Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway.

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.

FDA, CDC, and NIH Co-sponsored Public Workshop Summary-Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.

There is an unmet need for developing drugs for the treatment of gonorrhea, due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On April 23, 2021, the U.S. Food and Drug Administration; Centers for Disease Control and Prevention; and National Institute of Allergy and Infectious Diseases, National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of the workshop.

Why is Superlubricity of Diamond-Like Carbon Rare at Nanoscale?

Hydrogenated diamond-like carbon (HDLC) is a promising solid lubricant for its superlubricity which can benefit various industrial applications. While HDLC exhibits notable friction reduction in macroscale tests in inert or reducing environmental conditions, ultralow friction is rarely observed at the nanoscale. This study investigates this rather peculiar dependence of HDLC superlubricity on the contact scale. To attain superlubricity, HDLC requires i) removal of ≈2 nm-thick air-oxidized surface layer and ii) shear-induced transformation of amorphous carbon to highly graphitic and hydrogenated structure. The nanoscale wear depth exceeds the typical thickness of the air-oxidized layer, ruling out the possibility of incomplete removal of the air-oxidized layer. Raman analysis of transfer films indicates that shear-induced graphitization readily occurs at shear stresses lower than or comparable to those in the nanoscale test. Thus, the same is expected to occur at the nanoscale test. However, the graphitic transfer films are not detected in ex-situ analyses after nanoscale friction tests, indicating that the graphitic transfer films are pushed out of the nanoscale contact area due to the instability of transfer films within a small contact area. Combining all these observations, this study concludes the retention of highly graphitic transfer films is crucial to achieving HDLC superlubricity.

National Trends and Prevalence of Atopic Dermatitis and Pandemic-Related Factors among Korean Adults, 2007-2021.

INTRODUCTION: Previous studies have variably reported inconclusive trends in the prevalence of atopic dermatitis (AD) among adults, and there are limited data on the impact of the COVID-19 pandemic. We aimed to investigate the national trends and age-stratified prevalence of AD among adults from 2007 to 2021 in South Korea, focusing mainly on the impact of the COVID-19 pandemic-related factors. METHODS: A nationwide cross-sectional study was conducted using the Korea National Health and Nutrition Examination Survey data from 2007 to 2021. Overall and age-stratified prevalence for AD were assessed using weighted beta coefficients or odds ratios. RESULTS: A total of 83,566 adults over 20 years (male, 49.40%) were included. During the observation period, the prevalence of AD was stable in the overall population from 2.61% (95% CI, 2.29-2.93) in 2007-2009 to 2.15% (1.68-2.63) in 2020 and 2.38% (1.81-2.95) in 2021. However, the weighted prevalence of AD in adults aged 40-59 years old decreased during the pre-pandemic era, and the prevalence of AD in adults aged above 60 years significantly decreased during the pandemic, with a significant decline observed after the initial outbreak. From age-stratification analysis, the adults aged 40-59 years showed a significant increase after the pandemic outbreak which was evident in specific variables: individuals with rural residence, lower education, and lower household income quartiles. Adults aged above 60 years showed a significant decrease in the slope after the outbreak, evident in specific variables: individuals of female, rural residence, lower education, and lower household income quartiles. CONCLUSION: We observed a stable overall prevalence of AD throughout the 15-year observation period. However, the age-stratified analysis suggested significantly different trends according to age-stratified groups and the impact of the COVID-19 pandemic on the prevalence of AD.

Water Adsorption Isotherm and Surface Conductivity of Boroaluminosilicate Glasses.

The surface resistivity of boroaluminosilicate display glasses, which may affect the downstream display panel manufacturing, varies with the relative humidity (RH) of the environment, but the origin of this RH dependence has not been well understood. We have measured the water adsorption behavior on Corning Eagle XG (Glass-E) and Lotus NXT (Glass-L) glass panels using Brewster angle transmission infrared spectroscopy. The IR spectra of adsorbed water were analyzed to obtain the effective thickness of adsorbed water, the distribution of hydrogen-bonding interactions among the adsorbed water molecules, and the isosteric heat of water adsorption. These characteristics were compared with the electrical conductivity (inverse of resistivity) of these two glasses [Appl. Surf. Sci. 2015, 356, 1189]. This comparison revealed the correlation between the conductivity and the water layer structure, which could explain the surface resistivity difference between Glass-E and Glass-L as a function of RH. This study also disputed the previous hypothesis that the water adsorption isotherm would be governed by the areal density of the surface hydroxyl group; instead, it suggested that the network modifier ions may also play a critical role, especially in the intermediate RH regime.

NST3 induces ectopic transdifferentiation, forming secondary walls with diverse patterns and composition in Arabidopsis thaliana.

BACKGROUND AND AIMS: The master transcription factor NAC SECONDARY WALL THICKENING PROMOTING FACTOR3 (NST3), also known as SND1, plays a pivotal role in regulating secondary cell wall (SCW) development in interfascicular and xylary fibers in Arabidopsis thaliana. Despite progress in understanding SCW assembly in xylem vessel-like cells, the mechanisms behind its assembly across different cell types remain unclear. Overexpressing NST3 or its homolog NST1 leads to reduced fertility, posing challenges for studying their impact on secondary wall formation. This study aimed at developing a tightly regulated dexamethasone (DEX)-inducible expression system for NST3 and NST1 to elucidate the structure and assembly of diverse SCWs. METHODS: Using the DEX-inducible system, we characterized ectopically formed SCWs for their diverse patterns, mesoscale organization, cellulose microfibril orientation, and molecular composition using spinning disk confocal microscopy, field emission scanning electron microscopy (FESEM), vibrational sum-frequency generation (SFG) spectroscopy and, histochemical staining and time-of-flight secondary ion mass spectrometry (ToF-SIMS), respectively. KEY RESULTS: Upon DEX treatment, NST3 and NST1 transgenic hypocotyls underwent time-dependent transdifferentiation, progressing from protoxylem-like to metaxylem-like cells. NST3-induced plants exhibited normal growth but had rough secondary wall surfaces with delaminating S2 and S3 layers. Mesoscale examination of induced SCWs in epidermal cells revealed that macrofibril thickness and orientation were comparable to xylem vessels, while wall thickness resembled that of interfascicular fibers. Additionally, induced epidermal cells formed SCWs with altered cellulose and lignin contents. CONCLUSIONS: These findings suggest NST3 and/or NST1 induce SCWs with shared characteristics of both xylem and fiber-like cells forming loosely arranged cell wall layers and cellulose organized at multiple angles relative to the cell growth axis and with varied cellulose and lignin abundance. This inducible system opens avenues to explore ectopic SCWs for bioenergy and bioproducts, offering valuable insights into SCW patterning across diverse cell types and developmental stages.

Beyond the Average: Spatial and Temporal Fluctuations in Oxide Glass-Forming Systems.

Atomic structure dictates the performance of all materials systems; the characteristic of disordered materials is the significance of spatial and temporal fluctuations on composition-structure-property-performance relationships. Glass has a disordered atomic arrangement, which induces localized distributions in physical properties that are conventionally defined by average values. Quantifying these statistical distributions (including variances, fluctuations, and heterogeneities) is necessary to describe the complexity of glass-forming systems. Only recently have rigorous theories been developed to predict heterogeneities to manipulate and optimize glass properties. This article provides a comprehensive review of experimental, computational, and theoretical approaches to characterize and demonstrate the effects of short-, medium-, and long-range statistical fluctuations on physical properties (e.g., thermodynamic, kinetic, mechanical, and optical) and processes (e.g., relaxation, crystallization, and phase separation), focusing primarily on commercially relevant oxide glasses. Rigorous investigations of fluctuations enable researchers to improve the fundamental understanding of the chemistry and physics governing glass-forming systems and optimize structure-property-performance relationships for next-generation technological applications of glass, including damage-resistant electronic displays, safer pharmaceutical vials to store and transport vaccines, and lower-attenuation fiber optics. We invite the reader to join us in exploring what can be discovered by going beyond the average.

Nasal allergen challenge (NAC): Practical aspects and applications from an EU/US perspective-a Work Group Report of the AAAAI Rhinitis, Rhinosinusitis and Ocular Allergy Committee.

Nasal allergen challenge (NAC) is applied in a variety of settings (research centers, specialty clinics, and hospitals) as a useful diagnostic and research tool. NAC is indicated for diagnosis of seasonal and perennial allergic rhinitis, local allergic rhinitis, and occupational rhinitis; to design the composition of allergen immunotherapy in patients who are polysensitized; and to investigate the physio-pathological mechanisms of nasal diseases. NAC is currently a safe and reproducible technique, although it is time- and resource-consuming. NAC can be performed by a variety of methods, but the lack of a uniform technique for performing and recording the outcomes represents a challenge for those considering NAC as a clinical tool in the office. The availability of standardized allergens for NAC is also different in each country. The objective of this workgroup report is to review the current information about NAC, focusing on the practical aspects and application for diagnosis of difficult rhinitis phenotypes (eg, local allergic rhinitis, occupational rhinitis), taking into account the particular context of practice in the United States and the European Union.

Understanding and Preventing Lubrication Failure at the Carbon Atomic Steps.

Two-dimensional (2D) lamellar materials are normally capable of rendering super-low friction, wear protection, and adhesion reduction in nanoscale due to their ultralow shear strength between two basal plane surfaces. However, high friction at step edges prevents the 2D materials from achieving super-low friction in macroscale applications and eventually leads to failure of lubrication performance. Here, taking graphene as an example, the authors report that not all step edges are detrimental. The armchair (AC) step edges are found to have only a minor topographic effect on friction, while the zigzag (ZZ) edges cause friction two orders of magnitude larger than the basal plane. The AC step edge is less reactive and thus more durable. However, the ZZ structure prevails when step edges are produced mechanically, for example, through mechanical exfoliation or grinding of graphite. The authors found a way to make the high-friction ZZ edge superlubricious by reconstructing the (6,6) hexagon structure to the (5,7) azulene-like structure through thermal annealing in an inert gas environment. This will facilitate the realization of graphene-based superlubricity over a wide range of industrial applications in which avoiding the involvement of step edges is difficult.

Mutations in the Pectin Methyltransferase QUASIMODO2 Influence Cellulose Biosynthesis and Wall Integrity in Arabidopsis.

Pectins are abundant in the cell walls of dicotyledonous plants, but how they interact with other wall polymers and influence wall integrity and cell growth has remained mysterious. Here, we verified that QUASIMODO2 (QUA2) is a pectin methyltransferase and determined that QUA2 is required for normal pectin biosynthesis. To gain further insight into how pectin affects wall assembly and integrity maintenance, we investigated cellulose biosynthesis, cellulose organization, cortical microtubules, and wall integrity signaling in two mutant alleles of Arabidopsis (Arabidopsis thaliana) QUA2, qua2 and tsd2 In both mutants, crystalline cellulose content is reduced, cellulose synthase particles move more slowly, and cellulose organization is aberrant. NMR analysis shows higher mobility of cellulose and matrix polysaccharides in the mutants. Microtubules in mutant hypocotyls have aberrant organization and depolymerize more readily upon treatment with oryzalin or external force. The expression of genes related to wall integrity, wall biosynthesis, and microtubule stability is dysregulated in both mutants. These data provide insights into how homogalacturonan is methylesterified upon its synthesis, the mechanisms by which pectin functionally interacts with cellulose, and how these interactions are translated into intracellular regulation to maintain the structural integrity of the cell wall during plant growth and development.

Regiospecific Cellulose Orientation and Anisotropic Mechanical Property in Plant Cell Walls.

Cellulose microfibrils (CMFs) are a major load-bearing component in plant cell walls. Thus, their structures have been studied extensively with spectroscopic and microscopic characterization methods, but the findings from these two approaches were inconsistent, which hampers the mechanistic understanding of cell wall mechanics. Here, we report the regiospecific assembly of CMFs in the periclinal wall of plant epidermal cells. Using sum frequency generation spectroscopic imaging, we found that CMFs are highly aligned in the cell edge region where two cells form a junction, whereas they are mostly isotropic on average throughout the wall thickness in the flat face region of the epidermal cell. This subcellular-level heterogeneity in the CMF alignment provided a new perspective on tissue-level anisotropy in the tensile modulus of cell wall materials. This finding also has resolved a previous contradiction between the spectroscopic and microscopic imaging studies, which paves a foundation for better understanding of the cell wall architecture, especially structure-geometry relationships.

Shear-activated chemisorption and association of cyclic organic molecules.

Mechanochemical activation has created new opportunities for applications such as solvent-free chemical synthesis, polymer processing, and lubrication. However, mechanistic understanding of these processes is still limited because the mechanochemical response of a system is a complex function of many variables, including the direction of applied stress and the chemical features of the reactants in non-equilibrium conditions. Here, we studied shear-activated reactions of simple cyclic organic molecules to isolate the effect of chemical structure on reaction yield and pathway. Reactive molecular dynamics simulations were used to model methylcyclopentane, cyclohexane, and cyclohexene subject to pressure and shear stress between silica surfaces. Cyclohexene was found to be more susceptible to mechanochemical activation of oxidative chemisorption and subsequent oligomerization reactions than either methylcyclopentane or cyclohexane. The oligomerization trend was consistent with shear-driven polymerization yield measured in ball-on-flat sliding experiments. Analysis of the simulations showed the distribution of carbon atom sites at which oxidative chemisorption occurred and identified the double bond in cyclohexene as being the origin of its shear susceptibility. Lastly, the most common reaction pathways for association were identified, providing insight into how the chemical structures of the precursor molecules determined their response to mechanochemical activation.

Optimal sampling for positive only electronic health record data.

Identifying a patient's disease/health status from electronic medical records is a frequently encountered task in electronic health records (EHR) related research, and estimation of a classification model often requires a benchmark training data with patients' known phenotype statuses. However, assessing a patient's phenotype is costly and labor intensive, hence a proper selection of EHR records as a training set is desired. We propose a procedure to tailor the best training subsample with limited sample size for a classification model, minimizing its mean-squared phenotyping/classification error (MSE). Our approach incorporates "positive only" information, an approximation of the true disease status without false alarm, when it is available. In addition, our sampling procedure is applicable for training a chosen classification model which can be misspecified. We provide theoretical justification on its optimality in terms of MSE. The performance gain from our method is illustrated through simulation and a real-data example, and is found often satisfactory under criteria beyond MSE.

Recent Advances in Corrosion Science Applicable To Disposal of High-Level Nuclear Waste.

High-level radioactive waste is accumulating at temporary storage locations around the world and will eventually be placed in deep geological repositories. The waste forms and containers will be constructed from glass, crystalline ceramic, and metallic materials, which will eventually come into contact with water, considering that the period of performance required to allow sufficient decay of dangerous radionuclides is on the order of 105-106 years. Corrosion of the containers and waste forms in the aqueous repository environment is therefore a concern. This Review describes the recent advances of the field of materials corrosion that are relevant to fundamental materials science issues associated with the long-term performance assessment and the design of materials with improved performance, where performance is defined as resistance to aqueous corrosion. Glass, crystalline ceramics, and metals are discussed separately, and the near-field interactions of these different material classes are also briefly addressed. Finally, recommendations for future directions of study are provided.

Inverse Relationship between Thickness and Wear of Fluorinated Graphene: "Thinner Is Better".

Atomically thin two-dimensional (2D) materials are excellent candidates for utilization as a solid lubricant or additive at all length scales from macro-scale mechanical devices to micro/nano-electromechanical systems (MEMS/NEMS). In such applications, wear resistance of ultrathin 2D materials is critical for sustained lubrication performance. Here, we investigated the wear of fluorinated graphene (FG) nanosheets deposited on silicon surfaces using atomic force microscopy (AFM) and discovered that the wear resistance of FG improves as the FG thickness decreases from 4.2 to 0.8 nm (corresponding to seven layers to single layer) and the surface energy of the substrate underneath the FG nanosheets increases. On the basis of density function theory (DFT) calculations, the negative correlation of wear resistance to FG thickness and the positive correlation to substrate surface energy could be explained with the degree of interfacial charge transfer between FG and substrate which affects the strength of FG adhesion to the substrate.

Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment. The exposure-response analysis was conducted to identify the relationship between plazomicin exposure and nephrotoxicity incidence in cUTI patients with renal impairment. Classification and regression tree (CART) analysis was utilized to assess the TDM strategy. The receiver operating characteristics curve was plotted to compare two TDM thresholds in cUTI patients with renal impairment. The analyses suggested that dose reduction is necessary for cUTI patients with moderate or severe renal impairment. TDM should be implemented for cUTI patients with mild, moderate, or severe renal impairment to reduce the risk of nephrotoxicity. The trough concentration of 3 µg/mL is a reasonable TDM threshold to reduce the nephrotoxicity incidence while maintaining efficacy in cUTI patients with renal impairment. The application of population PK modeling, exposure-response analysis, and CART analysis allowed for the evaluation of a dosage regimen and TDM strategy for plazomicin in cUTI patients with renal impairment. Our study demonstrates the utility of pharmacometrics and statistical approaches to inform a dosage regimen and TDM strategy for drugs with narrow therapeutic windows.

Photothermal Atomic Force Microscopy Coupled with Infrared Spectroscopy (AFM-IR) Analysis of High Extinction Coefficient Materials: A Case Study with Silica and Silicate Glasses.

Photothermal atomic force microscopy coupled with infrared spectroscopy (AFM-IR) brings significant value as a spatially resolved surface analysis technique for disordered oxide materials such as glasses, but additional development and fundamental understanding of governing principles is needed to interpret AFM-IR spectra, since the existing theory described for organic materials does not work for materials with high extinction coefficients for infrared (IR) absorption. This paper describes theoretical calculation of a transient temperature profile inside the IR-absorbing material considering IR refraction at the interface as well as IR adsorption and heat transfer inside the sample. This calculation explains the differences in peak positions and amplitudes of AFM-IR spectra from those of specular reflectance and extinction coefficient spectra. It also addresses the information depth of the AFM-IR characterization of bulk materials. AFM-IR applied to silica and silicate glass surfaces has demonstrated novel capability of characterizing subsurface structural changes and surface heterogeneity due to mechanical stresses from physical contacts, as well as chemical alterations manifested in surface layers through aqueous corrosion.

Elucidating Interfacial Chain Conformation of Superhydrophilic Polymer Brushes by Vibrational Sum Frequency Generation Spectroscopy.

Surface-tethered macromolecules (polymer brushes) are a potent means to modify surfaces with stimuli-responsive properties while avoiding delamination problems. This vibrational sum frequency generation spectroscopy study describes how the conformation of hydrophilic polymer brushes changes in response to environmental conditions, that is, changes in humidity (in air) and upon exposure to liquid water. Three hydrophilic brushes were prepared on silicon oxide surfaces by surface-initiated reversible deactivation radical polymerization of cationic (quaternary ammonium), anionic (sulfonate), and zwitterionic (containing both) monomers. The average tilt angle of methyl groups was analyzed and used to deduce the chain conformations of the polymer brushes. In air, the brush films absorb water and swell with increasing humidity. This is accompanied by the rotation of interfacial polymer chains. The degree of water uptake and chain conformation vary with the nature of the charged hydrophilic moieties. The hydrophilic polymer brush surfaces appear to remain relatively dry except in near-condensation conditions. In water, the quaternary ammonium groups of cationic and zwitterionic brushes are aligned nearly parallel to the surface. The anionic brush chains appear to assume nearly random conformations in water.

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.