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Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.

ABSTRACT As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread around the world, there is an urgent need for new assay formats to characterize the humoral response to infection. Here, we present an efficient, competitive serological assay that can simultaneously determine an individual’s seroreactivity against the SARS-CoV-2 Spike protein and determine the proportion of anti-Spike antibodies that block interaction with the human angiotensin-converting enzyme 2 (ACE2) required for viral entry. In this approach based on the use of enzyme-linked immunosorbent assays (ELISA), we present natively folded viral Spike protein receptor-binding domain (RBD)-containing antigens via avidin-biotin interactions. Sera are then competed with soluble ACE2-Fc, or with a higher-affinity variant thereof, to determine the proportion of ACE2 blocking anti-RBD antibodies. Assessment of sera from 144 SARS-CoV-2 patients ultimately revealed that a remarkably consistent and high proportion of antibodies in the anti-RBD pool targeted the epitope responsible for ACE2 engagement (83% ± 11%; 50% to 107% signal inhibition in our largest cohort), further underscoring the importance of tailoring vaccines to promote the development of such antibodies. IMPORTANCE With the emergence and continued spread of the SARS-CoV-2 virus, and of the associated disease, coronavirus disease 2019 (COVID-19), there is an urgent need for improved understanding of how the body mounts an immune response to the virus. Here, we developed a competitive SARS-CoV-2 serological assay that can simultaneously determine whether an individual has developed antibodies against the SARS-CoV-2 Spike protein receptor-binding domain (RBD) and measure the proportion of these antibodies that block interaction with the human angiotensin-converting enzyme 2 (ACE2) required for viral entry. Using this assay and 144 SARS-CoV-2 patient serum samples, we found that a majority of anti-RBD antibodies compete for ACE2 binding. These results not only highlight the need to design vaccines to generate such blocking antibodies but also demonstrate the utility of this assay to rapidly screen patient sera for potentially neutralizing antibodies.

Summary: Comprehensive understanding of the serological response to SARS-CoV-2 infection is important for both pathophysiologic insight and diagnostic development. Here, we generate a pan-human coronavirus programmable phage display assay to perform proteome-wide profiling of coronavirus antigens enriched by 98 COVID-19 patient sera. Next, we use ReScan, a method to efficiently sequester phage expressing the most immunogenic peptides and print them onto paper-based microarrays using acoustic liquid handling, which isolates and identifies nine candidate antigens, eight of which are derived from the two proteins used for SARS-CoV-2 serologic assays: spike and nucleocapsid proteins. After deployment in a high-throughput assay amenable to clinical lab settings, these antigens show improved specificity over a whole protein panel. This proof-of-concept study demonstrates that ReScan will have broad applicability for other emerging infectious diseases or autoimmune diseases that lack a valid biomarker, enabling a seamless pipeline from antigen discovery to diagnostic using one recombinant protein source.

In the nervous system, protein activities are highly regulated in space and time. This regulation allows for fine modulation of neuronal structure and function during development and adaptive responses. For example, neurite extension and synaptogenesis both involve localized and transient activation of cytoskeletal and signaling proteins, allowing changes in microarchitecture to occur rapidly and in a localized manner. To investigate the role of specific protein regulation events in these processes, scientists have been developing tools for optical control of the activity of specific proteins. In this review, we focus on how some recently developed optical control modules have been used in neuroscience applications. These tools have demonstrated impressive versatility in controlling various protein families and thereby cellular functions, and possess enormous potential for future applications in nervous systems. Just as optogenetic control of neuronal firings using rhodopsins has changed how we investigate circuitry function in vivo, optical control may yet yield another revolution in how we study intracellular signaling activities in the brain.

Flooding of paddy fields enhances methane (CH 4 ) emissions and arsenic (As) mobilisation, which are crucial issues for agricultural greenhouse gas emissions and food safety. Birnessite (δ-MnO 2 ) is a common natural oxidant and scavenger for heavy metals. In this study, birnessite was applied to As-contaminated paddy soil. The capacity for simultaneously alleviating CH 4 emissions and As mobility was explored. Soil microcosm incubation results indicated that birnessite addition simultaneously reduced CH 4 emissions by 47 %-54 % and As release by 38 %-85 %. The addition of birnessite decreased the dissolved organic carbon (DOC) contents and altered its chemical properties. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) results showed that birnessite reduced the labile fractions of proteins, carbohydrates, lignins, tannins, and unsaturated hydrocarbons, however, increased the abundance of condensed aromatic structures, suggesting the polymerisation of dissolved organic matter (DOM) by birnessite. The degradation of labile fractions and the polymerisation of DOM resulted in an inventory of recalcitrant DOM, which is difficult for microbes to metabolise, thus inhibiting methanogenesis. In contrast, birnessite addition increased CH 4 oxidation, as the particulate methane monooxygenase (pmoA) gene abundance increased by 30 %. The enhanced polymerisation of DOM by birnessite also increased As complexation with organics, leading to the transfer of As to the organic bound phase. In addition, the decrease in ferrous ion [Fe(II)] concentrations with birnessite indicated that the reductive dissolution of Fe oxides was suppressed, which limited the release of arsenite [As(III)] under reducing conditions. Furthermore, birnessite decreased As methylation and shaped the soil microbial community structure by enriching the metal-reducing bacterium Bacillus. Overall, our results provide a promising method to suppress greenhouse gas emissions and the risk of As contamination in paddy soils, although further studies are needed to verify its efficacy and effectiveness under field conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The chemoresistance and systemic toxicity of cisplatin (CDDP) severely limit its application in the treatment of non-small cell lung cancer (NSCLC). Here, I-124 labeled cancer cell membrane biomimetic nanovesicles loading Polyphyllin VI (PPVI) and CDDP (termed 124 I-P/C@CMLvs) were constructed to enhance the sensitivity and efficacy of CDDP. The radiochemical purity (RCP) of 124 I-P/C@CMLvs reached more than 99% and maintained reliable stability in vitro. Micro-positron emission tomography (micro-PET) imaging of I-124 quantitatively revealed the distribution and specific homologous tumor targeting ability of 124 I-P/C@CMLvs in vivo with superior diagnosis performance, beneficial for dynamically monitoring the efficacy against NSCLC. Loaded PPVI significantly strengthened the sensitivity of NSCLC to CDDP therapy and exerted synergistic anti-tumor effect in vitro and in vivo, which was achieved by PPVI promoting p53 deubiquitination and stimulating reactive oxygen species (ROS) production to trigger the crosstalk between the amplification of GPX4 signaling-mediated ferroptosis and NLRP3/GSDMD/Caspase-1 axis-mediated pyroptosis. 124 I-P/C@CMLvs also significantly stimulated the infiltration of immune cells including dendritic cells, CD8 + T cells, and CD4 + T cells in tumor tissues ( P < 0.05). The combination of 124 I-P/C@CMLvs and anti-PD-L1 therapy further synergistically promoted NSCLC regression. Altogether, 124 I-P/C@CMLvs provide a transformational solution to the challenge of improving CDDP sensitivity and realizing the integration of diagnosis, treatment, and monitoring of NSCLC.

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed. While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT. Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

For the first time, polystyrene sulfonic acid solution (PSS) was observed to emit blue fluorescence. The photoluminescence (PL) behavior of PSS under different concentrations, pH values and magnetic field strengths was investigated, revealing the diversity and tunability of its PL properties. PSS possesses remarkable down-conversion properties and strong responsiveness to external magnetic fields.

Deep learning models are widely used for PM 2.5 prediction. However, neglecting temporal and spatial characteristics leads to low prediction accuracy. In this work, a new deep learning model (RCG - Attention model) was developed, which combines the residual neural network (ResNet) and the convolution gated recurrent network (ConvGRU) and is applied to extract the spatio - temporal features for predicting PM 2.5 concentration over the subsequent 24 h. The ResNet extracts the spatial distribution features of pollutants, and the ConvGRU extracts temporal features. The spatial and temporal features are fused by the multi - head attention mechanism to obtain multi - dimensional features. These features are finally fed into a series of fully connected layers to predict the future results. Incorporating these chemical components enhances the scientific validity of the dataset and strengthens the inherent logical connections among variables. The Mean Absolute Error (MAE), Mean Absolute Percentage Error (MAPE), Root Mean Square Error (RMSE), and R - squared (R 2 ) results indicate that the prediction performance of the RCG - Attention model surpasses that of other baseline models. The model demonstrates superior prediction performance across multiple monitoring stations, suggesting robust generalization capabilities and adaptability for various regions in one city. The SHAP results show that PM 10 , NO 2 , RH, NO 3 - , OC and NH 4+ are significant influencing features. The RCG - Attention model provides a comprehensive solution for PM 2.5 concentration prediction by integrating spatial and temporal feature extraction with chemical components., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To clarify the synergistic pathogenic mechanism of Nicotiana benthamiana double infection with alfalfa mosaic virus (AMV) and white clover mosaic virus (WCMV), AMV and WCMV co-inoculation of N. benthamiana as treatment and single inoculation of AMV or WCMV and phosphate buffer solution (pH 7.0, PBS) as control, respectively. The concentrations and the relative expression of AMV and WCMV coat proteins were determined by a double antibody sandwich enzyme-linked immune sorbent assay (DAS-ELISA) and real-time fluorescence quantitative PCR (RT-qPCR) in a double infection of N. benthamiana with AMV and WCMV. Meanwhile, virion morphology, ultrastructure morphology, and chlorophyll content were observed and determined by electron microscopy. The results showed that the diseased symptoms were more serious, and virus concentration and relative expression of AMV and WCMV coat proteins were also higher in N. benthamiana double infection with AMV and WCMV than in AMV or WCMV single infection. The main symptoms manifested as severe mottle mosaic, shrinkage, and chlorosis. The concentrations of AMV and WCMV were 182.23 pg/mL and 148.77 pg/mL of double infection with AMV and WCMV, which were 1.75-fold and 1.62-fold than AMV and WCMV single infection, respectively. The relative expression of AMV and WCMV coat proteins was 4.25-fold and 2.50-fold than the single virus infection, respectively. Electron microscopy also observed that chloroplast malformation, cell membrane deformation, contents dissolution, grana lamella disorder, fat granules increased and enlarged, starch granules enlarged, and mitochondria were seriously malformed in a double infection of N. benthamiana with AMV and WCMV. The chlorophyll content was significantly lower for double infection with AMV and WCMV than for AMV or WCMV single-infected and CK, reduced by 31.52 %, 22.83 %, and 76.09 %, respectively. This is the first report of a double infection of N. benthamiana with AMV and WCMV that increases both virus concentrations and synergistically changes both host organelle ultrastructure and chlorophyll content., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Liang qiaolan reports financial support was provided by National Natural Science Foundation of China. Liang qiaolan reports a relationship with National Natural Science Foundation of China that includes: consulting or advisory, funding grants, paid expert testimony, speaking and lecture fees, and travel reimbursement. Liang qiaolan, chen ying e has patent pending to liang qiaolan. The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Argonaute (AGO), a component of RNA-induced silencing complexes (RISCs), is a representative RNA-binding protein (RBP) known to bind with mature microRNAs (miRNAs) and is directly involved in post-transcriptional gene silencing. However, despite the biological significance of miRNAs, the roles of other miRNA-binding proteins (miRBPs) remain unclear in the regulation of miRNA loading, dissociation from RISCs and extracellular release. In this study, we performed protein arrays to profile miRBPs and identify 118 RBPs that directly bind to miRNAs. Among those proteins, the RBP quaking (QKI) inhibits extracellular release of the mature microRNA let-7b by controlling the loading of let-7b into extracellular vesicles via additional miRBPs such as AUF1 (also known as hnRNPD) and hnRNPK. The enhanced extracellular release of let-7b after QKI depletion activates Toll-like receptor 7 (TLR7) and promotes the production of proinflammatory cytokines in recipient cells, leading to brain inflammation in the mouse cortex. Thus, this study reveals the contribution of QKI to the inhibition of brain inflammation via regulation of extracellular let-7b release., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Objective: This study was performed to explore the clinical significance of the expression of human beta-defensin 2 (HBD-2) and chemokine ligand 1/2 (CXCL-1/2) in psoriasis vulgaris., Methods: This study retrospectively included the study group (n = 160) and control group (n = 100) for analysis. The levels of inflammatory indicators, blood biochemical indicators, and immune indicators using ELISA. The psoriasis area and severity index (PASI) was used to evaluate disease severity. Levels of HBD-2, CXCL-1, CXCL-2 and CCL20 were determined by RT-PCR. The correlations of HBD-2, CXCL-1 and CXCL-2 levels with CCL20 and PASI scores were analyzed. The diagnostic value of HBD-2, CXCL-1 and CXCL-2 in psoriasis vulgaris was analyzed by ROC curve., Results: HBD-2, CXCL-1 and CXCL-2 were highly expressed in the lesions of psoriasis vulgaris patients, and were positively correlated with CCL20 and PASI score. HBD-2, CXCL-1 and CXCL-2 alone or in combination had high diagnostic value for psoriasis vulgaris and severe psoriasis, and the combined diagnostic value of the three was higher than that of a single indicator., Conclusion: HBD-2, CXCL-1, and CXCL-2 levels are closely related to the severity of psoriasis vulgaris and can effectively diagnose the occurrence and progression of psoriasis vulgaris.

Genomic copy number changes are associated with antifungal drug resistance and virulence across diverse fungal pathogens, but the rate and dynamics of these genomic changes in the presence of antifungal drugs are unknown. Here we optimized a dual-fluorescent reporter system in the diploid pathogen Candida albicans to quantify haplotype-specific copy number variation (CNV) and loss of heterozygosity (LOH) at the single-cell level with flow cytometry. We followed the frequency and dynamics of CNV and LOH at two distinct genomic locations in the presence and absence of antifungal drugs in vitro and in a murine model of candidiasis. Copy number changes were rapid and dynamic during adaptation to fluconazole and frequently involved competing subpopulations with distinct genotypes. This study provides quantitative evidence for the rapid speed at which diverse genotypes arise and undergo dynamic population-level fluctuations during adaptation to antifungal drugs in vitro and in vivo., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The aim of this study was to investigate the application of PSMA-RADS version 2.0 in assessment of pulmonary metastases in patients with prostate cancer and whether PSMA PET/CT parameters provide incremental value., Patients and Methods: From October 2016 to July 2023, PC patients with pulmonary opacities (including pulmonary metastases, lung cancer, and pulmonary benign opacities) who underwent Al 18 F-PSMA-BCH PET/CT scans were retrospectively analyzed. CT imaging characteristics, including the longest diameter, density, smoothness, lobulation, pleural retraction, and vacuole sign, as well as PET parameters including SUV max and tumor-to-background ratio, were measured and analyzed. Additionally, the pulmonary PSMA-RADS score for each patient was determined. Independent predictors of pulmonary metastases were identified through univariate analysis and multivariate logistic regression analysis, which were utilized to construct a parallel diagnostic test. The differential diagnostic performances were evaluated using receiver operating characteristic analysis., Results: A total of 148 pulmonary opacities from 96 patients were retrospectively included. The number of pulmonary benign opacities, lung cancer, and pulmonary metastases were 48 (32.4%), 20 (13.5%), and 80 (54.1%), respectively. The number of opacities across different PSMA-RADS scores from 2 to 5 was 8 (5.4%), 88 (59.5%), 7 (4.7%), and 45 (30.4%). SUV max and smooth edges were independent predictors of pulmonary metastases (both P < 0.05), and the AUC of the parallel test for these 2 parameters was 0.86 (95% confidence interval: 0.79, 0.94; P < 0.001). Furthermore, the diagnostic accuracy of the parallel test across PSMA-RADS score from 2 to 5 was 85.7%, 79.6%, 100%, and 92.9%, respectively., Conclusions: Al 18 F-PSMA-BCH PET/CT parameters were helpful in differentiating pulmonary metastases in PC patients and provided incremental value when integrated with PSMA-RADS version 2.0., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To comprehensively assess the impact of aging, cigarette smoking, and chronic obstructive pulmonary disease (COPD) on pulmonary physiology using 129 Xe MR., Methods: A total of 90 subjects were categorized into four groups, including healthy young (HY, n = 20), age-matched control (AMC, n = 20), asymptomatic smokers (AS, n = 28), and COPD patients (n = 22). 129 Xe MR was utilized to obtain pulmonary physiological parameters, including ventilation defect percent (VDP), alveolar sleeve depth (h), apparent diffusion coefficient (ADC), total septal wall thickness (d), and ratio of xenon signal from red blood cells and interstitial tissue/plasma (RBC/TP)., Results: Significant differences were found in the measured VDP (p = 0.035), h (p = 0.003), and RBC/TP (p = 0.003) between the HY and AMC groups. Compared with the AMC group, higher VDP (p = 0.020) and d (p = 0.048) were found in the AS group; higher VDP (p < 0.001), d (p < 0.001) and ADC (p < 0.001), and lower h (p < 0.001) and RBC/TP (p < 0.001) were found in the COPD group. Moreover, significant differences were also found in the measured VDP (p < 0.001), h (p < 0.001), ADC (p < 0.001), d (p = 0.008), and RBC/TP (p = 0.032) between the AS and COPD groups., Conclusion: Our findings indicate that pulmonary structure and functional changes caused by aging, cigarette smoking, and COPD are various, and show a progressive deterioration with the accumulation of these risk factors, including cigarette smoking and COPD., Clinical Relevance Statement: Pathophysiological changes can be difficult to comprehensively understand due to limitations in common techniques and multifactorial etiologies. 129 Xe MRI can demonstrate structural and functional changes caused by several common factors and can be used to better understand patients' underlying pathology., Key Points: Standard techniques for assessing pathophysiological lung function changes, spirometry, and chest CT come with limitations. 129 Xe MR demonstrated progressive deterioration with accumulation of the investigated risk factors, without these limitations. 129 Xe MR can assess lung changes related to these risk factors to stage and evaluate the etiology of the disease., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

The pathophysiology of hypertrophic scar (HS) shares similarities with cancer. HOXC10, a gene significantly involved in cancer development, exhibits higher expression levels in HS than in normal skin (NS), suggesting its potential role in HS regulation. And the precise functions and mechanisms by which HOXC10 influences HS require further clarification. Gene and protein expressions were analyzed using raeal-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. Cell proliferation and migration were evaluated using EdU proliferation assays, CCK-8 assays, scratch assays, and Transwell assays. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to investigate the interactions between HOXC10 and STMN2. HOXC10 and STMN2 expression levels were significantly higher in HS tissues compared with NS tissues. Silencing HOXC10 led to decreased activation, proliferation, migration, and fibrosis in hypertrophic scar fibroblasts (HSFs). Our findings also indicate that HOXC10 directly targets STMN2. The promotional effects of HOXC10 knockdown on HSF activation, proliferation, migration, and fibrosis were reversed by STMN2 overexpression. We further demonstrated that HOXC10 regulates HSF activity through the TGF-β/Smad signaling pathway. HOXC10 induces the activation and fibrosis of HSFs by promoting the transcriptional activation of STMN2 and engaging the TGF-β/Smad signaling pathway. This study suggests that HOXC10 could be a promising target for developing treatments for HS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study explored the feasibility of employing hyperspectral imaging (HSI) technology to quantitatively assess the effect of silicon (Si) on lead (Pb) content in oilseed rape leaves. Aiming at the defects of hyperspectral data with high dimension and redundant information, this paper proposed two improved feature wavelength extraction algorithms, repetitive interval combination optimization (RICO) and interval combination optimization (ICO) combined with stepwise regression (ICO-SR). The entire oilseed rape leaves were taken as the region of interest (ROI) to extract the visible near-infrared hyperspectral data within the 400.89-1002.19 nm range. In data processing, Savitzky-Golay (SG) smoothing, detrending (DT), and multiple scatter correction (MSC) were utilized for spectral data preprocessing, while recursive feature elimination (RFE), iteratively variable subset optimization (IVSO), ICO, and the two enhanced algorithms were employed to identify characteristic wavelengths. Subsequently, based on the spectral data of preprocessing and feature extraction, partial least squares regression (PLSR) and support vector regression (SVR) methods were used to construct various Pb content prediction models in oilseed rape leaves, with a comparison and analysis of each model performance. The results indicated that the two improved algorithms were more efficient in extracting representative spectral information than conventional methods, and the performance of SVR models was better than PLSR models. Finally, to further improve the prediction accuracy and robustness of the SVR models, the whale optimization algorithm (WOA) was introduced to optimize their parameters. The findings demonstrated that the MSC-RICO-WOA-SVR model achieved the best comprehensive performance, with R p 2 of 0.9436, RMSEP of 0.0501 mg/kg, and RPD of 3.4651. The results further confirmed the great potential of HSI combined with feature extraction algorithms to evaluate the effectiveness of Si in alleviating Pb stress in oilseed rape and provided a theoretical basis for determining the appropriate amount of Si application to alleviate Pb pollution in oilseed rape., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Individuals with Down syndrome (DS) have a higher incidence of hearing loss (HL) compared with their peers without developmental disabilities. Little is known about the associations between HL and functional hearing for individuals with DS. This study investigated two aspects of auditory functions, "what" (understanding the content of sound) and "where" (localizing the source of sound), in young adults with DS. Speech reception thresholds in quiet and in the presence of interferers provided insight into speech recognition, that is, the "what" aspect of auditory maturation. Insights into "where" aspect of auditory maturation were gained from evaluating speech reception thresholds in colocated versus separated conditions (quantifying spatial release from masking) as well as right versus left discrimination and sound location identification. Auditory functions in the "where" domain develop during earlier stages of cognitive development in contrast with the later developing "what" functions. We hypothesized that young adults with DS would exhibit stronger "where" than "what" auditory functioning, albeit with the potential impact of HL. Considering the importance of auditory working memory and receptive vocabulary for speech recognition, we hypothesized that better speech recognition in young adults with DS, in quiet and with speech interferers, would be associated with better auditory working memory ability and receptive vocabulary., Design: Nineteen young adults with DS (aged 19 to 24 years) participated in the study and completed assessments on pure-tone audiometry, right versus left discrimination, sound location identification, and speech recognition in quiet and with speech interferers that were colocated or spatially separated. Results were compared with published data from children and adults without DS and HL, tested using similar protocols and stimuli. Digit Span tests assessed auditory working memory. Receptive vocabulary was examined using the Peabody Picture Vocabulary Test Fifth Edition., Results: Seven participants (37%) had HL in at least 1 ear; 4 individuals had mild HL, and 3 had moderate HL or worse. Participants with mild or no HL had ≥75% correct at 5° separation on the discrimination task and sound localization root mean square errors (mean ± SD: 8.73° ± 2.63°) within the range of adults in the comparison group. Speech reception thresholds in young adults with DS were higher than all comparison groups. However, spatial release from masking did not differ between young adults with DS and comparison groups. Better (lower) speech reception thresholds were associated with better hearing and better auditory working memory ability. Receptive vocabulary did not predict speech recognition., Conclusions: In the absence of HL, young adults with DS exhibited higher accuracy during spatial hearing tasks as compared with speech recognition tasks. Thus, auditory processes associated with the "where" pathways appear to be a relative strength than those associated with "what" pathways in young adults with DS. Further, both HL and auditory working memory impairments contributed to difficulties in speech recognition in the presence of speech interferers. Future larger-sized samples are needed to replicate and extend our findings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Substance use disorder has been associated with increased morbidity in COVID-19 infection. However, less is known about the impact of active substance use and medications for opioid use disorder (MOUD) on COVID-19 outcomes. We conducted a retrospective cohort study to evaluate the impact of substance use, namely, cannabis, cocaine, alcohol, sedative and opioid use; and buprenorphine or methadone on COVID-19 morbidity and mortality., Methods: Using electronic health record data at a large urban hospital system, patients who tested positive for COVID-19 between January 1, 2020, and December 31, 2021, were included. Substance use was identified from urine toxicology and MOUD prescriptions within 90 days prior to admission. COVID-19 outcomes included mortality, ICU admission, need for intubation, and number and duration of hospitalizations. Multivariable logistic regression was performed controlling for variables such as age, sex, medical comorbidity, tobacco use, and social disadvantage., Results: Among COVID-19-positive patients (n = 17,423), sedative, cannabis, cocaine, and opioid use was associated with statistically significant increases in need for ICU care, need for ventilatory support, number of hospitalizations, and duration of hospitalization. Substance use was not associated with an increase in all-cause mortality. There were no statistically significant differences between methadone, buprenorphine, and other opioids on COVID-19 outcomes., Conclusions: Active substance use was associated with increased morbidity in COVID-19 infection. MOUD was not associated with worse COVID-19 outcomes compared to other opioids. Future studies focused on MOUD treatments that reduce morbidity may help improve clinical outcomes in COVID-19., Competing Interests: The authors do not have any financial conflicts of interest. Nicholaus Christian's effort was sponsored by HSR&D postdoctoral fellowship through the VA Office of Academic Affairs. Rajiv Radhakrishnan's effort was supported by NIDA grant (R21DA057540). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH, VA or the funding agencies., (Copyright © 2024 American Society of Addiction Medicine.)

Background: FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants., Methods: We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants., Results: In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential., Conclusion: For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications., (© 2024. The Author(s).)

2-Ethylhexyl diphenyl phosphate (EHDPP), ubiquitously monitored in environmental media, is highly bioaccumulative and may pose long-term risks, even after short-term exposure. In this investigation, larval zebrafish were exposed to 0.05, 0.5, and 5.0 μg/L EHDPP from 4 to 120 h postfertilization (hpf) to examine the long-term neurotoxicity effects of early exposure. Exposure to 5.0 μg/L EHDPP yielded hyperactive locomotor behavior, which was characterized by increased swimming speed, larger turning angles, and heightened sensitivity to light-dark stimulation. The predicted targets of EHDPP (top 100 potential macromolecules) were primarily associated with brain diseases like Alzheimer's disease (AD). Comparisons of differentially expressed genes (DEGs) from AD patients (GSE48350) and RNA-seq data from EHDPP-exposed zebrafish confirmed consistently abnormal regulatory pathways. EHDPP's interaction with M1 and M5 muscarinic acetylcholine receptors likely disrupted calcium homeostasis, leading to mitochondrial dysfunction and neurotransmitter imbalance as well as abnormal locomotor behavior. Especially, 5.0 μg/L EHDPP exposure during early development (4-120 hpf) triggered early- and midstage AD-like symptoms in adulthood (180 dpf), characterized by cognitive confusion, aggression, blood-brain barrier disruption, and mitochondrial damage in brains. These findings provide deep insights into the long-term neurotoxicity effects and Alzheimer's disease risks of early EHDPP exposure at extremely low dosages.

Purpose: To investigate whether a bounce in plasma Epstein-Barr virus (EBV) DNA during posttreatment surveillance of nasopharyngeal carcinoma (NPC) informs the risk of clinical recurrence and its implication for early therapeutic intervention., Methods: 950 non-disseminated NPC patients with completed remission in 3 months after treatment were retrospectively screened. Detectable EBV DNA with no evidence of clinical relapse during follow-up was deemed as DNA bounce. The diagnostic and prognostic performance of EBV DNA bounce was assessed for subsequent failures., Results: Tumor recurrence occurred in 6.6 %, 10.1 % and 65.8 % in the group with persistently negative EBV DNA, single positive test and ≥ 2 positive tests, respectively. EBV DNA bounce over twice was associated with worse disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) than the other two groups. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the prediction of recurrence were 0.56, 0.95, 0.66, 0.93 and 0.90 using two positive tests, which were hence deemed as biological relapse. Serial cutoffs (EBV DNA 1 ≥ 40 copies/ml or EBV DNA 2 ≥100 copies/ml) further defined a high-risk subgroup with an eventual recurrence rate of 77.9 % and 3-year DFS of merely 20.5 %. Prophylactic medical intervention with capecitabine or S1 significantly improved the 3-year DFS when compared to those with observation., Conclusions: The earliest two positive tests of EBV DNA represent a biomarker of biological relapse that allows early detection of clinical recurrence in EBV-related NPC. For high-risk biological relapse, preemptive intervention provides potential survival benefits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sandwich composites made of particle-filled hollow sphere structures (PHSS) and steel sheets offer excellent lightweight and damping properties, ideal for high-speed machine tool components under dynamic loads. Previous research has focused on single particle-filled hollow sphere (PHS) and small PHSS, leaving a gap understanding of PHSS/steel sandwich composites. In this study a test rig was developed, and Design of Experiments and Response Surface Analysis were used to investigate the effects of sheet and core thickness (design parameters), filling ratio, and particle size (particle parameters) on the damping performance of PHSS/steel sandwiches. The results indicate that the design parameters have a significant influence on damping performance. The interaction between design and particle parameters also substantially affects damping. Minimizing particle size, increasing filling ratio, thinning the face layer, and thickening the core layer significantly improve structural damping. To address manufacturing tolerances, a finite element (FE) model-based optimization was developed to accurately determine PHSS material parameters. These parameters were used in an FE model of the PHSS-steel composite, with identified contact parameters minimizing measurement and simulation differences. The homogenized material model and the linear model using global damping parameters accurately reproduce the dynamic properties of the PHSS-steel sandwich composite in low vibration modes., (© 2024. The Author(s).)

Background: Large soft tissue defects of the lower limb and foot are common occurrence in clinical practice and a considerable number of flaps have been used to treat them. However, there have been few reports using the superficial inferior epigastric artery (SIEA) flap. This review aims to present the experience of using the SIEA flaps for the repair of large soft tissue defects of the lower limb and foot., Methods: A retrospective review of data from 11 patients who underwent coverage of lower limb and foot defects exceeding 120 cm 2 (15 × 9 cm) using SIEA flaps from March 2018 to July 2022 were retrospectively reviewed. The average size of the defects was 18 × 11 cm 2 (range 15 × 9 cm 2 -32 × 16 cm 2 ). Flap survival rates, surgical complications and overall long-term outcomes were recorded., Results: All 11 flaps survived. One flap was partially necrotic at the edge and healed after several changes of dressing. Additionally, one flap presented with mild venous congestion. The mean follow-up period was 18 months (ranging from 12 to 30 months). The mean size of the flaps was 20 × 12 cm 2 (range 17 × 9 cm 2 -34 × 18 cm 2 ). The flaps were observed to be aesthetically pleasing and exhibited a well-defined texture. The donor wounds were successfully closed primarily, with only linear scarring remaining., Conclusions: The SIEA flap is characterised by concealed donor area, superficial vascular location, easy access and primary closure, which results in favourable aesthetic outcomes. It is an appropriate choice for the repair of large soft tissue defects of the lower limb and foot., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Liu, Xie, Chu, Zhou, Luo and Li.)

Nature often provides invaluable insights into technological innovation and the construction of nanomaterials. Inspired by the pitaya fruit's strategy of wrapping seeds within its pulp to enhance seed survival, a unique nanocomposite based on metal-organic framework (MOF)-encapsulated CuS nanoparticles (NPs) is developed. This design effectively addresses the challenge of short retention time afforded by CuS NPs for therapeutic and imaging purposes. The MOF acts as the "pitaya pulp" protecting the internal CuS NPs ("pitaya seeds"), thereby increasing their retention time in vivo. This system exhibits triple-enzyme-mimicking activities and is proposed for application in photoacoustic and magnetic resonance imaging-guided therapies, including chemodynamic therapy, photothermal therapy, and cuproptosis-related therapy. The exceptional enzyme-mimicking activities of superoxide dismutase, catalase, and peroxidase not only produce oxygen to alleviate hypoxia but also generate a reactive oxygen species (ROS) storm for effective tumor destruction. By combining these multienzymatic properties, superior photothermal performance, and Cu-induced cuproptosis, nanozyme-treated mice exhibited an 84% inhibition of tumor growth-approximately double the effect observed in mice treated with CuS NPs alone. This study presents a smart strategy for integrating imaging with therapeutic modalities, achieving exceptional outcomes for precise imaging-guided tumor therapy., (© 2024 Wiley‐VCH GmbH.)

Single-crystalline covalent organic frameworks (COFs) are highly desirable toward understanding their pore chemistry and functions. Herein, two 50-100 μm single-crystalline three-dimensional (3D) COFs, TAM-TFPB-COF and TAPB-TFS-COF, were prepared from the condensation of 4,4',4″,4‴-methanetetrayltetraaniline (TAM) with 3,3',5,5'-tetrakis(4-formylphenyl)bimesityl (TFPB) and 3,3',5,5'-tetrakis(4-aminophenyl)bimesityl (TAPB) with 4,4',4″,4‴-silanetetrayltetrabenzaldehyde (TFS), respectively, in 1,4-dioxane under the catalysis of acetic acid. Single-crystal 3D electron diffraction reveals the triply interpenetrated dia-b networks of TAM-TFPB-COF with atom resolution, while the isostructure of TAPB-TFS-COF was disclosed by synchrotron single-crystal X-ray diffraction and synchrotron powder X-ray diffraction with Le Bail refinements. The nitrogen sorption measurements at 77 K disclose the microporosity nature of both activated COFs with their exceptionally high Brunauer-Emmett-Teller surface areas of 3533 and 4107 m 2 g -1 , representing the thus far record high specific surface area among imine-bonded COFs. This enables the activated COFs to exhibit also the record high methane uptake capacities up to 28.9 wt % (570 cm 3 g -1 ) at 25 °C and 200 bar among all COFs reported thus far. This work not only presents the structures of two single-crystalline COFs with exceptional microporosity but also provides an example of atom engineering to adjust permanent microporous structures for methane storage.

Driving anger is a serious global issue that poses risks to road safety, thus necessitating the development of effective detection and intervention methods. This study investigated the feasibility of using smartphones to capture facial expressions to detect event-related driving anger. Sixty drivers completed the driving tasks in scenarios with and without multi-stage road events and were induced to angry and neutral states, respectively. Their physiological signals, facial expressions, and subjective data were collected. Four feature combinations and six machine learning algorithms were used to construct driving anger detection models. The model combining facial features and the XGBoost algorithm outperformed models using physiological features or other algorithms, achieving an accuracy of 87.04% and an F1-score of 85.06%. Eyes, mouth, and brows were identified as anger-sensitive facial areas. Additionally, incorporating individual characteristics into models further improved classification performance. This study provides a contactless and highly accessible approach for event-related driving anger detection. Practitioner Summary: This study proposed a cost-effective and contactless approach for event-related and real-time driving anger detection and could potentially provide insights into the design of emotional interactions in intelligent vehicles.