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At least 703 records · Page 39

Structural insights into the mechanism defining substrate affinity in Arabidopsis thaliana dUTPase: the role of tryptophan 93 in ligand orientation

Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) hydrolyzes dUTP to dUMP and pyrophosphate to maintain the cellular thymine-uracil ratio. dUTPase is also a target for cancer chemotherapy. However, the mechanism defining its substrate affinity remains unclear. Sequence comparisons of various dUTPases revealed that Arabidopsis thaliana dUTPase has a unique tryptophan at position 93, which potentially contributes to its degree of substrate affinity. To better understand the roles of tryptophan 93, A. thaliana dUTPase was studied. Enzyme assays showed that A. thaliana dUTPase belongs to a high-affinity group of isozymes, which also includes the enzymes from Escherichia coli and Mycobacterium tuberculosis. Enzymes from Homo sapiens and Saccharomyces cerevisiae are grouped as low-affinity dUTPases. The structure of the homo-trimeric A. thaliana dUTPase showed three active sites, each with a different set of ligand interactions between the amino acids and water molecules. On an α-helix, tryptophan 93 appears to keep serine 89 in place via a water molecule and to specifically direct the ligand. Upon being oriented in the active site, the C-terminal residues close the active site to promote the reaction. In the high-affinity group, the prefixed direction of the serine residues was oriented by a positively charged residue located four amino acids away, while low-affinity enzymes possess small hydrophobic residues at the corresponding sites.

59 BASIC BIOLOGICAL SCIENCES↗

Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex. We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A 1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A 1 , APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.

59 BASIC BIOLOGICAL SCIENCES↗

The River Corridor Closure Contract How Washington Closure Hanford is Closing A Unique Department of Energy Project - 12425

Cleanup of the Hanford River Corridor has been one of Hanford Site's top priorities since the early 1990's. This urgency is due to the proximity of hundreds of waste sites to the Columbia River and the groundwater that continues to threaten the Columbia River. In April 2005, the U.S. Department of Energy, Richland Operations Office (DOE-RL) awarded the Hanford River Corridor Closure Contract (RCCC), a cost-plus incentive-fee closure contract with a 2015 end date and first of its kind at Hanford Site, to Washington Closure Hanford (WCH), a limited-liability company owned by URS, Bechtel National, and CH2M HILL. WCH is a single-purpose company whose goal is to safely, compliantly, and efficiently accelerate cleanup in the Hanford River Corridor and reduce or eliminate future obligations to DOE-RL for maintaining long-term stewardship over the site. Accelerated performance of the work-scope while keeping a perspective on contract completion presents challenges that require proactive strategies to support the remaining work-scope through the end of the RCCC. This paper outlines the processes to address the challenges of completing work-scope while planning for contract termination. WCH is responsible for cleanup of the River Corridor 569.8 km{sup 2} (220 mi{sup 2}) of the 1,517.7 km{sup 2} (586 mi{sup 2}) Hanford Site's footprint reduction. At the end of calendar year 2011, WCH's closure implementation is well underway. Fieldwork is complete in three of the largest areas within the RCCC scope (Segments 1, 2, and 3), approximately 44.5% of the River Corridor (Figure 3). Working together, DOE-RL and WCH are in the process of completing the 'paper work' that will document the completion of the work-scope and allow DOE-RL to relieve WCH of contractual responsibilities and transition the completed areas to the Long-Term Stewardship Program, pending final action RODs. Within the next 4 years, WCH will continue to complete cleanup of the River Corridor following the completion goals. As field work-scope is completed, progressive reductions of business processes, physical facilities, and staff will occur. Organizations will collapse and flatten commensurate with workload. WCH employees will move on to new endeavors, proud of their accomplishments and the legacy they are leaving behind as being the first and largest environmental cleanup closure contract at Hanford. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Thermodynamic Band Gap Model for Photoinduced Phase Segregation in Mixed-Halide Perovskites

Provided is a comprehensive description of a band gap thermodynamic model, which predicts and explains key features of photosegregation in lead-based, mixed-halide perovskites. The model gives a prescription for illustrating halide migration driven by photocarrier energies. Where possible, model predictions are compared with experimental results. Free energy derivations are provided for three assumptions: (1) halide mixing in the dark, (2) a fixed number of photogenerated carriers funneling to and localizing in low band gap inclusions of the alloy, and (3) the statistical occupancy of said inclusions from a bath of thermalized photocarriers in the parent material. Model predictions include excitation intensity (I exc )-dependent terminal halide stoichiometries (x terminal ), temperature-independent x terminal , excitation intensity thresholds (I exc,threshold ) below which photosegregation is suppressed, and reduced segregation in nanocrystals as compared to thin films. Here, the model also offers insight into kinetically manipulating photosegregation rates via control of underlying mediators and rationalizes asymmetries in forward and reverse photosegregation rate constants/activation energies. What emerges is a cohesive framework for understanding ubiquitous photosegregation in mixed-halide perovskites and a rational basis by which to manage the phenomenon.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Structure of the cytoplasmic domain of Yersinia pestis YscD, an essential component of the type III secretion system

The Yersinia pestis YscD protein is an essential component of the type III secretion system. YscD consists of an N-terminal cytoplasmic domain (residues 1-121), a transmembrane linker (122-142) and a large periplasmic domain (143-419). Both the cytoplasmic and the periplasmic domains are required for the assembly of the type III secretion system. Here, the structure of the YscD cytoplasmic domain solved by SAD phasing is presented. Although the three-dimensional structure is similar to those of forkhead-associated (FHA) domains, comparison with the structures of canonical FHA domains revealed that the cytoplasmic domain of YscD lacks the conserved residues that are required for binding phosphothreonine and is therefore unlikely to function as a true FHA domain.

59 BASIC BIOLOGICAL SCIENCES↗

CsrA-mediated regulation of a virulence switch in Acinetobacter baumannii

CsrA is an RNA binding protein that functions as a global regulator in bacteria. We demonstrate that, in Acinetobacter baumannii, CsrA acts as a positive regulator of the switch from virulent (VIR-O) to avirulent (AV-T) subpopulations. This regulation is mediated, in part, by CsrA interfering with Rho-dependent termination in the mRNA leader region of the ABUW_1645 gene, encoding the primary TetR-type transcriptional regulator that drives cells from the VIR-O to the AV-T state. We demonstrate that CsrA directly binds to the ABUW_1645 mRNA leader region and interferes with Rho binding. We identify three small RNAs (sRNAs) designated CsrB, CsrC, and CsrD that bind to CsrA and inhibit its activity. Individual overexpression of each sRNA greatly decreased the rate of VIR-O to AV-T switching. Individual deletions of each sRNA increased the frequency of VIR-O to AV-T switching, with loss of CsrB giving the highest increase at 2.4-fold. The expression of each sRNA was strongly dependent on the GacA response regulator and the expression of each sRNA was higher in VIR-O cells than in AV-T variants. Furthermore, this regulation provides a mechanism for the differential control of CsrA activity between VIR-O and AV-T variants.

59 BASIC BIOLOGICAL SCIENCES↗

Inter-Area Oscillation Damping with Type-5 Wind Power Plant: Preprint

This paper investigates the potential of using brushless excitation (BLE) for not only riding through the fault but also to damp inter-area power oscillation with the help of a synchronous generator (SG) used in Type 5 Wind Power Plant (WPP). In BLE, an auxiliary synchronous generator (ASG) behaving like an exciter is coupled and driven by the rotor of the main SG. The BLE's field current's ASG is fed by two separate loops of the automatic voltage regulator (AVR) and Power System Stabilizer (PSS). The AVR system implements a control loop to regulate the generator terminal voltage, VT. For the PSS, the kinetic energy of the wind turbine is utilized according to the estimated rotational speed of the synchronous generator shaft of the SG. It mitigates the necessity of any curtailment of active power for damping. The effectiveness of the proposed control scheme is verified with a three-phase short circuit fault in a two-area power system.

brushless↗

Operational Aspects of an International Sub-seabed HLW Repository - 18450

The advantages of and the need for an internationally available repository for SNF and other HLW has been recognized since the 1980's. Various proposals have been pursued over the years but none have been able to overcome the hurdle of the Not-In-My-Backyard (NIMBY) syndrome. Sub-seabed disposal has no NIMBY concerns because the disposal facilities are located in sediments below approximately 4000 meters of international waters. This simple approach precisely emplaces HLW canisters using penetrators released from a ship and driven by gravity ∼50 meters into the sub-seabed ooze. The concept was actively studied and demonstrated by 200+ researchers from 10 different countries for over 12 years. Although it was found to be technically feasible and cost effective, social pressures to keep the oceans off-limits to most disposal activities resulted in termination of the coordinated international effort. By 1994 an International Maritime Organization (IMO) treaty, commonly referred to as the 'London Convention/ London Protocol' was in place banning all such activities. However, the list of banned activities has been amended as recently as 2006. The sub-seabed repository effort has been conducted on three fronts. First, previous research was evaluated to confirm the technical feasibility and identify areas requiring additional research or development. Secondly, the probability of successfully amending the London Convention/London Protocol was assessed. Third, an operational and business model was developed to ensure the private enterprise endeavor was worth pursuing from a business standpoint. The latter is the focus of this paper. (author)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Variably Saturated Flow and Multicomponent Biogeochemical Reactive Transport Modeling of a Uranium Bioremediation Field Experiment

Field experiments at a former uranium mill tailings site have identified the potential for stimulating indigenous bacteria to catalyze the conversion of aqueous uranium in the +6 oxidation state to immobile solid-associated uranium in the +4 oxidation state. This effectively removes uranium from solution resulting in groundwater concentrations below actionable standards. Three-dimensional, coupled variably-saturated flow and biogeochemical reactive transport modeling of a 2008 in situ uranium bioremediation field experiment is used to better understand the interplay of transport rates and biogeochemical reaction rates that determine the location and magnitude of key reaction products. A comprehensive reaction network, developed largely through previous 1-D modeling studies, was used to simulate the impacts on uranium behavior of pulsed acetate amendment, seasonal water table variation, spatially-variable physical (hydraulic conductivity, porosity) and geochemical (reactive surface area) material properties. A principal challenge is the mechanistic representation of biologically-mediated terminal electron acceptor process (TEAP) reactions whose products significantly alter geochemical controls on uranium mobility through increases in pH, alkalinity, exchangeable cations, and highly reactive reduction products. In general, these simulations of the 2008 Big Rusty acetate biostimulation field experiment in Rifle, Colorado confirmed previously identified behaviors including (1) initial dominance by iron reducing bacteria that concomitantly reduce aqueous U(VI), (2) sulfate reducing bacteria that become dominant after {approx}30 days and outcompete iron reducers for the acetate electron donor, (3) continuing iron-reducer activity and U(VI) bioreduction during dominantly sulfate reducing conditions, and (4) lower apparent U(VI) removal from groundwater during dominantly sulfate reducing conditions. New knowledge on simultaneously active metal and sulfate reducers has been incorporated into the modeling. In this case, an initially small population of slow growing sulfate reducers is active from the initiation of biostimulation. Three-dimensional, variably saturated flow modeling was used to address impacts of a falling water table during acetate injection. These impacts included a significant reduction in aquifer saturated thickness and isolation of residual reactants and products, as well as unmitigated uranium, in the newly unsaturated vadose zone. High permeability sandy gravel structures resulted in locally high flow rates in the vicinity of injection wells that increased acetate dilution. In downgradient locations, these structures created preferential flow paths for acetate delivery that enhanced local zones of TEAP reactivity and subsidiary reactions. Conversely, smaller transport rates associated with the lower permeability lithofacies (e.g., fine) and vadose zone were shown to limit acetate access and reaction. Once accessed by acetate, however, these same zones limited subsequent acetate dilution and provided longer residence times that resulted in higher concentrations of TEAP products when terminal electron donors and acceptors were not limiting. Finally, facies-based porosity and reactive surface area variations were shown to affect aqueous uranium concentration distributions; however, the ranges were sufficiently small to preserve general trends. Large computer memory and high computational performance were required to simulate the detailed coupled process models for multiple biogeochemical components in highly resolved heterogeneous materials for the 110-day field experiment and 50 days of post-biostimulation behavior. In this case, a highly-scalable subsurface simulator operating on 128 processor cores for 12 hours was used to simulate each realization. An equivalent simulation without parallel processing would have taken 60 days, assuming sufficient memory was available.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

Structure and vibrational modes of AgI-doped AsSe glasses: Raman scattering and ab initio calculations

We report an investigation of the structure and vibrational modes of (AgI){sub x} (AsSe){sub 100-x}, bulk glasses using Raman spectroscopy and first principles calculations. The short- and medium-range structural order of the glasses was elucidated by analyzing the reduced Raman spectra, recorded at off-resonance conditions. Three distinct local environments were revealed for the AsSe glass including stoichiometric-like and As-rich network sub-structures, and cage-like molecules (As{sub 4}Se{sub n}, n=3, 4) decoupled from the network. To facilitate the interpretation of the Raman spectra ab initio calculations are employed to study the geometric and vibrational properties of As{sub 4}Se{sub n} molecular units that are parts of the glass structure. The incorporation of AgI causes appreciable structural changes into the glass structure. AgI is responsible for the population reduction of molecular units and for the degradation of the As-rich network-like sub-structure via the introduction of As-I terminal bonds. Ab initio calculations of mixed chalcohalide pyramids AsSe{sub m}I{sub 3-m} provided useful information augmenting the interpretation of the Raman spectra. -- Graphical abstract: Raman scattering and ab initio calculations are employed to study the structure of AgI-AsSe superionic glasses. The role of mixed chalcohalide pyramidal units as illustrated in the figure is elucidated. Display Omitted Research highlights: {yields} Doping binary As-Se glasses with AgI cause dramatic changes in glass structure. {yields} Raman scattering and ab initio calculations determine changes in short- and medium-range order. {yields} Three local environments exist in AsSe glass including a network sub-structure and cage-like molecules. {yields} Mixed chalcohalide pyramids AsSe{sub m}I{sub 3-m} dominate the AgI-doped glass structure.

36 MATERIALS SCIENCE↗

The N‐terminal intrinsically disordered region of Ncb5or docks with the cytochrome b 5 core to form a helical motif that is of ancient origin

Abstract NADH cytochromeb 5 oxidoreductase (Ncb5or) is a cytosolic ferric reductase implicated in diabetes and neurological conditions. Ncb5or comprises cytochromeb 5 (b 5 ) and cytochromeb 5 reductase (b 5 R) domains separated by a CHORD‐Sgt1 (CS) linker domain. Ncb5or redox activity depends on proper inter‐domain interactions to mediate electron transfer from NADH or NADPH via FAD to heme. While full‐length human Ncb5or has proven resistant to crystallization, we have succeeded in obtaining high‐resolution atomic structures of theb 5 domain and a construct containing the CS andb 5 R domains (CS/b 5 R). Ncb5or also contains an N‐terminal intrinsically disordered region of 50 residues that has no homologs in other protein families in animals but features a distinctive, conserved L 34 MDWIRL 40 motif also present in reduced lateral root formation (RLF) protein in rice and increased recombination center 21 in baker's yeast, all attaching to ab 5 domain. After unsuccessful attempts at crystallizing a human Ncb5or construct comprising the N‐terminal region naturally fused to theb 5 domain, we were able to obtain a high‐resolution atomic structure of a recombinant rice RLF construct corresponding to residues 25–129 of human Ncb5or (52% sequence identity; 74% similarity). The structure reveals Trp 120 (corresponding to invariant Trp 37 in Ncb5or) to be part of an 11‐residue α‐helix (S 116 QMDWLKLTRT 126 ) packing against two of the four helices in theb 5 domain that surround heme (α2 and α5). The Trp 120 side chain forms a network of interactions with the side chains of four highly conserved residues corresponding to Tyr 85 and Tyr 88 (α2), Cys 124 (α5), and Leu 47 in Ncb5or. Circular dichroism measurements of human Ncb5or fragments further support a key role of Trp 37 in nucleating the formation of the N‐terminal helix, whose location in the N/b 5 module suggests a role in regulating the function of this multi‐domain redox enzyme. This study revealed for the first time an ancient origin of a helical motif in the N/b 5 module as reflected by its existence in a class of cytochromeb 5 proteins from three kingdoms among eukaryotes.

Biochemistry & Molecular Biology↗

Characterization of the fusion core in zebrafish endogenous retroviral envelope protein

Zebrafish endogenous retrovirus (ZFERV) is the unique endogenous retrovirus in zebrafish, as yet, containing intact open reading frames of its envelope protein gene in zebrafish genome. Similarly, several envelope proteins of endogenous retroviruses in human and other mammalian animal genomes (such as syncytin-1 and 2 in human, syncytin-A and B in mouse) were identified and shown to be functional in induction of cell–cell fusion involved in placental development. ZFERV envelope protein (Env) gene appears to be also functional in vivo because it is expressible. After sequence alignment, we found ZFERV Env shares similar structural profiles with syncytin and other type I viral envelopes, especially in the regions of N- and C-terminal heptad repeats (NHR and CHR) which were crucial for membrane fusion. We expressed the regions of N + C protein in the ZFERV Env (residues 459–567, including predicted NHR and CHR) to characterize the fusion core structure. We found N + C protein could form a stable coiled-coil trimer that consists of three helical NHR regions forming a central trimeric core, and three helical CHR regions packing into the grooves on the surface of the central core. The structural characterization of the fusion core revealed the possible mechanism of fusion mediated by ZFERV Env. These results gave comprehensive explanation of how the ancient virus infects the zebrafish and integrates into the genome million years ago, and showed a rational clue for discovery of physiological significance (e.g., medicate cell–cell fusion). - Highlights: • ZFERV Env shares similar structural profiles with syncytin and other type I viral envelopes. • The fusion core of ZFERV Env forms stable coiled-coil trimer including three NHRs and three CHRs. • The structural mechanism of viral entry mediated by ZFERV Env is disclosed. • The results are helpful for further discovery of physiological function of ZFERV Env in zebrafish.

60 APPLIED LIFE SCIENCES↗

Solution structure of the N-terminal domain of proteasome lid subunit Rpn5

The 26S proteasome is the major protein degradation machinery in living cells. The Rpn5 protein is one scaffolding subunit in the lid subcomplex of the 19S regulatory particle in the proteasome holoenzyme. Herein we report the solution structure of the N-terminal domain (NTD) of yeast Rpn5 at high resolution by NMR spectroscopy. The results show that Rpn5 NTD adopts α-solenoid-like fold in right-handed superhelical configuration formed by a number of α-helices. Structural comparisons with currently available cryo-EM structures reveal local structural differences in the first three helices between yeast and human Rpn5. The results further highlight the conformational flexibility in three possible protein interaction sites. Moreover, the structures of the NTD show large variations among different PCI-containing Rpn subunits. Our current results provide atomic-level structural basis for further investigations of protein-protein interactions and the proteasome assembly pathway.

60 APPLIED LIFE SCIENCES↗

Control of Energy Flow Dynamics between Tetracene Ligands and PbS Quantum Dots by Size Tuning and Ligand Coverage

We have prepared a series of samples with the ligand 6,13-bistri(iso-propyl)silylethynyl tetracene 2-carboxylic acid (TIPS-Tc-COOH) attached to PbS quantum dot (QD) samples of three different sizes in order to monitor and control the extent and time scales of energy flow after photoexcitation. Fast energy transfer (~1 ps) to the PbS QD occurs upon direct excitation of the ligand for all samples. The largest size QD maintains the microsecond exciton lifetime characteristic of the as-prepared oleate terminated PbS QDs. However, two smaller QD sizes with lowest exciton energies similar to or larger than the TIPS-Tc-COO- triplet energy undergo energy transfer between QD core and ligand triplet on nanosecond to microsecond timescales. For the intermediate size QDs in particular, energy can be recycled many times between ligand and core, but the triplet remains the dominant excited species at long times, living for ~3 us for fully exchanged QDs and up to 30 us for partial ligand exchange, which is revealed as a method for controlling the triplet lifetime. A unique upconverted luminescence spectrum is observed that results from annihilation of triplets after exclusive excitation of the QD core.

36 MATERIALS SCIENCE↗

Structural and electronic properties of AlN(0001) surface under partial N coverage as determined by ab initio approach

Properties of bare and nitrogen-covered Al-terminated AlN(0001) surface were determined using density functional theory (DFT) calculations. At a low nitrogen coverage, the Fermi level is pinned by Al broken bond states located below conduction band minimum. Adsorption of nitrogen is dissociative with an energy gain of 6.05 eV/molecule at a H3 site creating an overlap with states of three neighboring Al surface atoms. During this adsorption, electrons are transferred from Al broken bond to topmost N adatom states. Accompanying charge transfer depends on the Fermi level. In accordance with electron counting rule (ECR), the DFT results confirm the Fermi level is not pinned at the critical value of nitrogen coverage θ{sub N}(1) = 1/4 monolayer (ML), but it is shifted from an Al-broken bond state to Np{sub z} state. The equilibrium thermodynamic potential of nitrogen in vapor depends drastically on the Fermi level pinning being shifted by about 4 eV for an ECR state at 1/4 ML coverage. For coverage above 1/4 ML, adsorption is molecular with an energy gain of 1.5 eV at a skewed on-top position above an Al surface atom. Electronic states of the admolecule are occupied as in the free molecule, no electron transfer occurs and adsorption of a N{sub 2} molecule does not depend on the Fermi level. The equilibrium pressure of molecular nitrogen above an AlN(0001) surface depends critically on the Fermi level position, being very low and very high for low and high coverage, respectively. From this fact, one can conclude that at typical growth conditions, the Fermi level is not pinned, and the adsorption and incorporation of impurities depend on the position of Fermi level in the bulk.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4)

Interleukin-1 receptor–associated kinase 4 (IRAK4) is a key factor in innate immune and inflammatory responses, performing a critical role in signal transduction downstream of Toll-like receptors and interleukin-1 (IL-1) receptors. Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation. To date, all known IRAK4 structures are in the active conformation, precluding a good understanding of IRAK4's conformational dynamics. To address this issue, here we first solved three crystal structures of the IRAK4 kinase domain (at ≤2.6 Å resolution), in its unphosphorylated, inactive state bound to either the ATP analog AMP-PNP or to one of the two small-molecule inhibitors JH-I-25 and JH-I-17. The structures disclosed that although the structure in complex with AMP-PNP is in an “αC-out” inactive conformation, those in complex with type I inhibitors assume an active “Asp–Phe–Gly (DFG)-in” and “αC-in” conformation. The ability of unphosphorylated IRAK4 to take on variable conformations prompted us to screen for small-molecule inhibitors that bind preferentially to unphosphorylated IRAK4, leading to the identification of ponatinib and HG-12-6. Solving the structures of unphosphorylated IRAK4 in complex with these two inhibitors, we found that they both bind as type II inhibitors with IRAK4 in a “DFG-out” conformation. Collectively, these structures reveal conformational flexibility of unphosphorylated IRAK4 and provide unexpected insights into the potential use of small molecules to modulate IRAK4 activity in cancer, autoimmunity, and inflammation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

First observation of plasma healing via helical equilibrium in tokamak disruptions

A prompt transition of equilibrium states in a disruptive plasma is observed in the presence of three-dimensional (3D) resonant magnetic fields. A dominantly stochastic field line state heals into a 3D equilibrium with intact flux surfaces, resembling a single helicity magnetic island in the plasma core. As a consequence, the current quench process is bifurcated, i.e., from a completed quench accompanied by a vertically unstable disruption to a rapid termination of current decay followed by a full recovery to its predisruption value. Finally, this observation implies prompt stochastic fields healing through the rapid non-linear growth of magnetic island in plasma core may provide a plausible path for a soft-landing scenario of tokamak disruption in high plasma current regime.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗