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result(s) for
"Wagner, Jon G"
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Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (
r
̂
g
~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
A genetic study identifies hundreds of loci associated with risk tolerance and risky behaviors, finds evidence of substantial shared genetic influences across these phenotypes, and implicates genes involved in neurotransmission.
Journal Article
Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer
Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in
ABCC1
and deletions in
MYCL, MSH2
, and
MSH6
, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including
CHD8
and
APC
. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.
Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.
Journal Article
Dynamic omnivory shapes the functional role of large carnivores under global change
Omnivory is increasingly recognized as a dynamic stabilizing force under environmental change. Despite its ubiquity across ecosystems, trophic levels and spatiotemporal scales, our empirical understanding of how omnivores respond to changing conditions in terrestrial ecosystems is limited. Here we combine macroecological and paleoecological approaches across seven bear species—the largest terrestrial carnivores—and discover they dynamically adapt their trophic position in food webs to resource availability. Throughout their ranges, bears shift to carnivory in unproductive ecosystems with short growing seasons and to herbivory in productive ecosystems with long growing seasons. In line with this, isotopic evidence from the Late Pleistocene and Holocene reveals a sharp decrease in the trophic position of the European brown bear in response to increasing net primary productivity and growing season length. These findings reveal a mechanism of trophic rewiring that alters the functional role of large carnivores in ecosystems and may simultaneously stabilize food web dynamics under global change.
Omnivores like bears can switch between plant and animal diets, potentially helping them respond to changing conditions. By combining modern and fossil data, this study shows that bears shift toward carnivory in harsher climates and toward herbivory in more productive environments.
Journal Article
Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group
Class IIa histone deacetylases (HDACs) are generally viewed as noncatalytic readers of acetylated lysines within proteins. Specific inhibitors of class IIa HDACs, based on a new zinc-binding scaffold, offer chemical probes to explore the biological function and potential druggability of this enzyme subclass.
In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.
Journal Article
Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain
The voltage-gated sodium Na V 1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human Na V 1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human Na V 1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC 50 s of 7 nM and 4 nM for hNa V 1.7 and more than 1000-fold selectivity over human Na V 1.1, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.8, and Na V 1.9 channels. PTx2-3127 inhibits Na V 1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally designed peptide inhibitors of human Na V 1.7 channels have transformative potential to define a new class of biologics to treat pain.
Journal Article
One voice and vision: How the RISE network built a collective identity as the foundation for strategic dissemination
A collective identity is a set of shared values and value propositions that an investigator network projects as they deliver data and knowledge generated through their studies to community partners, policymakers, research participants, public health authorities, and prospective end users. The strategic process of identifying common values and establishing procedures to ensure the consistent communication of a collective identity across a diverse network of research teams is often not considered in research networks' dissemination of results. This paper describes how the HEAL Research on Interventions for Stability and Engagement (RISE) network co-created communication pillars that embody a set of common values and shared research imperatives to frame dissemination activities.
Early in the development of RISE, project teams participated in an in-person workshop to identify attributes and core values that they believed to be representative of their individual research programs. Dissemination coordinators analyzed and synthesized themes from workshop material, including presentations and posterboard illustrations, and used Mural whiteboarding software to distill these themes into core values and value propositions to collectively share across the research sites.
The four communication pillars, which encompass our collective identity and are the foundation of our dissemination program, are (1) Doing Research with Communities, (2) Centering on the Lives and Experiences of People Who Use Drugs, (3) Emphasizing Scientific Rigor and Integrity; and (4) Focusing on Social Determinants. We present examples of how project teams are demonstrating the pillars throughout the research process and outline how the communication pillars inform the planning and dissemination of RISE-produced evidence to end users.
Applying concepts from strategic communication and social marketing, we demonstrate how a research network of independent investigators can create a collective identity, formulate a cogent narrative communicating their contributions to a field of practice, and establish a foundation for a successful research dissemination program.
Journal Article
Search for pairs of scalar leptoquarks decaying into quarks and electrons or muons in s = 13 TeV pp collisions with the ATLAS detector
A
bstract
A search for new-physics resonances decaying into a lepton and a jet performed by the ATLAS experiment is presented. Scalar leptoquarks pair-produced in
pp
collisions at
s
= 13 TeV at the Large Hadron Collider are considered using an integrated luminosity of 139 fb
−
1
, corresponding to the full Run 2 dataset. They are searched for in events with two electrons or two muons and two or more jets, including jets identified as arising from the fragmentation of
c
- or
b
-quarks. The observed yield in each channel is consistent with the Standard Model background expectation. Leptoquarks with masses below 1.8 TeV and 1.7 TeV are excluded in the electron and muon channels, respectively, assuming a branching ratio into a charged lepton and a quark of 100%, with minimal dependence on the quark flavour. Upper limits on the aforementioned branching ratio are also given as a function of the leptoquark mass.
Journal Article
Performance of electron and photon triggers in ATLAS during LHC Run 2
Electron and photon triggers covering transverse energies from 5
GeV
to several
TeV
are essential for the ATLAS experiment to record signals for a wide variety of physics: from Standard Model processes to searches for new phenomena in both proton–proton and heavy-ion collisions. To cope with a fourfold increase of peak LHC luminosity from 2015 to 2018 (Run 2), to
2.1
×
10
34
cm
-
2
s
-
1
, and a similar increase in the number of interactions per beam-crossing to about 60, trigger algorithms and selections were optimised to control the rates while retaining a high efficiency for physics analyses. For proton–proton collisions, the single-electron trigger efficiency relative to a single-electron offline selection is at least 75% for an offline electron of 31
GeV
, and rises to 96% at 60
GeV
; the trigger efficiency of a 25
GeV
leg of the primary diphoton trigger relative to a tight offline photon selection is more than 96% for an offline photon of 30
GeV
. For heavy-ion collisions, the primary electron and photon trigger efficiencies relative to the corresponding standard offline selections are at least 84% and 95%, respectively, at 5
GeV
above the corresponding trigger threshold.
Journal Article