5 research outputs found
Physical Activity Promotion: Highlights from the 2018 Physical Activity Guidelines Advisory Committee Systematic Review.
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RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers
Radical reversal of vasoactive intestinal peptide (VIP) receptors during early lymphopoiesis
An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning
Male germ cells of all placental mammals express an ancient nuclear RNA binding protein of unknown function called RBMXL2. Here we find that deletion of the retrogene encoding RBMXL2 blocks spermatogenesis. Transcriptome analyses of age-matched deletion mice show that RBMXL2 controls splicing patterns during meiosis. In particular, RBMXL2 represses the selection of aberrant splice sites and the insertion of cryptic and premature terminal exons. Our data suggest a Rbmxl2 retrogene has been conserved across mammals as part of a splicing control mechanism that is fundamentally important to germ cell biology. We propose that this mechanism is essential to meiosis because it buffers the high ambient concentrations of splicing activators, thereby preventing poisoning of key transcripts and disruption to gene expression by aberrant splice site selection
Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies
Flare frequency distributions represent a key approach to addressing one of
the largest problems in solar and stellar physics: determining the mechanism
that counter-intuitively heats coronae to temperatures that are orders of
magnitude hotter than the corresponding photospheres. It is widely accepted
that the magnetic field is responsible for the heating, but there are two
competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To
date, neither can be directly observed. Nanoflares are, by definition,
extremely small, but their aggregate energy release could represent a
substantial heating mechanism, presuming they are sufficiently abundant. One
way to test this presumption is via the flare frequency distribution, which
describes how often flares of various energies occur. If the slope of the power
law fitting the flare frequency distribution is above a critical threshold,
as established in prior literature, then there should be a
sufficient abundance of nanoflares to explain coronal heating. We performed
600 case studies of solar flares, made possible by an unprecedented number
of data analysts via three semesters of an undergraduate physics laboratory
course. This allowed us to include two crucial, but nontrivial, analysis
methods: pre-flare baseline subtraction and computation of the flare energy,
which requires determining flare start and stop times. We aggregated the
results of these analyses into a statistical study to determine that . This is below the critical threshold, suggesting that Alfv\'en
waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The
Astrophysical Journal on 2023-05-09, volume 948, page 7