Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is modulated by T cells.

Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.

The interplay of future solar energy, land cover change, and their projected impacts on natural lands and croplands in the US.

Projections for deep decarbonization require large amounts of solar energy, which may compete with other land uses such as agriculture, urbanization, and conservation of natural lands. Existing capacity expansion models do not integrate land use land cover change (LULC) dynamics into projections. We explored the interaction between projected LULC, solar photovoltaic (PV) deployment, and solar impacts on natural lands and croplands by integrating projections of LULC with a model that can project future deployment of solar PV with high spatial resolution for the conterminous United States. We used scenarios of LULC projections from the Intergovernmental Panel on Climate Change Special Report on Emission Scenarios from 2010 to 2050 and two electricity grid scenarios to model future PV deployment and compared those results against a baseline that held 2010 land cover constant through 2050. Though solar PV's overall technical potential was minimally impacted by LULC scenarios, deployed PV varied by -16.5 to 11.6 % in 2050 from the baseline scenario. Total land requirements for projected PV were similar to other studies, but measures of PV impacts on natural systems depended on the underlying land change dynamics occurring in a scenario. The solar PV deployed through 2050 resulted in 1.1 %-2.4 % of croplands and 0.3 %-0.7 % of natural lands being converted to PV. However, the deepest understanding of PV impacts and interactions with land cover emerged when the complete net gains and losses from all land cover change dynamics, including PV, were integrated. For example, one of the four LULC projections allows for high solar development and a net gain in natural lands, even though PV drives a larger percentage of natural land conversion. This paper shows that integrating land cover change dynamics with energy expansion models generates new insights into trade offs between decarbonization, impacts of renewables, and ongoing land cover change.

An Immobilized (Carbene)Nickel Catalyst for Water Oxidation.

The oxygen evolution reaction (OER) of water splitting is essential to electrochemical energy storage applications. While nickel electrodes are widely available heterogeneous OER catalysts, homogeneous nickel catalysts for OER are underexplored. Here we report two carbene-ligated nickel(II) complexes that are exceptionally robust and efficient homogeneous water oxidation catalysts. Remarkably, these novel nickel complexes can assemble a stable thin film onto a metal electrode through poly-imidazole bridges, making them supported heterogeneous electrochemical catalysts that are resilient to leaching and stripping. Unlike molecular catalysts and nanoparticle catalysts, such electrode-supported metal-complex catalysts for OER are rare and have the potential to inspire new designs. The electrochemical OER with our nickel-carbene catalysts exhibits excellent current densities with high efficiency, low Tafel slope, and useful longevity for a base metal catalyst. Our data show that imidazole carbene ligands stay bonded to the nickel(II) centers throughout the catalysis, which allows the facile oxygen evolution.

Association Between the Medicare Advantage Quartile Adjustment System and Plan Behavior and Enrollment.

Importance: Medicare Advantage (MA) has grown in popularity, but critics believe that insurers are overpaid, partially due to the quartile adjustment system that determines plan benchmarks. However, elimination of the quartile adjustments may be associated with less generous benefits and fewer plan offerings, which could slow MA enrollment growth. Objective: To examine whether the quartile adjustment system is associated with differences in county-level benefits, insurer offerings, and MA enrollment. Design, Setting, and Participants: The quartile adjustments create discontinuous jumps in county-level base payments based on historical traditional Medicare spending. Data from January 2017 to December 2021 and a regression discontinuity design were used to examine changes in insurer behavior and MA enrollment between quartiles. The analytic sample included 1557 county observations. Main Outcomes and Measures: Study outcomes included monthly premiums, the share of plans charging premiums, primary care copayments, the share of plans using rebates to reduce Part B premiums, supplemental benefits, plan and contract availability, and MA enrollment. Results: Discontinuities were found in the quartile adjustments and benchmarks. A 1-percentage point (pp) increase in the quartile adjustment was associated with a $6.36 increase in monthly benchmarks (95% CI, 5.10-7.62), a $0.51 decrease in monthly premiums (95% CI, -0.96 to -0.07), and a 0.68 pp decrease in the share of plans charging premiums (95% CI, -1.25 to -0.10). Significant changes were not found in primary care copayments (-$0.04; 95% CI, -0.17 to 0.09), the share of plans using rebates to reduce Part B premiums (-0.17 pp; 95% CI, -0.34 to 0.01), supplemental benefits (eg, preventive dental coverage; 0.17 pp; 95% CI, -0.25 to 0.0), the number of plans (1.06; 95% CI, -3.44 to 5.57) or contracts (0.31; 95% CI, -0.18 to 0.81), or the MA enrollment rate (0.16 pp; 95% CI, -0.61 to 0.94). Conclusions and Relevance: The study results suggest that MA plans are not very sensitive to modest changes in payment rates. Modifications to the quartile adjustment system may generate savings without substantially affecting MA beneficiaries.

Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells.

Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.

Favorable Selection In Medicare Advantage Is Linked To Inflated Benchmarks And Billions In Overpayments To Plans.

Increases in Medicare Advantage (MA) enrollment, coupled with concerns about overpayment to plans, have prompted calls for change. Benchmark setting in MA, which determines plan payment, has received relatively little attention as an avenue for reform. In this study we used national data from the period 2010-20 to examine the relationships among unobserved favorable selection, benchmark setting, and payments to plans in MA. We found that unobserved favorable selection in MA led to underpayment to counties with lower MA penetration and overpayment to counties with higher MA penetration. Because the distribution of MA beneficiaries has shifted over time toward counties that were overpaid, we estimate that plans were overpaid by an average of $9.3 billion per year between 2017 and 2020. Changes to risk adjustment in benchmark setting could likely mitigate the impact of favorable selection in MA.

Topology stabilized fluctuations in a magnetic nodal semimetal.

The interplay between magnetism and electronic band topology enriches topological phases and has promising applications. However, the role of topology in magnetic fluctuations has been elusive. Here, we report evidence for topology stabilized magnetism above the magnetic transition temperature in magnetic Weyl semimetal candidate CeAlGe. Electrical transport, thermal transport, resonant elastic X-ray scattering, and dilatometry consistently indicate the presence of locally correlated magnetism within a narrow temperature window well above the thermodynamic magnetic transition temperature. The wavevector of this short-range order is consistent with the nesting condition of topological Weyl nodes, suggesting that it arises from the interaction between magnetic fluctuations and the emergent Weyl fermions. Effective field theory shows that this topology stabilized order is wavevector dependent and can be stabilized when the interband Weyl fermion scattering is dominant. Our work highlights the role of electronic band topology in stabilizing magnetic order even in the classically disordered regime.

Legislative and Regulatory Options for Improving Medicare Advantage.

The Medicare Advantage program was created to expand beneficiary choice and to reduce spending through capitated payment to private insurers. However, many stakeholders now argue that Medicare Advantage is failing to deliver on its promise to reduce spending. Three problematic design features in Medicare Advantage payment policy have received particular scrutiny: (1) how baseline payments to insurers are determined, (2) how variation in patient risk affects insurer payment, and (3) how payments to insurers are adjusted for quality performance. The authors analyze the statute underlying these three design features and explore legislative and regulatory strategies for improving Medicare Advantage. They conclude that regulatory approaches for improving risk adjustment and for recouping overpayments from risk-score gaming have the highest potential impact and are the most feasible improvement measures to implement.

An ambient pressure, direct hydrogenation of ketones.

We report two bifunctional (pyridyl)carbene-iridium(I) complexes that catalyze ketone and aldehyde hydrogenation at ambient pressure. Aryl, heteroaryl, and alkyl groups are demonstrated, and mechanistic studies reveal an unusual polarization effect in which the rate is dependant of proton, rather than hydride, transfer. This method introduces a convenient, waste-free alternative to traditional borohydride and aluminum hydride reagents.

Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis.

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

SEEMS: A Single Event Effects and Muon Spectroscopy facility at the Spallation Neutron Source.

This study outlines a concept that would leverage the existing proton accelerator at the Spallation Neutron Source (SNS) of Oak Ridge National Laboratory to enable transformative science via one world-class facility serving two missions: Single Event Effects (SEE) and Muon Spectroscopy (µSR). The µSR portion would deliver the world's highest flux and highest resolution pulsed muon beams for material characterization purposes, with precision and capabilities well beyond comparable facilities. The SEE capabilities deliver neutron, proton, and muon beams for aerospace industries that are facing an impending challenge to certify equipment for safe and reliable behavior under bombardment from atmospheric radiation originating from cosmic and solar rays. With negligible impact on the primary neutron scattering mission of the SNS, the proposed facility will have enormous benefits for both science and industry. We have designated this facility "SEEMS."

APE2 Promotes AID-Dependent Somatic Hypermutation in Primary B Cell Cultures That Is Suppressed by APE1.

Somatic hypermutation (SHM) is necessary for Ab diversification and involves error-prone DNA repair of activation-induced cytidine deaminase-induced lesions in germinal center (GC) B cells but can also cause genomic instability. GC B cells express low levels of the DNA repair protein apurinic/apyrimidinic (AP) endonuclease (APE)1 and high levels of its homolog APE2. Reduced SHM in APE2-deficient mice suggests that APE2 promotes SHM, but these GC B cells also exhibit reduced proliferation that could impact mutation frequency. In this study, we test the hypothesis that APE2 promotes and APE1 suppresses SHM. We show how APE1/APE2 expression changes in primary murine spleen B cells during activation, impacting both SHM and class-switch recombination (CSR). High levels of both APE1 and APE2 early after activation promote CSR. However, after 2 d, APE1 levels decrease steadily with each cell division, even with repeated stimulation, whereas APE2 levels increase with each stimulation. When GC-level APE1/APE2 expression was engineered by reducing APE1 genetically (apex1+/-) and overexpressing APE2, bona fide activation-induced cytidine deaminase-dependent VDJH4 intron SHM became detectable in primary B cell cultures. The C terminus of APE2 that interacts with proliferating cell nuclear Ag promotes SHM and CSR, although its ATR-Chk1-interacting Zf-GRF domain is not required. However, APE2 does not increase mutations unless APE1 is reduced. Although APE1 promotes CSR, it suppresses SHM, suggesting that downregulation of APE1 in the GC is required for SHM. Genome-wide expression data compare GC and cultured B cells and new models depict how APE1 and APE2 expression and protein interactions change during B cell activation and affect the balance between accurate and error-prone repair during CSR and SHM.

Synthesis of 1,4-Diazacycles by Hydrogen Borrowing.

We report the syntheses of 1,4-diazacycles by diol-diamine coupling, uniquely made possible with a (pyridyl)phosphine-ligated ruthenium(II) catalyst (1). The reactions can exploit either two sequential N-alkylations or an intermediate tautomerization pathway to yield piperazines and diazepanes; diazepanes are generally inaccessible by catalytic routes. Our conditions tolerate different amines and alcohols that are relevant to key medicinal platforms. We show the syntheses of the drugs cyclizine and homochlorcyclizine in 91% and 67% yields, respectively.

Polystyrene Upcycling into Fungal Natural Products and a Biocontrol Agent.

Polystyrene (PS) is one of the most used yet infrequently recycled plastics. Although manufactured on the scale of 300 million tons per year globally, current approaches toward PS degradation are energy- and carbon-inefficient, slow, and/or limited in the value that they reclaim. We recently reported a scalable process to degrade post-consumer polyethylene-containing waste streams into carboxylic diacids. Engineered fungal strains then upgrade these diacids biosynthetically to synthesize pharmacologically active secondary metabolites. Herein, we apply a similar reaction to rapidly convert PS to benzoic acid in high yield. Engineered strains of the filamentous fungus Aspergillus nidulans then biosynthetically upgrade PS-derived crude benzoic acid to the structurally diverse secondary metabolites ergothioneine, pleuromutilin, and mutilin. Further, we expand the catalog of plastic-derived products to include spores of the industrially relevant biocontrol agent Aspergillus flavus Af36 from crude PS-derived benzoic acid.

Conversion of Polyethylenes into Fungal Secondary Metabolites.

Waste plastics represent major environmental and economic burdens due to their ubiquity, slow breakdown rates, and inadequacy of current recycling routes. Polyethylenes are particularly problematic, because they lack robust recycling approaches despite being the most abundant plastics in use today. We report a novel chemical and biological approach for the rapid conversion of polyethylenes into structurally complex and pharmacologically active compounds. We present conditions for aerobic, catalytic digestion of polyethylenes collected from post-consumer and oceanic waste streams, creating carboxylic diacids that can then be used as a carbon source by the fungus Aspergillus nidulans. As a proof of principle, we have engineered strains of A. nidulans to synthesize the fungal secondary metabolites asperbenzaldehyde, citreoviridin, and mutilin when grown on these digestion products. This hybrid approach considerably expands the range of products to which polyethylenes can be upcycled.

A rapid electrochemical method to recycle carbon fiber composites using methyl radicals.

We introduce an electrochemical approach to recycle carbon fiber (CF) fabrics from amine-epoxy carbon fiber-reinforced polymers (CFRPs). Our novel method utilizes a Kolbe-like mechanism to generate methyl radicals from CH3COOH to cleave C-N bonds within epoxy matrices via hydrogen atom abstraction. Recovered CFs are then remanufactured into CFRPs without resizing.

Out of Thin Air? Catalytic Oxidation of Trace Aqueous Aldehydes with Ambient Dissolved Oxygen.

Water reuse is expanding due to increased water scarcity. Water reuse facilities treat wastewater effluent to a very high purity level, typically resulting in a product water that is essentially deionized water, often containing less than 100 µg/L organic carbon. However, recent research has found that low-molecular-weight aldehydes, which are toxic electrophiles, comprise a significant fraction of the final organic carbon pool in recycled wastewater in certain treatment configurations. In this manuscript, we demonstrate oxidation of trace aqueous aldehydes to their corresponding acids using a heterogeneous catalyst (5% Pt on C), with ambient dissolved oxygen serving as the terminal electron acceptor. Mass balances are essentially quantitative across a range of aldehydes, and pseudo-first-order reaction kinetics are observed in batch reactors, with kobs varying from 0.6 h-1 for acetaldehyde to 4.6 h-1 for hexanal, while they are low for unsaturated aldehydes. Through kinetic and isotopic labeling experiments, we demonstrate that while oxygen is essential for the reaction to proceed, it is not involved in the rate-limiting step, and the reaction appears to proceed primarily through a base-promoted ß-hydride elimination mechanism from the hydrated gem-diol form of the corresponding aldehyde. This is the first report we are aware of that demonstrates useful abiotic oxidation of a trace organic contaminant using dissolved oxygen.

Kinetics and mechanistic details of bulk ZnO dissolution using a thiol-imidazole system.

Oxide dissolution is important for metal extraction from ores and has become an attractive route for the preparation of inks for thin film solution deposition; however, oxide dissolution is often kinetically challenging. While binary "alkahest" systems comprised of thiols and N-donor species, such as amines, are known to dissolve a wide range of oxides, the mechanism of dissolution and identity of the resulting solute(s) remain unstudied. Here, we demonstrate facile dissolution of both bulk synthetic and natural mineral ZnO samples using an "alkahest" that operates via reaction with thiophenol and 1-methylimidazole (MeIm) to give a single, pseudotetrahedral Zn(SPh)2(MeIm)2 molecular solute identified by X-ray crystallography. The kinetics of ZnO dissolution were measured using solution 1H NMR, and the reaction was found to be zero-order in the presence of excess ligands, with more electron withdrawing para-substituted thiophenols resulting in faster dissolution. A negative entropy of activation was measured by Eyring analysis, indicating associative ligand binding in, or prior to, the rate determining step. Combined experimental and computational surface binding studies on ZnO reveal stronger, irreversible thiophenol binding compared to MeIm, leading to a proposed dissolution mechanism initiated by thiol binding to the ZnO surface with the liberation of water, followed by alternating MeIm and thiolate ligand additions, and ultimately cleavage of the ligated zinc complex from the ZnO surface. Design rules garnered from the mechanistic insight provided by this study should inform the dissolution of other bulk oxides into inks for solution processed thin films.

Pressurized Formic Acid Dehydrogenation: An Entropic Spring Replaces Hydrogen Compression Cost.

Formic acid is unique among liquid organic hydrogen carriers (LOHCs), because its dehydrogenation is highly entropically driven. This enables the evolution of high-pressure hydrogen at mild temperatures that is difficult to achieve with other LOHCs, conceptually by releasing the "spring" of energy stored entropically in the liquid carrier. Applications calling for hydrogen-on-demand, such as vehicle filling, require pressurized H2. Hydrogen compression dominates the cost for such applications, yet there are very few reports of selective, catalytic dehydrogenation of formic acid at elevated pressure. Herein, we show that homogenous catalysts with various ligand frameworks, including Noyori-type tridentate (PNP, SNS, SNP, SNPO), bidentate chelates (pyridyl)NHC, (pyridyl)phosphine, (pyridyl)sulfonamide, and their metallic precursors, are suitable catalysts for the dehydrogenation of neat formic acid under self-pressurizing conditions. Quite surprisingly, we discovered that their structural differences can be related to performance differences in their respective structural families, with some tolerant or intolerant of pressure and others that are significantly advantaged by pressurized conditions. We further find important roles for H2 and CO in catalyst activation and speciation. In fact, for certain systems, CO behaves as a healing reagent when trapped in a pressurizing reactor system, enabling extended life from systems that would be otherwise deactivated.

Radiomics in surgical oncology: applications and challenges.

Surgery is a curative treatment option for many patients with malignant tumors. Increased attention has focused on the combination of surgery with chemotherapy, as multimodality treatment has been associated with promising results in certain cancer types. Despite these data, there remains clinical equipoise on optimal timing and patient selection for neoadjuvant or adjuvant strategies. Radiomics, an emerging field involving the extraction of advanced features from radiographic images, has the potential to revolutionize oncologic treatment and contribute to the advance of personalized therapy by helping predict tumor behavior and response to therapy. This review analyzes and summarizes studies that use radiomics with machine learning in patients who have received neoadjuvant and/or adjuvant chemotherapy to predict prognosis, recurrence, survival, and therapeutic response for various cancer types. While studies in both neoadjuvant and adjuvant settings demonstrate above average performance on ability to predict progression-free and overall survival, there remain many challenges and limitations to widespread implementation of this technology. The lack of standardization of common practices to analyze radiomics, limited data sharing, and absence of auto-segmentation have hindered the inclusion and rapid adoption of radiomics in prospective, clinical studies.