Analysis of plasma metabolomes from 11 309 subjects in five population-based cohorts.

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50-80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies.

Imaging 3D chemistry at 1 nm resolution with fused multi-modal electron tomography.

Measuring the three-dimensional (3D) distribution of chemistry in nanoscale matter is a longstanding challenge for metrological science. The inelastic scattering events required for 3D chemical imaging are too rare, requiring high beam exposure that destroys the specimen before an experiment is completed. Even larger doses are required to achieve high resolution. Thus, chemical mapping in 3D has been unachievable except at lower resolution with the most radiation-hard materials. Here, high-resolution 3D chemical imaging is achieved near or below one-nanometer resolution in an Au-Fe3O4 metamaterial within an organic ligand matrix, Co3O4-Mn3O4 core-shell nanocrystals, and ZnS-Cu0.64S0.36 nanomaterial using fused multi-modal electron tomography. Multi-modal data fusion enables high-resolution chemical tomography often with 99% less dose by linking information encoded within both elastic (HAADF) and inelastic (EDX/EELS) signals. We thus demonstrate that sub-nanometer 3D resolution of chemistry is measurable for a broad class of geometrically and compositionally complex materials.

Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.

Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd-/-) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd-/- mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd-/- animals, while depletion does not have additive protective effects in Gsdmd-/- mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.

Chiroptical Strain Sensors from Electrospun Cadmium Sulfide Quantum-Dot Fibers.

Controllable synthesis of homochiral nano/micromaterials has been a constant challenge for fabricating various stimuli-responsive chiral sensors. To provide an avenue to this goal, we report electrospinning as a simple and economical strategy to form continuous homochiral microfibers with strain-sensitive chiroptical properties. First, electrospun homochiral microfibers from self-assembled cadmium sulfide (CdS) quantum dot magic-sized clusters (MSCs) are produced. Highly sensitive and reversible strain sensors are then fabricated by embedding these chiroptically active fibers into elastomeric films. The chiroptical response on stretching is indicated quantitatively as reversible changes in magnitude, spectral position (wavelength), and sign in circular dichroism (CD) and linear dichroism (LD) signals and qualitatively as a prominent change in the birefringence features under cross-polarizers. The observed periodic twisted helical fibrils at the surface of fibers provide insights into the origin of the fibers' chirality. The measurable shifts in CD and LD are caused by elastic deformations of these helical fibrillar structures of the fiber. To elucidate the origin of these chiroptical properties, we used field emission-electron microscopy (FE-SEM), atomic force microscopy (AFM), synchrotron X-ray analysis, polarized optical microscopy, as well as measurements to isolate the true CD, and contributions from photoelastic modulators (PEM) and LD. Our findings thus offer a promising strategy to fabricate chiroptical strain-sensing devices with multiple measurables/observables using electric-field-assisted spinning of homochiral nano/microfibers.

MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery.

We herein describe the development and application of a modular technology platform which incorporates recent advances in plate-based microscale chemistry, automated purification, in situ quantification, and robotic liquid handling to enable rapid access to high-quality chemical matter already formatted for assays. In using microscale chemistry and thus consuming minimal chemical matter, the platform is not only efficient but also follows green chemistry principles. By reorienting existing high-throughput assay technology, the platform can generate a full package of relevant data on each set of compounds in every learning cycle. The multiparameter exploration of chemical and property space is hereby driven by active learning models. The enhanced compound optimization process is generating knowledge for drug discovery projects in a time frame never before possible.

Scalable Route to Colloidal NixCo3-xS4 Nanoparticles with Low Dispersity Using Amino Acids.

The thiospinel group of nickel cobalt sulfides (NixCo3-xS4) are promising materials for energy applications such as supercapacitors, fuel cells, and solar cells. Solution-processible nanoparticles of NixCo3-xS4 have advantages of low cost and fabrication of high-performance energy devices due to their high surface-to-volume ratio, which increases the electrochemically active surface area and shortens the ionic diffusion path. The current approaches to synthesize NixCo3-xS4 nanoparticles are often based on hydrothermal or solvothermal methods that are difficult to scale up safely and efficiently and that preclude monitoring the reaction through aliquots, making optimization of size and dispersity challenging, typically resulting in aggregated nanoparticles with polydisperse sizes. In this work, we report a scalable "heat-up" method to colloidally synthesize NixCo3-xS4 nanoparticles that are smaller than 15 nm in diameter with less than 15% in size dispersion, using two inexpensive, earth-abundant sulfur sources. Our method provides a reliable synthetic pathway to produce phase-pure, low-dispersity, gram-scale nanoparticles of ternary metal sulfides. This method enhances the current capabilities of NixCo3-xS4 nanoparticles to meet the performance demands to improve renewable energy technologies.

The emergence of SARS-CoV-2 lineages and associated saliva antibody responses among asymptomatic individuals in a large university community.

SARS-CoV-2 (CoV2) infected, asymptomatic individuals are an important contributor to COVID transmission. CoV2-specific immunoglobulin (Ig)-as generated by the immune system following infection or vaccination-has helped limit CoV2 transmission from asymptomatic individuals to susceptible populations (e.g. elderly). Here, we describe the relationships between COVID incidence and CoV2 lineage, viral load, saliva Ig levels (CoV2-specific IgM, IgA and IgG), and ACE2 binding inhibition capacity in asymptomatic individuals between January 2021 and May 2022. These data were generated as part of a large university COVID monitoring program in Ohio, United States of America, and demonstrate that COVID incidence among asymptomatic individuals occurred in waves which mirrored those in surrounding regions, with saliva CoV2 viral loads becoming progressively higher in our community until vaccine mandates were established. Among the unvaccinated, infection with each CoV2 lineage (pre-Omicron) resulted in saliva Spike-specific IgM, IgA, and IgG responses, the latter increasing significantly post-infection and being more pronounced than N-specific IgG responses. Vaccination resulted in significantly higher Spike-specific IgG levels compared to unvaccinated infected individuals, and uninfected vaccinees' saliva was more capable of inhibiting Spike function. Vaccinees with breakthrough Delta infections had Spike-specific IgG levels comparable to those of uninfected vaccinees; however, their ability to inhibit Spike binding was diminished. These data are consistent with COVID vaccines having achieved hoped-for effects in our community, including the generation of mucosal antibodies that inhibit Spike and lower community viral loads, and suggest breakthrough Delta infections were not due to an absence of vaccine-elicited Ig, but instead limited Spike binding activity in the face of high community viral loads.

General Route to Colloidally Stable, Low-Dispersity Manganese-Based Ternary Spinel Oxide Nanocrystals.

While certain ternary spinel oxides have been well-explored with colloidal nanochemistry, notably the ferrite spinel family, ternary manganese (Mn)-based spinel oxides have not been tamed. A key composition is cobalt (Co)-Mn oxide (CMO) spinel, CoxMn3-xO4, that, despite exemplary performance in multiple electrochemical applications, has few reports in the colloidal literature. Of these reports, most show aggregated and polydisperse products. Here, we describe a synthetic method for small, colloidally stable CMO spinel nanocrystals with tunable composition and low dispersity. By reacting 2+ metal-acetylacetonate (M(acac)2) precursors in an amine solvent under an oxidizing environment, we developed a pathway that avoids the highly reducing conditions of typical colloidal synthesis reactions; these reducing conditions typically push the system toward a monoxide impurity phase. Through surface chemistry studies, we identify organic byproducts and their formation mechanism, enabling us to engineer the surface and obtain colloidally stable nanocrystals with low organic loading. We report a CMO/carbon composite with low organic contents that performs the oxygen reduction reaction (ORR) with a half-wave potential (E1/2) of 0.87 V vs RHE in 1.0 M potassium hydroxide at 1600 rpm, rivaling previous reports for the highest activity of this material in ORR electrocatalysis. We extend the general applicability of this procedure to other Mn-based spinel nanocrystals such as Zn-Mn-O, Fe-Mn-O, Ni-Mn-O, and Cu-Mn-O. Finally, we show the scalability of this method by producing inorganic nanocrystals at the gram scale.

Mass spectroscopy study of the intermediate magic-size cluster species during cooperative cation exchange.

Cation exchange is a versatile post-synthetic method to explore a wide range of nanoparticle compositions, phases, and morphologies. Recently, several studies have expanded the scope of cation exchange to magic-size clusters (MSCs). Mechanistic studies indicated that MSC cation exchange undergoes a two-stage reaction pathway instead of the continuous diffusion-controlled mechanism found in nanoparticle cation exchange reactions. The cation exchange intermediate, however, has not been well-identified despite it being the key to understanding the reaction mechanism. Only indirect evidence, such as exciton peak shifts and powder x-ray diffraction, has been used to indicate the formation of the cation exchange intermediate. In this paper, we investigate the unusual nature of cation exchange in nanoclusters using our previously reported CdS MSC. High-resolution mass spectra reveal two cation exchanged reaction intermediates [Ag2Cd32S33(L) and AgCd33S33(L), L: oleic acid] as well as the fully exchanged Ag2S cluster. Crystal and electronic structure characterizations also confirm the two-stage reaction mechanism. Additionally, we investigate the Cu/CdS MSC cation exchange reaction and find a similar two-stage reaction mechanism. Our study shows that the formation of dilutely exchanged intermediate clusters can be generally found in the first stage of the MSC cation exchange reaction. By exchanging different cations, these intermediate clusters can access varying properties compared to their unexchanged counterparts.

Increases in income-support payments reduce the demand for charity: A difference-in-difference analysis of charitable-assistance data from Australia over the COVID-19 pandemic.

Charities play an increasingly important role in helping people experiencing poverty. However, institutionalized charity shifts the burden of poverty reduction away from the state and exposes recipients to stress and stigma. In this paper, we examine whether the need for institutionalized charity can be offset through enhanced state support. As in other countries, the Australian government responded to the COVID-19 pandemic by substantially increasing the level of income support to citizens through several temporary payments. We draw on this natural experiment and time-series data from the two largest charity organizations in Queensland, Australia to examine how these payments altered the demand for institutionalized charity. We model these data using difference-in-difference regression models to approximate causal effects. By exploiting the timing and varying amounts of the payments, our analyses yield evidence that more generous income support reduces reliance on charity. Halving the demand for charity requires raising pre-pandemic income-support by AUD$42/day, with supplements of approximately AUD$18/day yielding the greatest return on investment.

Classification of formalin-fixed bladder cancer cells with laser tweezer Raman spectroscopy.

Bladder cancer is a common cancer that is relatively hard to detect at an early stage because of its non-obvious symptoms. It is known that bladder cells can be found in urine samples which potentially could be used for early detection of bladder cancer. Raman spectroscopy is a powerful non-invasive tool for accessing biochemical information of cells. Combined with laser tweezers, to allow isolation of single cells, Raman spectroscopy has been used to characterise a number of bladder cells that might be found in a urine sample. Using principal component-canonical variates analysis (PC-CVA) and k-fold validation, the results shows that the invasive bladder cancer cells can be identified with accuracy greater than 87%. This demonstrates the potential of developing an early detection method that identifies the invasive bladder cancer cells in urine samples.

Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rß2.

IL-35 is an immunosuppressive cytokine with roles in cancer, autoimmunity, and infectious disease. In the conventional model of IL-35 biology, the p35 and Ebi3 domains of this cytokine interact with IL-12Rß2 and gp130, respectively, on the cell surface of regulatory T and regulatory B cells, triggering their suppression of Th cell activity. Here we use a human IL-12 bioactivity reporter cell line, protein binding assays, and primary human Th cells to demonstrate an additional mechanism by which IL-35 suppresses Th cell activity, wherein IL-35 directly inhibits the association of IL-12 with its surface receptor IL-12Rß2 and downstream IL-12-dependent activities. IL-12 binding to the surface receptor IL-12Rß1 was unaffected by IL-35. These data demonstrate that in addition to acting via regulatory T and regulatory B cells, human IL-35 can also directly suppress IL-12 bioactivity and its interaction with IL-12Rß2.

Can we still measure circular dichroism with circular dichroism spectrometers: The dangers of anisotropic artifacts.

Chiral materials with strong linear anisotropies are difficult to accurately characterize with circular dichroism (CD) because of artifactual contributions to their spectra from linear dichroism (LD) and birefringence (LB). Historically, researchers have used a second-order Taylor series expansion on the Mueller matrix to model the LDLB interaction effects on the spectra in conventional materials, but this approach may no longer be sufficient to account for the artifactual CD signals in emergent materials. In this work, we present an expression to model the measured CD using a third-order expansion, which introduces "pairwise interference" terms that, unlike the LDLB terms, cannot be averaged out of the signal. We find that the third-order pairwise interference terms can make noticeable contributions to the simulated CD spectra. Using numerical simulations of the measured CD across a broad range of linear and chiral anisotropy parameters, the LDLB interactions are most prominent in samples that have strong linear anisotropies (LD, LB) but negligible chiral anisotropies, where the measured CD strays from the chirality-induced CD by factors greater than 103 . Additionally, the pairwise interactions are most significant in systems with moderate-to-strong chiral and linear anisotropies, where the measured CD is inflated twofold, a figure that grows as linear anisotropies approach their maximum. In summary, media with moderate-to-strong linear anisotropy are in great danger of having their CD altered by these effects in subtle manners. This work highlights the significance of considering distortions in CD measurements through higher-order pairwise interference effects in highly anisotropic nanomaterials.

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery. Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.

Influenza virus activates cellular inflammasome pathways, which can be either beneficial or detrimental to infection outcomes. Here, we investigated the role of the inflammasome-activated pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice significantly attenuated virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected GSDMD KO mice exhibited decreased inflammatory gene signatures revealed by lung transcriptomics, which also implicated a diminished neutrophil response. Importantly, neutrophil depletion in infected WT mice recapitulated the reduced mortality and lung inflammation observed in GSDMD KO animals, while having no additional protective effects in GSDMD KOs. These findings reveal a new function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a new therapeutic avenue for treating severe influenza.

A role for Toll-like receptor 3 in lung vascular remodeling associated with SARS-CoV-2 infection.

Cardiovascular sequelae of severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) disease 2019 (COVID-19) contribute to the complications of the disease. One potential complication is lung vascular remodeling, but the exact cause is still unknown. We hypothesized that endothelial TLR3 insufficiency contributes to lung vascular remodeling induced by SARS-CoV-2. In the lungs of COVID-19 patients and SARS-CoV-2 infected Syrian hamsters, we discovered thickening of the pulmonary artery media and microvascular rarefaction, which were associated with decreased TLR3 expression in lung tissue and pulmonary artery endothelial cells (ECs). In vitro , SARS-CoV-2 infection reduced endothelial TLR3 expression. Following infection with mouse-adapted (MA) SARS-CoV-2, TLR3 knockout mice displayed heightened pulmonary artery remodeling and endothelial apoptosis. Treatment with the TLR3 agonist polyinosinic:polycytidylic acid reduced lung tissue damage, lung vascular remodeling, and endothelial apoptosis associated with MA SARS-CoV-2 infection. In conclusion, repression of endothelial TLR3 is a potential mechanism of SARS-CoV-2 infection associated lung vascular remodeling and enhancing TLR3 signaling is a potential strategy for treatment.

Predictors of attrition in an interdisciplinary pain management program.

PURPOSE/OBJECTIVE: This study sought to investigate the extent to which demographic and clinical characteristics predict which patients drop out of an interdisciplinary pain management program (IPP). RESEARCH METHOD/DESIGN: Participants (N = 178 outpatients, 18-75 years of age) received treatment for various chronic pain conditions in an IPP (including biopsychosocial assessment, cognitive-behavioral, and physical therapies). Separate logistic regression analyses identified the demographic and clinical variables most predictive of attrition across five domains: (a) demographics, (b) number of medical and non/psychiatric diagnoses, (c) opioid use (yes versus no)/risk of misuse, (d) pain-related cognition and behavior, and (e) physical, social, and mental well-being. Significant predictors from the five domains were integrated in a final multivariable logistic regression model. RESULTS: Among patients exposed to a 4-week IPP, 34% dropped out. In the final model, significant predictors of higher odds of attrition included younger age or being unemployed. Also, patients on opioids at preintervention had higher odds of completing the IPP than patients not on opioids at preintervention. Follow-up analyses revealed 24 of 37 completers (65%) on opioids at preintervention reduced or eliminated use over the course of the IPP. CONCLUSIONS/IMPLICATIONS: Because findings are limited by sample and design characteristics, they require replication yet offer novel hypotheses for identifying patients at risk of attrition. Specifically, patients with preintervention opioid use (contrasted with opioid dependence) may particularly benefit from an IPP. Patients at highest risk for early dropout can be targeted for specific engagement interventions to promote completion and effectiveness of IPP. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ultrafast Demagnetization Control in Magnetophotonic Surface Crystals.

Magnetic memory combining plasmonics and magnetism is poised to dramatically increase the bit density and energy efficiency of light-assisted ultrafast magnetic storage, thanks to nanoplasmon-driven enhancement and confinement of light. Here we devise a new path for that, simultaneously enabling light-driven bit downscaling, reduction of the required energy for magnetic memory writing, and a subtle control over the degree of demagnetization in a magnetophotonic surface crystal. It features a regular array of truncated-nanocone-shaped Au-TbCo antennas showing both localized plasmon and surface lattice resonance modes. The ultrafast magnetization dynamics of the nanoantennas show a 3-fold resonant enhancement of the demagnetization efficiency. The degree of demagnetization is further tuned by activating surface lattice modes. This reveals a platform where ultrafast demagnetization is localized at the nanoscale and its extent can be controlled at will, rendering it multistate and potentially opening up so-far-unforeseen nanomagnetic neuromorphic-like systems operating at femtosecond time scales controlled by light.