Search

Dual phase xenon detectors are widely used in experimental searches for galactic dark matter particles. The origin of single electron backgrounds following prompt scintillation and proportional scintillation signals in these detectors is not fully understood, although there has been progress in recent years. In this paper, we describe single electron backgrounds in 83mKr calibration events and their correlation with drift and extraction fields, using the Particle Identification in Xenon at Yale (PIXeY) dual-phase xenon time projection chamber. The single electron background induced by the Fowler-Nordheim (FN) effect is measured, and its electric field dependence is quantified. The photoionization of grids and impurities by prompt scintillation and proportional scintillation also contributes to the single electron background.

The Large Underground Xenon (LUX) dark matter search was a 250-kg active mass dual-phase time projection chamber that operated by detecting light and ionization signals from particles incident on a xenon target. In December 2015, LUX reported a minimum 90% upper C.L. of 6×10-46 cm2 on the spin-independent WIMP-nucleon elastic scattering cross section based on a 1.4×104 kg·day exposure in its first science run. Tension between experiments and the absence of a definitive positive detection suggest it would be prudent to search for WIMPs outside the standard spin-independent/spin-dependent paradigm. Recent theoretical work has identified a complete basis of 14 independent effective field theory (EFT) operators to describe WIMP-nucleon interactions. In addition to spin-independent and spin-dependent nuclear responses, these operators can produce novel responses such as angular-momentum-dependent and spin-orbit couplings. Here we report on a search for all 14 of these EFT couplings with data from LUX's first science run. Limits are placed on each coupling as a function of WIMP mass.

The Large Underground Xenon (LUX) dark matter search was a 250-kg active massdual-phase time projection chamber that operated by detecting light andionization signals from particles incident on a xenon target. In December 2015,LUX reported a minimum 90% upper C.L. of 6e-46 cm^2 on the spin-independentWIMP-nucleon elastic scattering cross section based on a 1.4e4 kg*day exposurein its first science run. Tension between experiments and the absence of adefinitive positive detection suggest it would be prudent to search for WIMPsoutside the standard spin-independent/spin-dependent paradigm. Recenttheoretical work has identified a complete basis of 14 independent effectivefield theory (EFT) operators to describe WIMP-nucleon interactions. In additionto spin-independent and spin-dependent nuclear responses, these operators canproduce novel responses such as angular-momentum-dependent and spin-orbitcouplings. Here we report on a search for all 14 of these EFT couplings withdata from LUX's first science run. Limits are placed on each coupling as afunction of WIMP mass.

The LUX experiment has performed searches for dark-matter particles scattering elastically on xenon nuclei, leading to stringent upper limits on the nuclear scattering cross sections for dark matter. Here, for results derived from 1.4×104 kg days of target exposure in 2013, details of the calibration, event-reconstruction, modeling, and statistical tests that underlie the results are presented. Detector performance is characterized, including measured efficiencies, stability of response, position resolution, and discrimination between electron- and nuclear-recoil populations. Models are developed for the drift field, optical properties, background populations, the electron- and nuclear-recoil responses, and the absolute rate of low-energy background events. Innovations in the analysis include in situ measurement of the photomultipliers' response to xenon scintillation photons, verification of fiducial mass with a low-energy internal calibration source, and new empirical models for low-energy signal yield based on large-sample, in situ calibrations.

The (x, y) position reconstruction method used in the analysis of the complete exposure of the Large Underground Xenon (LUX) experiment is presented. The algorithm is based on a statistical test that makes use of an iterative method to recover the photomultiplier tube (PMT) light response directly from the calibration data. The light response functions make use of a two dimensional functional form to account for the photons reflected on the inner walls of the detector. To increase the resolution for small pulses, a photon counting technique was employed to describe the response of the PMTs. The reconstruction was assessed with calibration data including 83mKr (releasing a total energy of 41.5 keV) and 3H (andbeta;- with Q = 18.6 keV) decays, and a deuterium-deuterium (D-D) neutron beam (2.45 MeV) . Within the detector's fiducial volume, the reconstruction has achieved an (x, y) position uncertainty of andsigma; = 0.82 cm and andsigma; = 0.17 cm for events of only 200 and 4,000 detected electroluminescence photons respectively. Such signals are associated with electron recoils of energies andsim;0.25 keV and andsim;10 keV, respectively. The reconstructed position of the smallest events with a single electron emitted from the liquid surface (22 detected photons) has a horizontal (x, y) uncertainty of 2.13 cm.

The Large Underground Xenon (LUX) experiment operates at the Sanford Underground Research Facility to detect nuclear recoils from the hypothetical Weakly Interacting Massive Particles (WIMPs) on a liquid xenon target. Liquid xenon typically contains trace amounts of the noble radioactive isotopes 85Kr and 39Ar that are not removed by the in situ gas purification system. The decays of these isotopes at concentrations typical of research-grade xenon would be a dominant background for a WIMP search experiment. To remove these impurities from the liquid xenon, a chromatographic separation system based on adsorption on activated charcoal was built. 400 kg of xenon was processed, reducing the average concentration of krypton from 130 ppb to 3.5 ppt as measured by a cold-trap assisted mass spectroscopy system. A 50 kg batch spiked to 0.001 g/g of krypton was processed twice and reduced to an upper limit of 0.2 ppt.

We report an absolute calibration of the ionization yields (Qy) and fluctuations for electronic recoil events in liquid xenon at discrete energies between 186 eV and 33.2 keV. The average electric field applied across the liquid xenon target is 180 V/cm. The data are obtained using low energy Xe127 electron capture decay events from the 95.0-day first run from LUX (WS2013) in search of weakly interacting massive particles. The sequence of gamma-ray and x-ray cascades associated with I127 deexcitations produces clearly identified two-vertex events in the LUX detector. We observe the K-(binding energy, 33.2 keV), L-(5.2 keV), M-(1.1 keV), and N-(186 eV) shell cascade events and verify that the relative ratio of observed events for each shell agrees with calculations. The N-shell cascade analysis includes single extracted electron (SE) events and represents the lowest-energy electronic recoil in situ measurements that have been explored in liquid xenon.

LUX was the first dark matter experiment to use a Kr83m calibration source. In this paper, we describe the source preparation and injection. We also present several Kr83m calibration applications in the context of the 2013 LUX exposure, including the measurement of temporal and spatial variation in scintillation and charge signal amplitudes, and several methods to understand the electric field within the time projection chamber.

LUX was the first dark matter experiment to use a Kr83m calibration source. In this paper, we describe the source preparation and injection. We also present several Kr83m calibration applications in the context of the 2013 LUX exposure, including the measurement of temporal and spatial variation in scintillation and charge signal amplitudes, and several methods to understand the electric field within the time projection chamber.

We report an absolute calibration of the ionization yields (Qy) and fluctuations for electronic recoil events in liquid xenon at discrete energies between 186 eV and 33.2 keV. The average electric field applied across the liquid xenon target is 180 V/cm. The data are obtained using low energy Xe127 electron capture decay events from the 95.0-day first run from LUX (WS2013) in search of weakly interacting massive particles. The sequence of gamma-ray and x-ray cascades associated with I127 deexcitations produces clearly identified two-vertex events in the LUX detector. We observe the K-(binding energy, 33.2 keV), L-(5.2 keV), M-(1.1 keV), and N-(186 eV) shell cascade events and verify that the relative ratio of observed events for each shell agrees with calculations. The N-shell cascade analysis includes single extracted electron (SE) events and represents the lowest-energy electronic recoil in situ measurements that have been explored in liquid xenon.

This work details the development of a three-dimensional (3D) electric field model for the LUX detector. The detector took data to search for weakly interacting massive particles (WIMPs) during two periods. After the first period completed, a time-varying non-uniform negative charge developed in the polytetrafluoroethylene (PTFE) panels that define the radial boundary of the detector's active volume. This caused electric field variations in the detector in time, depth and azimuth, generating an electrostatic radially-inward force on electrons on their way upward to the liquid surface. To map this behavior, 3D electric field maps of the detector's active volume were generated on a monthly basis. This was done by fitting a model built in COMSOL Multiphysics to the uniformly distributed calibration data that were collected on a regular basis. The modeled average PTFE charge density increased over the course of the exposure from -3.6 to -5.5 μC/m2. From our studies, we deduce that the electric field magnitude varied locally while the mean value of the field of ∼200 V/cm remained constant throughout the exposure. As a result of this work the varying electric fields and their impact on event reconstruction and discrimination were successfully modeled.

We calibrate a two-phase xenon detector at 0.27 keV in the charge channel and at 2.8 keV in both the light and charge channels using a 37Ar source that is directly released into the detector. We map the light and charge yields as a function of electric drift field. For the 2.8 keV peak, we calculate the Thomas-Imel box parameter for recombination and determine its dependence on drift field. For the same peak, we achieve an energy resolution, Eσ/Emean, between 9.8% and 10.8% for 0.1 kV/cm to 2 kV/cm electric drift fields.

The first searches for axions and axionlike particles with the Large Underground Xenon experiment are presented. Under the assumption of an axioelectric interaction in xenon, the coupling constant between axions and electrons g_{Ae} is tested using data collected in 2013 with an exposure totaling 95 live days ×118  kg. A double-sided, profile likelihood ratio statistic test excludes g_{Ae} larger than 3.5×10^{-12} (90% C.L.) for solar axions. Assuming the Dine-Fischler-Srednicki-Zhitnitsky theoretical description, the upper limit in coupling corresponds to an upper limit on axion mass of 0.12  eV/c^{2}, while for the Kim-Shifman-Vainshtein-Zhakharov description masses above 36.6  eV/c^{2} are excluded. For galactic axionlike particles, values of g_{Ae} larger than 4.2×10^{-13} are excluded for particle masses in the range 1-16  keV/c^{2}. These are the most stringent constraints to date for these interactions.

We present experimental constraints on the spin-dependent WIMP-nucleon elastic cross sections from the total 129.5  kg yr exposure acquired by the Large Underground Xenon experiment (LUX), operating at the Sanford Underground Research Facility in Lead, South Dakota (USA). A profile likelihood ratio analysis allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=1.6×10^{-41}  cm^{2} (σ_{p}=5×10^{-40}  cm^{2}) at 35  GeV c^{-2}, almost a sixfold improvement over the previous LUX spin-dependent results. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.

This work presents an analysis of monoenergetic electronic recoil peaks in the dark-matter-search and calibration data from the first underground science run of the Large Underground Xenon (LUX) detector. Liquid xenon charge and light yields for electronic recoil energies between 5.2 and 661.7 keV are measured, as well as the energy resolution for the LUX detector at those same energies. Additionally, there is an interpretation of existing measurements and descriptions of electron-ion recombination fluctuations in liquid xenon as limiting cases of a more general liquid xenon recombination fluctuation model. Measurements of the standard deviation of these fluctuations at monoenergetic electronic recoil peaks exhibit a linear dependence on the number of ions for energy deposits up to 661.7 keV, consistent with previous LUX measurements between 2 and 16 keV with H3. We highlight similarities in liquid xenon recombination for electronic and nuclear recoils with a comparison of recombination fluctuations measured with low-energy calibration data.

We report constraints on spin-independent weakly interacting massive particle (WIMP)-nucleon scattering using a 3.35×10^{4}  kg day exposure of the Large Underground Xenon (LUX) experiment. A dual-phase xenon time projection chamber with 250 kg of active mass is operated at the Sanford Underground Research Facility under Lead, South Dakota (USA). With roughly fourfold improvement in sensitivity for high WIMP masses relative to our previous results, this search yields no evidence of WIMP nuclear recoils. At a WIMP mass of 50  GeV c^{-2}, WIMP-nucleon spin-independent cross sections above 2.2×10^{-46}  cm^{2} are excluded at the 90% confidence level. When combined with the previously reported LUX exposure, this exclusion strengthens to 1.1×10^{-46}  cm^{2} at 50  GeV c^{-2}.

LUX is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils resulting from interactions with dark matter particles. Signals from the detector are processed with an FPGA-based digital trigger system that analyzes the incoming data in real-time, with just a few microsecond latency. The system enables first pass selection of events of interest based on their pulse shape characteristics and 3D localization of the interactions. It has been shown to be >99% efficient in triggering on S2 signals induced by only few extracted liquid electrons. It is continuously and reliably operating since its full underground deployment in early 2013. This document is an overview of the systems capabilities, its inner workings, and its performance.

We present constraints on weakly interacting massive particles (WIMP)-nucleus scattering from the 2013 data of the Large Underground Xenon dark matter experiment, including 1.4×10^{4}  kg day of search exposure. This new analysis incorporates several advances: single-photon calibration at the scintillation wavelength, improved event-reconstruction algorithms, a revised background model including events originating on the detector walls in an enlarged fiducial volume, and new calibrations from decays of an injected tritium β source and from kinematically constrained nuclear recoils down to 1.1 keV. Sensitivity, especially to low-mass WIMPs, is enhanced compared to our previous results which modeled the signal only above a 3 keV minimum energy. Under standard dark matter halo assumptions and in the mass range above 4  GeV c^{-2}, these new results give the most stringent direct limits on the spin-independent WIMP-nucleon cross section. The 90% C.L. upper limit has a minimum of 0.6 zb at 33  GeV c^{-2} WIMP mass.

We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4}  kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41}  cm^{2} (σ_{p}=2.9×10^{-39}  cm^{2}) at 33  GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.

We present measurements of the electron-recoil (ER) response of the LUX dark matter detector based upon 170 000 highly pure and spatially uniform tritium decays. We reconstruct the tritium energy spectrum using the combined energy model and find good agreement with expectations. We report the average charge and light yields of ER events in liquid xenon at 180 and 105 V/cm and compare the results to the NEST model. We also measure the mean charge recombination fraction and its fluctuations, and we investigate the location and width of the LUX ER band. These results provide input to a reanalysis of the LUX run 3 weakly interacting massive particle search.

LUX (Large Underground Xenon) is a dark matter direct detection experiment deployed at the 4850' level of the Sanford Underground Research Facility (SURF) in Lead, SD, operating a 370 kg dual-phase xenon TPC. Results of the first WIMP search run were presented in late 2013, for the analysis of 85.3 live-days with a fiducial volume of 118 kg, taken during the period of April to August 2013. The experiment exhibited a sensitivity to spin-independent WIMP-nucleon elastic scattering with a minimum upper limit on the cross section of 7.6×10-46cm2 at a WIMP mass of 33 GeV/c2, becoming the world's leading WIMP search result, in conflict with several previous claimed hints of discovery.

The LUX (Large Underground Xenon) experiment aims at the direct detection of dark matter particles via their collisions with xenon nuclei. The 370 kg two-phase liquid xenon time projection chamber measures simultaneously the scintillation and ionization from interactions in the target. The ratio of these two signals provides very good discrimination between potential nuclear recoil and electronic recoil signals to search for WIMP-nucleon scattering. The LUX detector operates at the Sanford Underground Research Facility (Lead, South Dakota, USA) since February 2013. First results were presented in late 2013 setting the world's most stringent limits on WIMP-nucleon scattering cross-sections over a wide range of WIMP masses. A 300 day run beginning in 2014 will further improve the sensitivity and new calibration techniques will reduce systematics for the WIMP signal search.

© 2014 Elsevier B.V. The LUX (Large Underground Xenon) experiment aims at the direct detection of dark matter particles via their collisions with xenon nuclei. The 370. kg two-phase liquid xenon time projection chamber measures simultaneously the scintillation and ionization from interactions in the target. The ratio of these two signals provides very good discrimination between potential nuclear recoil and electronic recoil signals to search for WIMP-nucleon scattering. The LUX detector operates at the Sanford Underground Research Facility (Lead, South Dakota, USA) since February 2013. First results were presented in late 2013 setting the world's most stringent limits on WIMP-nucleon scattering cross-sections over a wide range of WIMP masses. A 300 day run beginning in 2014 will further improve the sensitivity and new calibration techniques will reduce systematics for the WIMP signal search.

The Large Underground Xenon (LUX) dark matter experiment aims to detect rare low-energy interactions from Weakly Interacting Massive Particles (WIMPs). The radiogenic backgrounds in the LUX detector have been measured and compared with Monte Carlo simulation. Measurements of LUX high-energy data have provided direct constraints on all background sources contributing to the background model. The expected background rate from the background model for the 85.3 day WIMP search run is (2.6±0.2stat±0.4sys) ×10-3 events keVee-1kg-1day-1 in a 118 kg fiducial volume. The observed background rate is (3.6±0.4 stat)×10-3 events keVee-1kg-1day- 1, consistent with model projections. The expectation for the radiogenic background in a subsequent one-year run is presented. © 2014 Elsevier B.V. All rights reserved.

The LUX detector is currently in operation at the Davis Campus at the 4850' level of the Sanford Underground Research Facility (SURF) in Lead, SD to directly search for WIMP dark matter. Knowing the type and rate of backgrounds is critical in a rare, low energy event search, and LUX was designed, constructed, and deployed to mitigate backgrounds, both internal and external. An important internal background are decays of radon and its daughters. These consist of alpha decays, which are easily tagged and are a tracer of certain backgrounds, and beta decays, some of which are not as readily tagged and present a background for the WIMP search. We report on studies of alpha decay and discuss implications for the WIMP search.

We present the status and prospects of the LUX experiment, which employs approximately 300 kg of two-phase xenon to search for WIMP dark matter interactions. The LUX detector was commissioned at the surface laboratory of the Sanford Underground Research Facility in Lead, SD, between December 2011 and February 2012 and the detector has been operating underground since January, 2013. These proceedings review the results of the commissioning run as well as the status of underground data-taking through the summer of 2013.

The Large Underground Xenon (LUX) experiment is a dual-phase xenon time-projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota). The LUX cryostat was filled for the first time in the underground laboratory in February 2013. We report results of the first WIMP search data set, taken during the period from April to August 2013, presenting the analysis of 85.3 live days of data with a fiducial volume of 118 kg. A profile-likelihood analysis technique shows our data to be consistent with the background-only hypothesis, allowing 90% confidence limits to be set on spin-independent WIMP-nucleon elastic scattering with a minimum upper limit on the cross section of 7.6 × 10(-46) cm(2) at a WIMP mass of 33 GeV/c(2). We find that the LUX data are in disagreement with low-mass WIMP signal interpretations of the results from several recent direct detection experiments.

LUX, the world's largest dual-phase xenon time-projection chamber, with afiducial target mass of 118 kg and 10,091 kg-days of exposure thus far, iscurrently the most sensitive direct dark matter search experiment. The initialnull-result limit on the spin-independent WIMP-nucleon scattering cross-sectionwas released in October 2013, with a primary scintillation threshold of 2 phe,roughly 3 keVnr for LUX. The detector has been deployed at the SanfordUnderground Research Facility (SURF) in Lead, South Dakota, and is the firstexperiment to achieve a limit on the WIMP cross-section lower than $10^{-45}$cm$^{2}$. Here we present a more in-depth discussion of the novel energy scaleemployed to better understand the nuclear recoil light and charge yields, andof the calibration sources, including the new internal tritium source. We foundthe LUX data to be in conflict with low-mass WIMP signal interpretations ofother results.

The search for dark matter reaches back generations and remains one of the most compelling endeavors in the hunt for physics beyond the Standard Model. Experiments attempting to directly detect WIMP dark matter have made re-markable progress in increasing sensitivity to elastic scattering of WIMPs on nuclei. The LUX experiment is a 370-kg, two-phase, xenon TPC currently running at SURF, 4850 feet below Lead, SD. LUX recently completed its first science run and was sensitive to spin independent WIMP scattering at cross sections below 10-45 cm2 for WIMP masses of approximately 20 to 80 GeV. Preparations for the final science run of LUX are currently underway, with final results expected in 2015. We will present results from and current status of the LUX experiment, as well as plans for a follow-on, multi-ton-scale xenon experiment at SURF.

© 2014 Elsevier B.V. The LUX (Large Underground Xenon) experiment aims at the direct detection of dark matter particles via their collisions with xenon nuclei. The 370. kg two-phase liquid xenon time projection chamber measures simultaneously the scintillation and ionization from interactions in the target. The ratio of these two signals provides very good discrimination between potential nuclear recoil and electronic recoil signals to search for WIMP-nucleon scattering. The LUX detector operates at the Sanford Underground Research Facility (Lead, South Dakota, USA) since February 2013. First results were presented in late 2013 setting the world's most stringent limits on WIMP-nucleon scattering cross-sections over a wide range of WIMP masses. A 300 day run beginning in 2014 will further improve the sensitivity and new calibration techniques will reduce systematics for the WIMP signal search.

The Large Underground Xenon (LUX) collaboration has designed and constructed a dual-phase xenon detector, in order to conduct a search for Weakly Interacting Massive Particles (WIMPs), a leading dark matter candidate. The goal of the LUX detector is to clearly detect (or exclude) WIMPS with a spin independent cross-section per nucleon of 2×10-46cm2, equivalent to ∼1event/100kg/month in the inner 100-kg fiducial volume (FV) of the 370-kg detector. The overall background goals are set to have

Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC 50 = 22 nM, K D = 40 nM, K I = 32 nM), and the most potent compound identified, H3B-968, has inhibitory activity IC 50 ∼ 10 nM. These kinetic properties trend toward other known covalent druglike molecules. Our work provides a new avenue for screening WRN for inhibitors that may be adaptable to different therapeutic modalities such as targeted protein degradation, as well as a proof of concept for the inhibition of WRN helicase activity by covalent molecules.

Three RNA helicases - DDX42, DDX46 and DHX15 - are found to be associated with human U2 snRNP, but their roles and mechanisms in U2 snRNP and spliceosome assembly are insufficiently understood. Here we report the cryo-electron microscopy (cryo-EM) structures of the DDX42-SF3b complex and a putative assembly precursor of 17S U2 snRNP that contains DDX42 (DDX42-U2 complex). DDX42 is anchored on SF3B1 through N-terminal sequences, with its N-plug occupying the RNA path of SF3B1. The binding mode of DDX42 to SF3B1 is in striking analogy to that of DDX46. In the DDX42-U2 complex, the N-terminus of DDX42 remains anchored on SF3B1, but the helicase domain has been displaced by U2 snRNA and TAT-SF1. Through in vitro assays, we show DDX42 and DDX46 are mutually exclusive in terms of binding to SF3b. Cancer-driving mutations of SF3B1 target the residues in the RNA path that directly interact with DDX42 and DDX46. These findings reveal the distinct roles of DDX42 and DDX46 in assembly of 17S U2 snRNP and provide insights into the mechanisms of SF3B1 cancer mutations., (© 2023. The Author(s).)

Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling., Competing Interests: Conflict of interest The main authors are employees of H3 Biomedicine. The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept., (© 2021. Crown.)

In this chapter, the essential role of the SF3b multi-protein complex will be discussed in the context of the overall spliceosome. SF3b is critical during spliceosome assembly for recognition of the branch point (BP) adenosine and, by de facto, selection of the 3' splice site. This complex is highly dynamic, undergoing significant conformational changes upon loading of the branch duplex RNA and in its relative positioning during spliceosomal remodeling from the A, pre-B, B, B act and B* complexes. Ultimately, during the spliceosome activation phase, SF3b must be displaced to unmask the branch point adenosine for the first splicing reaction to occur. In certain cancers, such as the hematological malignancies CML, CLL and MDS, the SF3b subunit SF3B1 is frequently mutated. Recent studies suggest these mutations lead to inappropriate branch point selection and mis-splicing events that appear to be drivers of disease. Finally, the SF3b complex is the target for at least three different classes of natural product-based inhibitors. These inhibitors bind in the BP adenosine-binding pocket and demonstrate a pre-mRNA competitive mechanism of action resulting in either intron retention or exon skipping. These compounds are extremely useful as chemical probes to isolate and characterize early stages of spliceosome assembly. They are also being explored preclinically and clinically as possible agents for hematological cancers.

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 ( 25 ), a potent allosteric inhibitor of CPS1 (IC 50 = 66 nM)., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Clostridioides difficile infection may be complicated by co-infection with other pathogens. We here describe the successful use of faecal microbiota transplantation to eradicate concomitant C. difficile and extensively drug-resistant (XDR) KPC-producing Klebsiella pneumoniae. Donor microbiota efficiently engrafted in the patient, and a donor-like microbial assemblage persisted in the patient during six months follow-up. The report explores the potential for the donor microbiota to eradicate and replace multi-resistant microorganisms.