Nitric Oxide Induces Cell Death by Regulating Anti-Apoptotic BCL-2 Family Members

Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim−/−/Puma−/− MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death

Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F16 advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Forbidden hugs in pandemic times: III. Observations of the luminous red nova AT 2021biy in the nearby galaxy NGC 4631

We present an observational study of the luminous red nova (LRN) AT 2021biy in the nearby galaxy NGC 4631. The field of the object was routinely imaged during the pre-eruptive stage by synoptic surveys, but the transient was detected only at a few epochs from ∼231 days before maximum brightness. The LRN outburst was monitored with unprecedented cadence both photometrically and spectroscopically. AT 2021biy shows a short-duration blue peak, with a bolometric luminosity of ∼1.6×1041 erg s-1, followed by the longest plateau among LRNe to date, with a duration of 210 days. A late-time hump in the light curve was also observed, possibly produced by a shell-shell collision. AT 2021biy exhibits the typical spectral evolution of LRNe. Early-time spectra are characterised by a blue continuum and prominent H emission lines. Then, the continuum becomes redder, resembling that of a K-type star with a forest of metal absorption lines during the plateau phase. Finally, late-time spectra show a very red continuum (TBB ≈ 2050 K) with molecular features (e.g., TiO) resembling those of M-type stars. Spectropolarimetric analysis indicates that AT 2021biy has local dust properties similar to those of V838 Mon in the Milky Way Galaxy. Inspection of archival Hubble Space Telescope data taken on 2003 August 3 reveals a ∼20 M⊙ progenitor candidate with log (L/L⊙) = 5.0 dex and Teff 5900 K at solar metallicity. The above luminosity and colour match those of a luminous yellow supergiant. Most likely, this source is a close binary, with a 17-24 M⊙ primary component

Multiple Roles of Alu-Related Noncoding RNAs

Repetitive Alu and Alu-related elements are present in primates, tree shrews (Scandentia), and rodents and have expanded to 1.3 million copies in the human genome by nonautonomous retrotransposition. Pol III transcription from these elements occurs at low levels under normal conditions but increases transiently after stress, indicating a function of Alu RNAs in cellular stress response. Alu RNAs assemble with cellular proteins into ribonucleoprotein complexes and can be processed into the smaller scAlu RNAs. Alu and Alu-related RNAs play a role in regulating transcription and translation. They provide a source for the biogenesis of miRNAs and, embedded into mRNAs, can be targeted by miRNAs. When present as inverted repeats in mRNAs, they become substrates of the editing enzymes, and their modification causes the nuclear retention of these mRNAs. Certain Alu elements evolved into unique transcription units with specific expression profiles producing RNAs with highly specific cellular functions