad ($\approx 8400$ km s$^{-1}$), double-peaked emission line of He I at $1.083 \mu$m, indicating an explosive origin. The NIR spectrum of SPIRITS 15c is similar to that of the Type IIb SN 2011dh at a phase of $\approx 200$ days. Assuming $A_V = 2.2$ mag of extinction in SPIRITS 15c provides a good match between their optical light curves. The IR light curves and the extreme $[3.6]-[4.5]$ color cannot be explained using only a standard extinction law. Another luminous ($M_{4.5} = -16.1\pm0.4$ mag) event, SPIRITS 14buu, was serendipitously discovered in the same galaxy. The source displays an optical plateau lasting $\gtrsim 80$ days, and we suggest a scenario similar to the low-luminosity Type IIP SN 2005cs obscured by $A_V \approx 1.5$ mag. Other classes of IR-luminous transients can likely be ruled out in both cases. If both events are indeed SNe, this may suggest $\gtrsim 18\%$ of nearby core-collapse SNe are missed by currently operating optical surveys.Comment: 19 pages, 7 Figures, 4 Table

SPIRITS 16tn in NGC 3556: A heavily obscured and low-luminosity supernova at 8.8 Mpc

We present the discovery by the SPitzer InfraRed Intensive Transients Survey (SPIRITS) of a likely supernova (SN) in NGC 3556 at only 8.8 Mpc, which, despite its proximity, was not detected by optical searches. A luminous infrared (IR) transient at $M_{[4.5]} = -16.7$ mag (Vega), SPIRITS 16tn is coincident with a dust lane in the inclined, star-forming disk of the host. Using IR, optical, and radio observations, we attempt to determine the nature of this event. We estimate $A_V \approx$ 8 - 9 mag of extinction, placing it among the three most highly obscured IR-discovered SNe to date. The [4.5] light curve declined at a rate of 0.013 mag day$^{-1}$, and the $[3.6] - [4.5]$ color grew redder from 0.7 to $\gtrsim$ 1.0 mag by 184.7 days post discovery. Optical/IR spectroscopy shows a red continuum, but no clearly discernible features, preventing a definitive spectroscopic classification. Deep radio observations constrain the radio luminosity of SPIRITS 16tn to $L_{\nu} \lesssim 10^{24}$ erg s$^{-1}$ Hz$^{-1}$ between 3 - 15 GHz, excluding many varieties of radio core-collapse SNe. A type Ia SN is ruled out by the observed red IR color, and lack of features normally attributed to Fe-peak elements in the optical and IR spectra. SPIRITS 16tn was fainter at [4.5] than typical stripped-envelope SNe by $\approx$ 1 mag. Comparison of the spectral energy distribution to SNe II suggests SPIRITS 16tn was both highly obscured, and intrinsically dim, possibly akin to the low-luminosity SN 2005cs. We infer the presence of an IR dust echo powered by a peak luminosity of the transient of $5 \times 10^{40}$ erg s$^{-1} < L_{\mathrm{peak}} < 4\times10^{43}$ erg s$^{-1}$, consistent with the observed range for SNe II. This discovery illustrates the power of IR surveys to overcome the compounding effects of visible extinction and optically sub-luminous events in completing the inventory of nearby SNe.Comment: 25 pages, 10 figures, submitted to Ap