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At least 631 records · Page 35

Multi-omics Signature of Candida auris , an Emerging and Multidrug-Resistant Pathogen

Candida auris is a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates of C. auris with distinct drug susceptibility profiles and a Candida albicans reference strain using a multi-omics approach. Our results show that, despite the distinct drug resistance profile, both C. auris isolates appear to be very similar, albeit with a few notable differences. However, compared to C. albicans both C. auris isolates have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multifactorial mechanism of drug resistance. The molecular profile displayed by C. auris helps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen. Candida auris was first described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has attracted the attention of the medical mycology, infectious disease, and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the United States and found that the omic profile of C. auris differs significantly from C. albicans . In addition to our insights into C. auris carbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.

59 BASIC BIOLOGICAL SCIENCES↗

Virulence factors and antimicrobial resistance profiles of Campylobacter isolates recovered from consecutively reused broiler litter

ABSTRACT Campylobacterinfections are a leading cause of bacterial diarrhea in humans globally. Infections are due to consumption of contaminated food products and are highly associated with chicken meat, with chickens being an important reservoir forCampylobacter. Here, we characterized the genetic diversity ofCampylobacter jejuni(C. jejuni) andCampylobacter coli(C. coli) detected in broiler chicken litter over three consecutive flocks and determined their antimicrobial resistance (ARM) and virulence factor (VF) profiles.Campylobacterwas detected in 9.38% (27/288) of litter samples collected. Antimicrobial susceptibility testing and whole genome sequencing were performed onC. jejuni(n= 39) andC. coli(n= 5) isolates.Campylobactervirulence factors differed within and across broiler houses but were explained by the broiler flock cohort raised on litter,Campylobacterspecies andCampylobactermultilocus sequence type (MLST). Virulence factors involved in the ability to invade and colonize host tissues and evade host defenses were present inC. jejuniisolates (ST-464) from flock cohorts 1 and 2 but absent inC. jejuniisolates (ST-48) from flock cohort 3.C. jejuniisolates from house three harbored a significantly higher proportion of virulence genes with functions related to glycosylation and immune evasion thanC. jejuniisolates from houses 1 and 2 (P< 0.01). AllC. jejuniisolates were susceptible to all antibiotics tested whileC. coli(n= 4) were resistant to tetracycline and harbored the tetracycline resistant ribosomal protection protein (TetO). Our results suggest that house environment and broiler management practices imposed selective pressures on virulence factors and antimicrobial resistance genes ofCampylobacter. IMPORTANCE Campylobacteris a leading cause of foodborne illness in the United States due to consumption of contaminated or mishandled food products, often associated with chicken meat.Campylobacteris common in the microbiota of avian and mammalian gut; however, acquisition of antimicrobial resistance genes (ARGs) and virulence factors (VFs) may result in strains that pose significant threat to public health. Although there are studies investigating the genetic diversity ofCampylobacterstrains isolated from post-harvest chicken samples, there are limited data on the genome characteristics of isolates recovered from preharvest broiler production. Here, we show thatCampylobacter jejuniandCampylobacter colidiffer in their carriage of antimicrobial resistance and virulence factors may also differ in their ability to persist in litter during consecutive grow-out of broiler flocks. We found that presence/absence of virulence factors needed for evasion of host defense mechanisms and gut colonization played an integral role in differentiatingCampylobacterstrains.

Microbiology↗

Mechanisms of Current Transport and Resistive Switching in Capacitors with Yttria-Stabilized Hafnia Layers

The peculiarities of resistive switching in capacitors with yttria-stabilized hafnia layers were studied. The characteristics of current transport in the initial state and after electroforming and resistive switching at different temperatures were examined. The parameters of a small-signal equivalent circuit of a capacitor were determined for switching into low- and high-resistance states. These parameters suggest that the resistance of filaments changes after each successive switching. This provides an opportunity to use such measurements to determine the nature of resistive switching and verify the reproducibility of its parameters. The contribution of electron traps to switching was revealed. Ion migration polarization was observed at temperatures above 500 K, and the activation energy of ion migration and the ion concentration were determined. The effect of resistive switching under the influence of temperature was observed and interpreted for the first time.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Exploring the Sensitivity of Photosynthesis and Stomatal Resistance Parameters in a Land Surface Model

Abstract Land surface models, like the Common Land Model component of the ParFlow integrated hydrologic model (PF-CLM), are used to estimate transpiration from vegetated surfaces. Transpiration rates quantify how much water moves from the subsurface through the plant and into the atmosphere. This rate is controlled by the stomatal resistance term in land surface models. The Ball–Berry stomatal resistance parameterization relies, in part, on the rate of photosynthesis, and together these equations require the specification of 20 input parameters. Here, the active subspace method is applied to 2100 year-long PF-CLM simulations, forced by atmospheric data from California, Colorado, and Oklahoma, to identify which input parameters are important and how they relate to three quantities of interest: transpiration, stomatal resistance from the sunlit portion of the canopy, and stomatal resistance from the shaded portion. The slope (mp) and intercept (bp) parameters associated with the Ball–Berry parameterization are consistently important for all locations, along with five parameters associated with ribulose bisphosphate carboxylase/oxygenase (RuBisCO)- and light-limited rates of photosynthesis [CO2 Michaelis–Menten constant at 25°C (kc25), maximum ratio of oxygenation to carboxylation (ocr), quantum efficiency at 25°C (qe25), maximum rate of carboxylation at 25°C (vcmx25), and multiplier in the denominator of the equation used to compute the light-limited rate of photosynthesis (wj1)]. The importance of these input parameters, quantified by the active variable weight, and the relationship between the input parameters and quantities of interest vary seasonally and diurnally. Input parameter values influence transpiration rates most during midday, summertime hours when fluxes are large. This research informs model users about which photosynthesis and stomatal resistance parameters should be more carefully selected. Quantifying sensitivities associated with the stomatal resistance term is necessary to better understand transpiration estimates from land surface models.

54 ENVIRONMENTAL SCIENCES↗

Impact of Different Oseltamivir Regimens on Treating Influenza A Virus Infection and Resistance Emergence: Insights from a Modelling Study

Several studies have proven oseltamivir to be efficient in reducing influenza viral titer and symptom intensity. However, the usefulness of oseltamivir can be compromised by the emergence and spread of drug-resistant virus. The selective pressure exerted by different oseltamivir therapy regimens have received little attention. Combining models of drug pharmacokinetics, pharmacodynamics, viral kinetics and symptom dynamics, we explored the efficacy of oseltamivir in reducing both symptoms (symptom efficacy) and viral load (virological efficacy). We simulated samples of 1000 subjects using previously estimated between-subject variability in viral and symptom dynamic parameters to describe the observed heterogeneity in a patient population. We simulated random mutations conferring resistance to oseltamivir. We explored the effect of therapy initiation time, dose, intake frequency and therapy duration on influenza infection, illness dynamics, and emergence of viral resistance. Symptom and virological efficacies were strongly associated with therapy initiation time. The proportion of subjects shedding resistant virus was 27-fold higher when prophylaxis was initiated during the incubation period compared with no treatment. It fell to below 1% when treatment was initiated after symptom onset for twice-a-day intakes. Lower doses and prophylaxis regimens led to lower efficacies and increased risk of resistance emergence. We conclude that prophylaxis initiated during the incubation period is the main factor leading to resistance emergence.

59 BASIC BIOLOGICAL SCIENCES↗

Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

PGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants in this trial with the sampled rebound viruses being entirely resistant to PGT121 mediated neutralization. However, two individuals experienced long-term ART-free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Here, we develop mathematical models of the HIV-1 dynamics during this phase I clinical trial. We utilize these models to understand the dynamics leading to PGT121 resistance and to identify the mechanisms driving the observed long-term viral control. Our modeling highlights the importance of the relative fitness difference between PGT121 sensitive and resistant subpopulations prior to treatment. Specifically, by fitting our models to data, we identify the treatment-induced competitive advantage of previously existing or newly generated resistant population as a primary driver of resistance. Finally, our modeling emphasizes the high neutralization ability of PGT121 in both participants who exhibited long-term viral control.

60 APPLIED LIFE SCIENCES↗

Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing

Francisella tularensis is classified as a Class A bioterrorism agent by the U.S. government due to its high virulence and the ease with which it can be spread as an aerosol. It is a facultative intracellular pathogen and the causative agent of tularemia. Ciprofloxacin (Cipro) is a broad spectrum antibiotic effective against Gram-positive and Gram-negative bacteria. Increased Cipro resistance in pathogenic microbes is of serious concern when considering options for medical treatment of bacterial infections. Identification of genes and loci that are associated with Ciprofloxacin resistance will help advance the understanding of resistance mechanisms and may, in the future, provide better treatment options for patients. It may also provide information for development of assays that can rapidly identify Cipro-resistant isolates of this pathogen. In this study, we then selected a large number of F. tularensis live vaccine strain (LVS) isolates that survived in progressively higher Ciprofloxacin concentrations, screened the isolates using a whole genome F. tularensis LVS tiling microarray and Illumina sequencing, and identified both known and novel mutations associated with resistance. For genes containing mutations encode DNA gyrase subunit A, a hypothetical protein, an asparagine synthase, a sugar transamine/perosamine synthetase and others. Finally, structural modeling performed on these proteins provides insights into the potential function of these proteins and how they might contribute to Cipro resistance mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗

Evaluation of a parasite-density based pooled targeted amplicon deep sequencing (TADS) method for molecular surveillance of Plasmodium falciparum drug resistance genes in Haiti

Sequencing large numbers of individual samples is often needed for countrywide antimalarial drug resistance surveillance. Pooling DNA from several individual samples is an alternative cost and time saving approach for providing allele frequency (AF) estimates at a population level. Using 100 individual patient DNA samples of dried blood spots from a 2017 nationwide drug resistance surveillance study in Haiti, we compared codon coverage of drug resistance-conferring mutations in four Plasmodium falciparum genes ( crt , dhps , dhfr , and mdr1 ), for the same deep sequenced samples run individually and pooled. Samples with similar real-time PCR cycle threshold (Ct) values (+/- 1.0 Ct value) were combined with ten samples per pool. The sequencing success for samples in pools were higher at a lower parasite density than the individual samples sequence method. The median codon coverage for drug resistance-associated mutations in all four genes were greater than 3-fold higher in the pooled samples than in individual samples. The overall codon coverage distribution for pooled samples was wider than the individual samples. The sample pools with < 40 parasites/μL blood showed more discordance in AF calls for dhfr and mdr1 between the individual and pooled samples. This discordance in AF estimation may be due to low amounts of parasite DNA, which could lead to variable PCR amplification efficiencies. Grouping samples with an estimated ≥ 40 parasites/μL blood prior to pooling and deep sequencing yielded the expected population level AF. Pooling DNA samples based on estimates of > 40 parasites/μL prior to deep sequencing can be used for rapid genotyping of a large number of samples for these four genes and possibly other drug resistant markers in population-based studies. As Haiti is a low malaria transmission country with very few mixed infections and continued chloroquine sensitivity, the pooled sequencing approach can be used for routine national molecular surveillance of resistant parasites.

Louha, Swarnali (ORCID:0000000207778507)↗

MicroRNAs Suppress NB Domain Genes in Tomato That Confer Resistance to Fusarium oxysporum

MicroRNAs (miRNAs) suppress the transcriptional and post-transcriptional expression of genes in plants. Several miRNA families target genes encoding nucleotide-binding site–leucine-rich repeat (NB-LRR) plant innate immune receptors. The fungus Fusarium oxysporum f. sp. lycopersici causes vascular wilt disease in tomato. Here, we explored a role for miRNAs in tomato defense against F. oxysporum using comparative miRNA profiling of susceptible (Moneymaker) and resistant (Motelle) tomato cultivars. slmiR482f and slmiR5300 were repressed during infection of Motelle with F. oxysporum. Two predicted mRNA targets each of slmiR482f and slmiR5300 exhibited increased expression in Motelle and the ability of these four targets to be regulated by the miRNAs was confirmed by co-expression in Nicotiana benthamiana. Silencing of the targets in the resistant Motelle cultivar revealed a role in fungal resistance for all four genes. All four targets encode proteins with full or partial nucleotide-binding (NB) domains. One slmiR5300 target corresponds to tm-2, a susceptible allele of the Tomato Mosaic Virus resistance gene, supporting functions in immunity to a fungal pathogen. The observation that none of the targets correspond to I-2, the only known resistance (R) gene for F. oxysporum in tomato, supports roles for additional R genes in the immune response. In conclusion, taken together, our findings suggest that Moneymaker is highly susceptible because its potential resistance is insufficiently expressed due to the action of miRNAs.

60 APPLIED LIFE SCIENCES↗

Erosion-Resistant Nanocoatings for Improved Energy Efficiency in Gas Turbines

The objective of this Stage Gate IV project was to test and substantiate the viability of an erosion-resistant nanocoating for application on compressor airfoils for gas turbines in both industrial power generation and commercial aviation applications. To effectively complete this project, the National Energy Technology Laboratory’s Office of Research & Development teamed with MDS Coating Technologies Inc. (MCT), Delta Air Lines - Technical Operations Division (Delta Tech Ops), and Calpine Corporation. The coating targeted for this application was MCT’s Next Generation Coating, version 4 (NGC-v4 - with the new registered trademark name of BlackGold®). The coating is an erosion and corrosion resistant composite nanostructured coating. This coating is comprised of a proprietary ceramic-metallic nano-composite construction which provides enhanced erosion resistance and also retains the aerodynamic geometry of the airfoils. The objective of the commercial aviation portion of the project was to substantiate the coating properties to allow certification from the FAA to apply an erosion-resistant coating in a commercial aviation engine. The goal of the series of tests was to demonstrate that the durability of the airfoils is not affected negatively with the application of the NGC v4 coating. Tests included erosion, corrosion, vibration and fatigue. The results of the testing demonstrated that the application of the coating did not negatively impact the properties of the blades, especially fatigue performance – which is of importance in acceptance for commercial aviation applications. The objective of the industrial gas turbine element of the project was to evaluate the coating as an enabling technology for inlet fogging during the operation of industrial gas turbines. Fluid erosion laboratory scale tests were conducted to simulate inlet fogging conditions. Results of these tests indicated that the application of the erosion resistant NGC-v4 nanocoating improved the resistance to simulated inlet fogging conditions by a factor of 10 times. These results gave confidence for a field trial at Calpine’s power plant in Corpus Christi, TX, which commenced in April 2012. This test is still on-going as of November 2013, and the nanocoated blades have accumulated over 13,000 operational hours on this specific power plant in approximately 19 months of operation.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

Development of a Long-Life-Cycle, Highly Water-Resistant Solar Reflective Retrofit Roof Coating

Highly water-resistant and solar-reflective coatings for low-slope roofs are potentially among the most economical retrofit approaches to thermal management of the building envelope. Therefore, they represent a key building technology research program within the Department of Energy. Research efforts in industry and the Department of Energy are currently under way to increase long-term solar reflectance on a number of fronts. These include new polymer coatings technologies to provide longer-lasting solar reflectivity and improved test methodologies to predict long-term soiling and microbial performance. The focus on long-term improvements in soiling and microbial resistance for maximum reflectance does not address the single most important factor impacting the long-term sustainability of low-slope roof coatings: excellent water resistance. The hydrophobic character of asphaltic roof products makes them uniquely suitable for water resistance, but their low albedo and poor exterior durability are disadvantages. A reflective coating that maintains very high water resistance with increased long-term resistance to soiling and microbial activity would provide additional energy savings and extend roof service life.

36 MATERIALS SCIENCE↗

GIF Supercritical Water Cooled Reactor: Proliferation Resistance and Physical Protection White Paper

This report is part of a series of six white papers, prepared jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the six System Steering Committees (SSCs) and provisional System Steering Committees (pSSCs). This publication is an update to a similar series published in 2011 presenting the status of Proliferation Resistance & Physical Protection (PR&PP) characteristics for each of the six systems selected by the Generation IV International Forum (GIF) for further research and development, namely: the Sodium-cooled fast Reactor (SFR), the Very high temperature reactor (VHTR), the gas-cooled fast reactor (GFR), the Molten salt reactor (MSR) and the Supercritical water–cooled reactor (SCWR). This white paper represents the status of Proliferation Resistance and Physical Protection (PR&PP) characteristics for the Supercritical Water-cooled Fast reactor (SCFR) reference designs selected by the Generation IV International Forum (GIF) SCWR System Steering Committee (SSC). The intent is to generate preliminary information about the PR&PP features of the SCWR reactor technology and to provide insights for optimizing their PR&PP performance for the benefit of SCWR system designers. It updates the SCWR analysis published in the 2011 report “Proliferation Resistance and Physical Protection of the Six Generation IV Nuclear Energy Systems”, prepared Jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the System Steering Committees and provisional System Steering Committees of the Generation IV International Forum, taking into account the evolution of both the systems, the GIF R&D activities, and an increased understanding of the PR&PP features. The white paper, prepared jointly by the GIF PRPPWG and the GIF SCWR SSC, follows the highlevel paradigm of the GIF PR&PP Evaluation Methodology to investigate the PR&PP features of the eight proposed GIF SCWR designs. Two small modular reactors, the Canadian SSR and the Canada/China/Europe ECC-SMART are also mentioned. An overview of the fuel cycles for the GIF designs are provided. For PR, the document analyses and discusses the proliferation resistance aspects in terms of robustness against State-based threats associated with diversion of materials, misuse of facilities, breakout scenarios, and production in clandestine facilities. Similarly, for PP, the document discusses the robustness against theft of material and sabotage by non-State actors. The document follows a common template adopted by all the white papers in the updated series.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

GIF Very High Temperature Reactor: Proliferation Resistance and Physical Protection White Paper

This report is part of a series of six white papers, prepared jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the six System Steering Committees (SSCs) and provisional System Steering Committees (pSSCs). This publication is an update to a similar series published in 2011 presenting the status of Proliferation Resistance & Physical Protection (PR&PP) characteristics for each of the six systems selected by the Generation IV International Forum (GIF) for further research and development, namely: the Sodium-cooled fast Reactor (SFR), the Very high temperature reactor (VHTR), the gas-cooled fast reactor (GFR), the Molten salt reactor (MSR) and the Supercritical water–cooled reactor (SCWR). This white paper represents the status of Proliferation Resistance and Physical Protection (PR&PP) characteristics for the Very-High-Temperature Reactor (VHTR) reference designs selected by the Generation IV International Forum (GIF) VHTR System Steering Committee (SSC). The intent is to generate preliminary information about the PR&PP features of the VHTR reactor technology and to provide insights for optimizing their PR&PP performance for the benefit of VHTR system designers. It updates the VHTR analysis published in the 2011 report “Proliferation Resistance and Physical Protection of the Six Generation IV Nuclear Energy Systems”, prepared Jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the System Steering Committees and provisional System Steering Committees of the Generation IV International Forum, taking into account the evolution of both the systems, the GIF R&D activities, and an increased understanding of the PR&PP features. The white paper, prepared jointly by the GIF PRPPWG and the GIF VHTR SSC, follows the high-level paradigm of the GIF PR&PP Evaluation Methodology to investigate the key points of PR&PP features extracted from the reference designs of VHTRs under consideration in various countries. A major update from the 2011 report is an explicit distinction between prismatic block-type VHTRs and pebble-bed VHTRs. The white paper also provides an overview of the TRISO fuel and fuel cycle. For PR, the document analyses and discusses the proliferation resistance aspects in terms of robustness against State-based threats associated with diversion of materials, misuse of facilities, breakout scenarios, and production in clandestine facilities. Similarly, for PP, the document discusses the robustness against theft of material and sabotage by non-State actors. The document follows a common template adopted by all the white papers in the updated series.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

Genetics and Genomics of Pathogen Resistance in Switchgrass (Final Report)

This project was funded by DOE under Grant no. DE-SC0016108. Originally approved for the 2016-2019 period, two no-cost extensions were solicited and approved, which prolonged the lifespan through July 2021. This final report informs on the results obtained so far from the research implemented. The research hinged on integrating genomics (genomic selection, RNAseq, virus-plant interactions) with classical genetics (conventional breeding) to incorporate durable resistance to fungal (rust) and viral (mosaic) diseases in switchgrass (Panicum virgatum) populations being bred for bioenergy. Higher biomass yield, higher quality (low lignin content), and durable disease resistance are key features to make lignocellulosic switchgrass feedstocks economically competitive and sustainable. Genomic selection is being applied on three generations of a switchgrass population derived from crossing two ecotypes (Kanlow as lowland female and Summer as upland male) with differential performance in terms of biomass yield and quality, disease resistance, and winter survivability. Target populations were screened for rust and mosaic in field and/or lab and phenotyped for biomass yield and quality traits. Genetic analyses were applied across generations to capture the joint inheritance of the targeted traits and predict breeding values for parents and progeny with greater accuracy. Parental and a panel of different switchgrass populations were genotyped with the DArTseq technology to develop SNP (0, 1, 2) and in-silico (presence/absence) DArT markers. Rust inoculations techniques were developed and applied successfully on switchgrass. The original populations (Kanlow and Summer) were sequenced with RNAseq to capture the gene expression profiles across sequential time-points and appraise the basis of greater resistance in the Kanlow vs the Summer ecotype. Constructs of PMV and sPMV mosaic virus were assembled and tested first on proso millet to find the best protocol to use later on switchgrass. Results from the preliminary analyses indicate that 1) ample additive genetic variation is available for selection and improving this inter-ecotypic population for yield, quality, and disease traits, 2) significant gains are to be expected with the genetic correlations being favorable between yield and lignin content and between yield and disease ratings, 3) substantial differences exist in the genetic regions controlling rust resistance in the two ecotypes, 4) co-infection with PMV isolates from Nebraska and its satellite from Kansas elicit severe mosaic symptoms, and 5) two different genetic systems are responsible for imparting resistance to rust and virus in switchgrass.

59 BASIC BIOLOGICAL SCIENCES↗

Machine learning reveals genes impacting oxidative stress resistance across yeasts

Reactive oxygen species (ROS) are highly reactive molecules encountered by yeasts during routine metabolism and during interactions with other organisms, including host infection. Here, we characterized the variation in resistance to ROS across the ancient yeast subphylum Saccharomycotina and used machine learning (ML) to identify gene families whose sizes were predictive of ROS resistance.

AI↗

General-relativistic Resistive Magnetohydrodynamics with Robust Primitive-variable Recovery for Accretion Disk Simulations

Recent advances in black hole astrophysics, particularly the first visual evidence of a supermassive black holeat the center of the galaxy M87 by the Event Horizon Telescope (EHT), and the detection of an orbiting “hot spot”nearby the event horizon of Sgr A* in the Galactic center by the Gravity Collaboration, require the developmentof novel numerical methods to understand the underlying plasma microphysics. Non-thermal emission related tosuch hot spots is conjectured to originate from plasmoids that form due to magnetic reconnection in thin currentlayers in the innermost accretion zone. Resistivity plays a crucial role in current sheet formation, magneticreconnection, and plasmoid growth in black hole accretion disks and jets. We included resistivity in the three-dimensional general-relativistic magnetohydrodynamics (GRMHD) codeBHACand present the implementationof an Implicit-Explicit scheme to treat the stiff resistive source terms of the GRMHD equations. The algorithmis tested in combination with adaptive mesh refinement to resolve the resistive scales and a constrained transportmethod to keep the magnetic field solenoidal. Several novel methods for primitive variable recovery, a key part inrelativistic magnetohydrodynamics codes, are presented and compared for accuracy, robustness, and efficiency.We propose a new inversion strategy that allows for resistive-GRMHD simulations of low gas-to-magneticpressure ratio and highly magnetized regimes as applicable for black hole accretion disks, jets, and neutron starmagnetospheres. We apply the new scheme to study the effect of resistivity on accreting black holes, accountingfor dissipative effects as reconnection

(magnetohydrodynamics:) MHD↗

Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

59 BASIC BIOLOGICAL SCIENCES↗

Effect of mechanical surface and heat treatments on erosion resistance

The effects of mechanical surface treatments as well as heat treatments on the erosion resistance of 6061 aluminum alloy and 1045 steel were studied. Mechanical surface treatments were found to have little or no effect on the erosion resistance. This is due to the formation by particle impact of a work hardened surface layer regardless of the initial surface condition. The erosion resistance of Al single crystals is found to be independent of orientation. This is due to destruction of the surface microstructure and formation of a polycrystalline surface layer by the impact of erodant particles as observed by X-ray diffraction. While upon solution treatment of annealed 6061 aluminum the increase in hardness is accompanied by an increase in erosion resistance, precipitation treatment which causes a further increase in hardness results in slightly lower erosion resistance. Using two types of erodant particles, glass beads and crushed glass, the erosion rate is found to be strongly dependent on erodant particle shape, being an order of magnitude higher for erosion with crushed glass as compared to glass beads. While for erosion with glass beads heat treatment of 1045 steel had a profound effect on its erosion resistance, little or no such effect was observed for erosion with crushed glass.

Salik, J.↗