The Chemical Distribution in a Subluminous Type Ia Supernova: HST Images of the SN 1885 Remnant

We present HST images of the remnant of SN 1885 seen in absorption against M31's bulge via resonance lines of Ca I, Ca II, Fe I, and Fe II. Viewed in CaII H & K line absorption, the remnant appears as a nearly black circular spot with an outermost angular radius of 0.40" +/- 0.025" implying r = 1.52 pc and a 120 yr average expansion velocity of 12400 +/-1400 km/s. The strongest Ca II absorption is organized in a broken ring structure with a radius of 0.20" (=6000 km/s) with several apparent absorption `clumps' of an angular size near the pixel scale of 0.05" (= 1500 km/s). The detection of Ca II clumps is the first direct evidence for some instabilities and the existence of a deflagration phase in SNe Ia or, alternatively, mixing induced by radioactive decay of 56^Ni over time scales of seconds or days. However, the degree of mixing allowed by the observed images is much smaller than current 3D calculations for Rayleigh-Taylor dominated deflagration fronts. The images also require a central region of no or little Ca but iron group elements indicative of burning under sufficiently high densities for electron capture taking place, i.e., burning prior to a significant pre-expansion of the WD.Comment: 18 pages, 14 figures. Accepted for publication in Ap

LATE-TIME X-RAY, UV, AND OPTICAL MONITORING OF SUPERNOVA 1979C

ABSTRACT We present results from observations of supernova (SN) 1979C with the Newton X-Ray Multi-Mirror (XMMNewton) mission in X-rays and in UV, archival X-ray, and Hubble Space Telescope (HST ) data, and follow-up ground-based optical imaging. The XMM-Newton MOS spectrum shows the best-fit two-temperature thermal plasma emission characteristics of both the forward (kT high ¼ 4:1 þ76 À2:4 keV) and reverse shock (kT low ¼ 0:79 þ0:24 À0:17 keV) with no intrinsic absorption. The long-term X-ray light curve, constructed from all X-ray data available, reveals that SN 1979C is still radiating at a flux level similar to that detected by ROSAT in 1995, showing no sign of a decline over the last 6 years, some 16-23 yr after its outburst. The high inferred X-ray luminosity (L 0:3 2 ¼ 8 ; 10 38 ergs s À1 ) is caused by the interaction of the SN shock with dense circumstellar matter, likely deposited by a strong stellar wind from the progenitor with a high mass-loss rate ofṀ % 1:5 ; 10 À4 M yr À1 (v w /10 km s À1 ). The X-ray data support a strongly decelerated shock and show a mass-loss rate history that is consistent with a constant progenitor mass-loss rate and wind velocity over the past k16,000 yr in the stellar evolution of the progenitor. We find a best-fit circumstellar medium (CSM) density profile of CSM / r Às with index s P 1:7 and high CSM densities (k10 4 cm À

NOS1AP is a novel molecular target and critical factor in TDP-43 pathology

Cappelli et al. reported that Nitric Oxide Synthase 1 Adaptor Protein is a co-regulated transcript of the TAR DNA-binding protein 43 kDa, reduced in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients with TAR DNA-binding protein 43 kDa pathology. Overall, their results highlight Nitric Oxide Synthase 1 Adaptor Protein as a novel druggable disease-relevant gene in TAR DNA-binding protein 43 kDa-related proteinopathies.Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies

mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein-enriched transcripts

Target prediction for animal microRNAs (miRNAs) has been hindered by the small number of verified targets available to evaluate the accuracy of predicted miRNA-target interactions. Recently, a dataset of 3,404 miRNA-associated mRNA transcripts was identified by immunoprecipitation of the RNA-induced silencing complex components AIN-1 and AIN-2. Our analysis of this AIN-IP dataset revealed enrichment for defining characteristics of functional miRNA-target interactions, including structural accessibility of target sequences, total free energy of miRNA-target hybridization and topology of base-pairing to the 5' seed region of the miRNA. We used these enriched characteristics as the basis for a quantitative miRNA target prediction method, miRNA targets by weighting immunoprecipitation-enriched parameters (mirWIP), which optimizes sensitivity to verified miRNA-target interactions and specificity to the AIN-IP dataset. MirWIP can be used to capture all known conserved miRNA-mRNA target relationships in Caenorhabditis elegans at a lower false-positive rate than can the current standard methods

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo

Organoid Models of Human and Mouse Ductal Pancreatic Cancer

Summary Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy