Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

N1 versus N2 and PMN-MDSC: A critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology.

Research on tumor-associated neutrophils (TAN) currently surges because of the well-documented strong clinical relevance of tumor-infiltrating neutrophils. This relevance is illustrated by strong correlations between high frequencies of intratumoral neutrophils and poor outcome in the majority of human cancers. Recent high-dimensional analysis of murine neutrophils provides evidence for unexpected plasticity of neutrophils in murine models of cancer and other inflammatory non-malignant diseases. New analysis tools enable deeper insight into the process of neutrophil differentiation and maturation. These technological and scientific developments led to the description of an ever-increasing number of distinct transcriptional states and associated phenotypes in murine models of disease and more recently also in humans. At present, functional validation of these different transcriptional states and potential phenotypes in cancer is lacking. Current functional concepts on neutrophils in cancer rely mainly on the myeloid-derived suppressor cell (MDSC) concept and the dichotomous and simple N1-N2 paradigm. In this manuscript, we review the historic development of those concepts, critically evaluate these concepts against the background of our own work and provide suggestions for a refinement of current concepts in order to facilitate the transition of TAN research from experimental insight to clinical translation.

Operando analysis reveals potential-driven in situ formation of single-Fe-atom electrocatalysts for green production of ammonia.

As a sustainable approach for N2 fixation, electrocatalytic N2 reduction reaction (N2RR) to produce ammonia (NH3) is highly desirable with a precise understanding to the structure-activity relationship of electrocatalysts. Here, firstly, we obtain a novel carbon-supported oxygen-coordinated single-Fe-atom catalyst for highly efficient production of ammonia from electrocatalytic N2RR. Based on such new type of N2RR electrocatalyst, by combining operando X-ray absorption spectra (XAS) with density function theory calculation, we reveal significantly that the as-prepared active coordination structure undergoes a potential-driven two-step restructuring, firstly from FeSAO4(OH)1a to FeSAO4(OH)1a'(OH)1b with the adsorption of another -OH on FeSA at open-circuit potential (OCP) of 0.58 VRHE, and subsequently restructuring from FeSAO4(OH)1a'(OH)1b to FeSAO3(OH)1a″ due to the breaking of one Fe-O bond and the dissociation of one -OH at working potentials for final electrocatalytic process of N2RR, thus revealing the first potential-induced in situ formation of the real electrocatalytic active sites to boost the conversion of N2 to NH3. Moreover, the key intermediate of Fe-NNHx was detected experimentally by both operando XAS and in situ attenuated total reflection-surface-enhanced infrared absorption spectra (ATR-SEIRAS), indicating the alternating mechanism followed by N2RR on such catalyst. The results indicate the necessity of considering the potential-induced restructuring of the active sites on all kinds of electrocatalysts for such as highly efficient ammonia production from N2RR. It also paves a new way for a precise understanding to the structure-activity relationship of a catalyst and helps the design of highly efficient catalysts.

Pathways of N2O production by marine ammonia-oxidizing archaea determined from dual-isotope labeling.

The ocean is a net source of the greenhouse gas and ozone-depleting substance, nitrous oxide (N2O), to the atmosphere. Most of that N2O is produced as a trace side product during ammonia oxidation, primarily by ammonia-oxidizing archaea (AOA), which numerically dominate the ammonia-oxidizing community in most marine environments. The pathways to N2O production and their kinetics, however, are not completely understood. Here, we use 15N and 18O isotopes to determine the kinetics of N2O production and trace the source of nitrogen (N) and oxygen (O) atoms in N2O produced by a model marine AOA species, Nitrosopumilus maritimus. We find that during ammonia oxidation, the apparent half saturation constants of nitrite and N2O production are comparable, suggesting that both processes are enzymatically controlled and tightly coupled at low ammonia concentrations. The constituent atoms in N2O are derived from ammonia, nitrite, O2, and H2O via multiple pathways. Ammonia is the primary source of N atoms in N2O, but its contribution varies with ammonia to nitrite ratio. The ratio of 45N2O to 46N2O (i.e., single or double labeled N) varies with substrate ratio, leading to widely varying isotopic signatures in the N2O pool. O2 is the primary source for O atoms. In addition to the previously demonstrated hybrid formation pathway, we found a substantial contribution by hydroxylamine oxidation, while nitrite reduction is an insignificant source of N2O. Our study highlights the power of dual 15N-18O isotope labeling to disentangle N2O production pathways in microbes, with implications for interpretation of pathways and regulation of marine N2O sources.

Transient Attention Gates Access Consciousness: Coupling N2pc and P3 Latencies Using Dynamic Time Warping.

The N2pc and P3 event-related potentials (ERPs), used to index selective attention and access to working memory and conscious awareness, respectively, have been important tools in cognitive sciences. Although it is likely that these two components and the underlying cognitive processes are temporally and functionally linked, such links have not yet been convincingly demonstrated. Adopting a novel methodological approach based on dynamic time warping (DTW), we provide evidence that the N2pc and P3 ERP components are temporally linked. We analyzed data from an experiment where 23 participants (16 women) monitored bilateral rapid serial streams of letters and digits in order to report a target digit indicated by a shape cue, separately for trials with correct responses and trials where a temporally proximal distractor was reported instead (distractor intrusion). DTW analyses revealed that N2pc and P3 latencies were correlated in time, both when the target or a distractor was reported. Notably, this link was weaker on distractor intrusion trials. This N2pc-P3 association is discussed with respect to the relationship between attention and access consciousness. Our results demonstrate that our novel method provides a valuable approach for assessing temporal links between two cognitive processes and their underlying modulating factors. This method allows to establish links and their modulator for any two time-series across all domains of the field (general-purpose MATLAB functions and a Python module are provided alongside this paper).

Tracking the Misallocation and Reallocation of Spatial Attention toward Auditory Stimuli.

Completely ignoring a salient distractor presented concurrently with a target is difficult, and sometimes attention is involuntarily attracted to the distractor's location (attentional capture). Employing the N2ac component as a marker of attention allocation toward sounds, in this study we investigate the spatiotemporal dynamics of auditory attention across two experiments. Human participants (male and female) performed an auditory search task, where the target was accompanied by a distractor in two-third of the trials. For a distractor more salient than the target (Experiment 1), we observe not only a distractor N2ac (indicating attentional capture) but the full chain of attentional dynamics implied by the notion of attentional capture, namely, (1) the distractor captures attention before the target is attended, (2) allocation of attention to the target is delayed by distractor presence, and (3) the target is attended after the distractor. Conversely, for a distractor less salient than the target (Experiment 2), although responses were delayed, no attentional capture was observed. Together, these findings reveal two types of spatial attentional dynamics in the auditory modality (distraction with and without attentional capture).

Revealing novel and conservative T-cell epitopes with MHC B2 restriction on H9N2 avian influenza virus (AIV).

B2 haplotype major histocompatibility complex (MHC) has been extensively reported to confer resistance to various avian diseases. But its peptide-binding motif is unknown, and the presenting peptide is rarely identified. Here, we identified its peptide-binding motif (X-A/V/I/L/P/S/G-X-X-X-X-X-X-V/I/L) in vitro using Random Peptide Library-based MHC I LC-MS/MS analysis. To further clarify the structure basis of motif, we determined the crystal structure of the BF2∗02:01-PB2552-560 complex at 1.9 Å resolution. We found that BF2∗02:01 had a relatively wide antigen-binding groove, and the structural characterization of pockets was consistent with the characterization of peptide-binding motif. The wider features of the peptide-binding motif and increased number of peptides bound by BF2∗02:01 than BF2∗04:01 might resolve the puzzles for the presence of potential H9N2 resistance in B2 chickens. Afterward, we explored the H9N2 avian influenza virus (AIV)-induced cellular immune response in B2 haplotype chickens in vivo. We found that ratio of CD8+ T cell and kinetic expression of cytotoxicity genes including Granzyme K, interferon-γ, NK lysin, and poly-(ADP-ribose) polymerase in peripheral blood mononuclear cells were significantly increased in defending against H9N2 AIV infection. Especially, we selected 425 epitopes as candidate epitopes based on the peptide-binding motif and further identified four CD8+ T-cell epitopes on H9N2 AIV including NS198-106, PB2552-560, NP182-190, and NP455-463 via ELI-spot interferon-γ detections after stimulating memory lymphocytes with peptides. More importantly, these epitopes were found to be conserved in H7N9 AIV and H9N2 AIV. These findings provide direction for developing effective T cell epitope vaccines using well-conserved internal viral antigens in chickens.

Recent H9N2 avian influenza virus lost hemagglutination activity due to a K141N substitution in hemagglutinin.

The H9N2 avian influenza virus (AIV) represents a significant risk to both the poultry industry and public health. Our surveillance efforts in China have revealed a growing trend of recent H9N2 AIV strains exhibiting a loss of hemagglutination activity at 37°C, posing challenges to detection and monitoring protocols. This study identified a single K141N substitution in the hemagglutinin (HA) glycoprotein as the culprit behind this diminished hemagglutination activity. The study evaluated the evolutionary dynamics of residue HA141 and studied the impact of the N141K substitution on aspects such as virus growth, thermostability, receptor-binding properties, and antigenic properties. Our findings indicate a polymorphism at residue 141, with the N variant becoming increasingly prevalent in recent Chinese H9N2 isolates. Although both wild-type and N141K mutant strains exclusively target α,2-6 sialic acid receptors, the N141K mutation notably impedes the virus's ability to bind to these receptors. Despite the mutation exerting minimal influence on viral titers, antigenicity, and pathogenicity in chicken embryos, it significantly enhances viral thermostability and reduces plaque size on Madin-Darby canine kidney (MDCK) cells. Additionally, the N141K mutation leads to decreased expression levels of HA protein in both MDCK cells and eggs. These findings highlight the critical role of the K141N substitution in altering the hemagglutination characteristics of recent H9N2 AIV strains under elevated temperatures. This emphasizes the need for ongoing surveillance and genetic analysis of circulating H9N2 AIV strains to develop effective control and prevention measures.IMPORTANCEThe H9N2 subtype of avian influenza virus (AIV) is currently the most prevalent low-pathogenicity AIV circulating in domestic poultry globally. Recently, there has been an emerging trend of H9N2 AIV strains acquiring increased affinity for human-type receptors and even losing their ability to bind to avian-type receptors, which raises concerns about their pandemic potential. In China, there has been a growing number of H9N2 AIV strains that have lost their ability to agglutinate chicken red blood cells, leading to false-negative results during surveillance efforts. In this study, we identified a K141N mutation in the HA protein of H9N2 AIV to be responsible for the loss of hemagglutination activity. This finding provides insight into the development of effective surveillance, prevention, and control strategies to mitigate the threat posed by H9N2 AIV to both animal and human health.

The H9N2 avian influenza virus increases APEC adhesion to oviduct epithelia by viral NS1 protein-mediated activation of the TGF-ß pathway.

H9N2 avian influenza is a low-pathogenic avian influenza circulating in poultry and wild birds worldwide and frequently contributes to chicken salpingitis that is caused by avian pathogenic Escherichia coli (APEC), leading to huge economic losses and risks for food safety. Currently, how the H9N2 virus contributes to APEC infection and facilitates salpingitis remains elusive. In this study, in vitro chicken oviduct epithelial cell (COEC) model and in vivo studies were performed to investigate the role of H9N2 viruses on secondary APEC infection, and we identified that H9N2 virus enhances APEC infection both in vitro and in vivo. To understand the mechanisms behind this phenomenon, adhesive molecules on the cell surface facilitating APEC adhesion were checked, and we found that H9N2 virus could upregulate the expression of fibronectin, which promotes APEC adhesion onto COECs. We further investigated how fibronectin expression is regulated by H9N2 virus infection and revealed that transforming growth factor beta (TGF-ß) signaling pathway is activated by the NS1 protein of the virus, thus regulating the expression of adhesive molecules. These new findings revealed the role of H9N2 virus in salpingitis co-infected with APEC and discovered the molecular mechanisms by which the H9N2 virus facilitates APEC infection, offering new insights to the etiology of salpingitis with viral-bacterial co-infections.IMPORTANCEH9N2 avian influenza virus (AIV) widely infects poultry and is sporadically reported in human infections. The infection in birds frequently causes secondary bacterial infections, resulting in severe symptoms like pneumonia and salpingitis. Currently, the mechanism that influenza A virus contributes to secondary bacterial infection remains elusive. Here we discovered that H9N2 virus infection promotes APEC infection and further explored the underlying molecular mechanisms. We found that fibronectin protein on the cell surface is vital for APEC adhesion and also showed that H9N2 viral protein NS1 increased the expression of fibronectin by activating the TGF-ß signaling pathway. Our findings offer new information on how AIV infection promotes APEC secondary infection, providing potential targets for mitigating severe APEC infections induced by H9N2 avian influenza, and also give new insights on the mechanisms on how viruses promote secondary bacterial infections in animal and human diseases.

Auditory change detection and visual selective attention: association between MMN and N2pc.

While the auditory and visual systems each provide distinct information to our brain, they also work together to process and prioritize input to address ever-changing conditions. Previous studies highlighted the trade-off between auditory change detection and visual selective attention; however, the relationship between them is still unclear. Here, we recorded electroencephalography signals from 106 healthy adults in three experiments. Our findings revealed a positive correlation at the population level between the amplitudes of event-related potential indices associated with auditory change detection (mismatch negativity) and visual selective attention (posterior contralateral N2) when elicited in separate tasks. This correlation persisted even when participants performed a visual task while disregarding simultaneous auditory stimuli. Interestingly, as visual attention demand increased, participants whose posterior contralateral N2 amplitude increased the most exhibited the largest reduction in mismatch negativity, suggesting a within-subject trade-off between the two processes. Taken together, our results suggest an intimate relationship and potential shared mechanism between auditory change detection and visual selective attention. We liken this to a total capacity limit that varies between individuals, which could drive correlated individual differences in auditory change detection and visual selective attention, and also within-subject competition between the two, with task-based modulation of visual attention causing within-participant decrease in auditory change detection sensitivity.

Relative saliency affects attentional capture and suppression of color and face singleton distractors: evidence from event-related potential studies.

Prior research has yet to fully elucidate the impact of varying relative saliency between target and distractor on attentional capture and suppression, along with their underlying neural mechanisms, especially when social (e.g. face) and perceptual (e.g. color) information interchangeably serve as singleton targets or distractors, competing for attention in a search array. Here, we employed an additional singleton paradigm to investigate the effects of relative saliency on attentional capture (as assessed by N2pc) and suppression (as assessed by PD) of color or face singleton distractors in a visual search task by recording event-related potentials. We found that face singleton distractors with higher relative saliency induced stronger attentional processing. Furthermore, enhancing the physical salience of colors using a bold color ring could enhance attentional processing toward color singleton distractors. Reducing the physical salience of facial stimuli by blurring weakened attentional processing toward face singleton distractors; however, blurring enhanced attentional processing toward color singleton distractors because of the change in relative saliency. In conclusion, the attentional processes of singleton distractors are affected by their relative saliency to singleton targets, with higher relative saliency of singleton distractors resulting in stronger attentional capture and suppression; faces, however, exhibit some specificity in attentional capture and suppression due to high social saliency.

Photosynthetic biohybrid coculture for tandem and tunable CO2 and N2 fixation.

Solar-driven bioelectrosynthesis represents a promising approach for converting abundant resources into value-added chemicals with renewable energy. Microorganisms powered by electrochemical reducing equivalents assimilate CO2, H2O, and N2 building blocks. However, products from autotrophic whole-cell biocatalysts are limited. Furthermore, biocatalysts tasked with N2 reduction are constrained by simultaneous energy-intensive autotrophy. To overcome these challenges, we designed a biohybrid coculture for tandem and tunable CO2 and N2 fixation to value-added products, allowing the different species to distribute bioconversion steps and reduce the individual metabolic burden. This consortium involves acetogen Sporomusa ovata, which reduces CO2 to acetate, and diazotrophic Rhodopseudomonas palustris, which uses the acetate both to fuel N2 fixation and for the generation of a biopolyester. We demonstrate that the coculture platform provides a robust ecosystem for continuous CO2 and N2 fixation, and its outputs are directed by substrate gas composition. Moreover, we show the ability to support the coculture on a high-surface area silicon nanowire cathodic platform. The biohybrid coculture achieved peak faradaic efficiencies of 100, 19.1, and 6.3% for acetate, nitrogen in biomass, and ammonia, respectively, while maintaining product tunability. Finally, we established full solar to chemical conversion driven by a photovoltaic device, resulting in solar to chemical efficiencies of 1.78, 0.51, and 0.08% for acetate, nitrogenous biomass, and ammonia, correspondingly. Ultimately, our work demonstrates the ability to employ and electrochemically manipulate bacterial communities on demand to expand the suite of CO2 and N2 bioelectrosynthesis products.

Resolving the amine-promoted hydrolysis mechanism of N2O5 under tropospheric conditions.

Hydrolysis of N2O5 under tropospheric conditions plays a critical role in assessing the fate of O3, OH, and NOx in the atmosphere. However, its removal mechanism has not been fully understood, and little is known about the role of entropy. Herein, we propose a removal path of N2O5 on the water clusters/droplet with the existence of amine, which entails a low free-energy barrier of 4.46 and 3.76 kcal/mol on a water trimer and droplet, respectively, at room temperature. The free-energy barrier exhibits strong temperature dependence; a barrierless hydrolysis process of N2O5 at low temperature (≤150 K) is observed. By coupling constrained ab initio molecular dynamics (constrained AIMD) simulations with thermodynamic integration methods, we quantitively evaluated the entropic contributions to the free energy and compared NH3-, methylamine (MA)-, and dimethylamine (DMA)-promoted hydrolysis of N2O5 on water clusters and droplet. Our results demonstrate that methylation of NH3 stabilizes the product state and promotes hydrolysis of N2O5 by reducing the free-energy barriers. Furthermore, a quantitative analysis of the internal coordinate distribution of the reaction center and the relative position of surrounding species reveals that the significant entropic contribution primarily results from the ensemble effect of configurations observed in the AIMD simulations. Such an ensemble effect becomes more significant with more water molecules included. Lowering the temperature effectively minimizes the entropic contribution, making the hydrolysis more exothermic and barrierless. This study sheds light on the importance of the promoting effect of amines and the entropic effect on gas-phase hydrolysis reactions, which may have far-reaching implications in atmospheric chemistry.

A gap in nitrous oxide emission reporting complicates long-term climate mitigation.

Nitrous oxide (N2O) is an important greenhouse gas (GHG) that also contributes to depletion of ozone in the stratosphere. Agricultural soils account for about 60% of anthropogenic N2O emissions. Most national GHG reporting to the United Nations Framework Convention on Climate Change assumes nitrogen (N) additions drive emissions during the growing season, but soil freezing and thawing during spring is also an important driver in cold climates. We show that both atmospheric inversions and newly implemented bottom-up modeling approaches exhibit large N2O pulses in the northcentral region of the United States during early spring and this increases annual N2O emissions from croplands and grasslands reported in the national GHG inventory by 6 to 16%. Considering this, emission accounting in cold climate regions is very likely underestimated in most national reporting frameworks. Current commitments related to the Paris Agreement and COP26 emphasize reductions of carbon compounds. Assuming these targets are met, the importance of accurately accounting and mitigating N2O increases once CO2 and CH4 are phased out. Hence, the N2O emission underestimate introduces additional risks into meeting long-term climate goals.

Enhanced N2 Adsorption and Activation by Combining Re Clusters and In Vacancies as Dual Sites for Efficient and Selective Electrochemical NH3 Synthesis.

The electrochemical N2 reduction reaction (NRR) is a green and energy-saving sustainable technology for NH3 production. However, high activity and high selectivity can hardly be achieved in the same catalyst, which severely restricts the development of the electrochemical NRR. In2Se3 with partially occupied p-orbitals can suppress the H2 evolution reaction (HER), which shows excellent selectivity in the electrochemical NRR. The presence of VIn can simultaneously provide active sites and confine Re clusters through strong charge transfer. Additionally, well-isolated Re clusters stabilized on In2Se3 by the confinement effect of VIn result in Re-VIn active sites with maximum availability. By combining Re clusters and VIn as dual sites for spontaneous N2 adsorption and activation, the electrochemical NRR performance is enhanced significantly. As a result, the Re-In2Se3-VIn/CC catalyst delivers a high NH3 yield rate (26.63 µg h-1 cm-2) and high FEs (30.8%) at -0.5 V vs RHE.

Direct Eight-Electron N2O Electroreduction to NH3 Enabled by an Fe Double-Atom Catalyst.

N2O is a dominant atmosphere pollutant, causing ozone depletion and global warming. Currently, electrochemical reduction of N2O has gained increasing attention to remove N2O, but its product is worthless N2. Here, we propose a direct eight-electron (8e) pathway to electrochemically convert N2O into NH3. As a proof of concept, using density functional theory calculation, an Fe2 double-atom catalyst (DAC) anchored by N-doped porous graphene (Fe2@NG) was screened out to be the most active and selective catalyst for N2O electroreduction toward NH3 via the novel 8e pathway, which benefits from the unique bent N2O adsorption configuration. Guided by theoretical prediction, Fe2@NG DAC was fabricated experimentally, and it can achieve a high N2O-to-NH3 Faradaic efficiency of 77.8% with a large NH3 yield rate of 2.9 mg h-1 cm-2 at -0.6 V vs RHE in a neutral electrolyte. Our study offers a feasible strategy to synthesize NH3 from pollutant N2O with simultaneous N2O removal.

Pathogenesis and Transmission Assessment of 3 Swine-Origin Influenza A(H3N2) Viruses With Zoonotic Risk to Humans Isolated in the United States, 2017-2020.

The sporadic occurrence of human infections with swine-origin influenza A(H3N2) viruses and the continual emergence of novel A(H3N2) viruses in swine herds underscore the necessity for ongoing assessment of the pandemic risk posed by these viruses. Here, we selected 3 recent novel swine-origin A(H3N2) viruses isolated between 2017 to 2020, bearing hemagglutinins from the 1990.1, 2010.1, or 2010.2 clades, and evaluated their ability to cause disease and transmit in a ferret model. We conclude that despite considerable genetic variances, all 3 contemporary swine-origin A(H3N2) viruses displayed a capacity for robust replication in the ferret respiratory tract and were also capable of limited airborne transmission. These findings highlight the continued public health risk of swine-origin A(H3N2) strains, especially in human populations with low cross-reactive immunity.

Intranasal M2SR (M2-deficient Single Replication) Influenza Vaccine Induces Broadly Reactive Mucosal Antibody Production in Adults.

Intranasal M2SR (M2-deficient Single Replication influenza virus) vaccine induces robust immune responses in animal models and human subjects. A high-throughput multiplexed platform was used to analyze hemagglutinin-specific mucosal antibody responses in adults after a single dose of H3N2 M2SR. Nasal swab specimens were analyzed for total and hemagglutinin-specific IgA. Significant, dose-dependent increases in mucosal antibody responses to vaccine-matched and drifted H3N2 hemagglutinin were observed in M2SR vaccinated subjects regardless of baseline serum and mucosal immune status. These data suggest that M2SR induces broadly cross-reactive mucosal immune responses which may provide better protection against drifted and newly emerging influenza strains.

Influenza Vaccine Effectiveness Against Influenza A-Associated Emergency Department, Urgent Care, and Hospitalization Encounters Among US Adults, 2022-2023.

BACKGROUND: The 2022-2023 United States influenza season had unusually early influenza activity with high hospitalization rates. Vaccine-matched A(H3N2) viruses predominated, with lower levels of A(H1N1)pdm09 activity also observed. METHODS: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022-2023 season against influenza A-associated emergency department/urgent care (ED/UC) visits and hospitalizations from October 2022 to March 2023 among adults (aged ≥18 years) with acute respiratory illness (ARI). VE was estimated by comparing odds of seasonal influenza vaccination among case-patients (influenza A test positive by molecular assay) and controls (influenza test negative), applying inverse-propensity-to-be-vaccinated weights. RESULTS: The analysis included 85 389 ED/UC ARI encounters (17.0% influenza A positive; 37.8% vaccinated overall) and 19 751 hospitalizations (9.5% influenza A positive; 52.8% vaccinated overall). VE against influenza A-associated ED/UC encounters was 44% (95% confidence interval [CI], 40%-47%) overall and 45% and 41% among adults aged 18-64 and ≥65 years, respectively. VE against influenza A-associated hospitalizations was 35% (95% CI, 27%-43%) overall and 23% and 41% among adults aged 18-64 and ≥65 years, respectively. CONCLUSIONS: VE was moderate during the 2022-2023 influenza season, a season characterized with increased burden of influenza and co-circulation with other respiratory viruses. Vaccination is likely to substantially reduce morbidity, mortality, and strain on healthcare resources.

Inhibition of Benzo[a]pyrene-induced DNA Adduct in Buccal Cells of Smokers by Black Raspberry Lozenges.

Using LC-MS/MS analysis we previously showed for the first time (Carcinogenesis 43:746-753, 2022) that levels of DNA damage-induced by benzo[a]pyrene (B[a]P), an oral carcinogen and tobacco smoke (TS) constituent, were significantly higher in buccal cells of smokers than those in non-smokers; these results suggest the potential contribution of B[a]P in the development of oral squamous cell carcinoma (OSCC) in humans. Treating cancers, including OSCC at late stages even with improved targeted therapies, continues to be a major challenge. Thus interception/prevention remains a preferable approach for OSCC management and control. In previous preclinical studies we and others demonstrated the protective effects of black raspberry (BRB) against carcinogen-induced DNA damage and OSCC. Thus, to translate preclinical findings we tested the hypothesis, in a Phase 0 clinical study, that BRB administration reduces DNA damage induced by B[a]P in buccal cells of smokers. After enrolling 27 smokers, baseline buccal cells were collected before the administration of BRB lozenges (5/day for 8 weeks, 1 gm BRB powder/lozenge) at baseline, at the middle and the end of BRB administration. The last samples were collected at four weeks after BRB cessation (washout period). B[a]P-induced DNA damage (BPDE-N2-dG) was evaluated by LC-MS/MS. BRB administration resulted in a significant reduction in DNA damage: 26.3% at the midpoint (p = 0.01506) compared to baseline, 36.1% at the end of BRB administration (p = 0.00355), and 16.6% after BRB cessation (p = 0.007586). Our results suggest the potential benefits of BRB as a chemopreventive agent against the development of TS-initiated OSCC.