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Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

Stable, hydrogen-burning, M dwarf stars make up about 75% of all stars in the Galaxy. They are extremely long-lived, and because they are much smaller in mass than the Sun (between 0.5 and 0.08 M(Sun)), their temperature and stellar luminosity are low and peaked in the red. We have re-examined what is known at present about the potential for a terrestrial planet forming within, or migrating into, the classic liquid-surface-water habitable zone close to an M dwarf star. Observations of protoplanetary disks suggest that planet-building materials are common around M dwarfs, but N-body simulations differ in their estimations of the likelihood of potentially habitable, wet planets that reside within their habitable zones, which are only about one-fifth to 1/50th of the width of that for a G star. Particularly in light of the claimed detection of the planets with masses as small as 5.5 and 7.5 M(Earth) orbiting M stars, there seems no reason to exclude the possibility of terrestrial planets. Tidally locked synchronous rotation within the narrow habitable zone does not necessarily lead to atmospheric collapse, and active stellar flaring may not be as much of an evolutionarily disadvantageous factor as has previously been supposed. We conclude that M dwarf stars may indeed be viable hosts for planets on which the origin and evolution of life can occur. A number of planetary processes such as cessation of geothermal activity or thermal and nonthermal atmospheric loss processes may limit the duration of planetary habitability to periods far shorter than the extreme lifetime of the M dwarf star. Nevertheless, it makes sense to include M dwarf stars in programs that seek to find habitable worlds and evidence of life. This paper presents the summary conclusions of an interdisciplinary workshop (http://mstars.seti.org) sponsored by the NASA Astrobiology Institute and convened at the SETI Institute.

In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed 'seed' sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Spe-cifically in high-grade gliomas, miR-376a * accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a * and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a * promoted glioma cell migration and invasion, while the edited miR-376a * suppressed these features. The effects of the unedited miR-376a * were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a * sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a * as a potential therapeutic target in glioblastoma cells., Introduction MicroRNAs (miRNAs) are short, noncoding RNAs that mediate post-transcriptional silencing of a set of target genes. The target gene specificity of each miRNA is dictated by sequence-dependent interaction between [...]

Although intervals of faunal stasis have been identified in the Paleozoic and Cenozoic, here we report the first quantitative documentation of long-term faunal stasis in the Mesozoic, a time of great biological and ecological change. On the basis of an analysis of previously published and newly collected data on Jurassic benthic marine invertebrates from the U.S. Western Interior, we find that significant proportions of bivalve species and associations persisted through major sea-level and environmental changes. In the six Jurassic marine depositional units studied, each spanning 2-6 m.y., 32% to 100% (averaging 56%) of bivalve species were holdovers from the preceding unit, while the proportion of carryover species that persisted into the next unit ranges from 16% to 81% (averaging 46%). Bivalve associations also commonly persisted through depositional units and stratigraphic breaks. The ecological stability documented here does not suggest any coordination of origination or turnover among taxa. We conclude that the pattern of faunal stability is due to stasis within individual species and not to community-level processes. Environmental conditions of the Jurassic Western Interior seaway may have selected for generalist taxa capable of withstanding environmental disturbances and persisting for long intervals of time.