Effect of High-Intensity vs Low-Intensity Noninvasive Positive Pressure Ventilation on the Need for Endotracheal Intubation in Patients With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease: The HAPPEN Randomized Clinical Trial.

Importance: The effect of high-intensity noninvasive positive pressure ventilation (NPPV) on the need for endotracheal intubation in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) is unknown. Objective: To determine whether the use of high-intensity NPPV vs low-intensity NPPV reduces the need for endotracheal intubation in patients with an acute exacerbation of COPD and hypercapnia. Design, Setting, and Participants: Randomized clinical trial conducted at 30 general respiratory non-intensive care unit wards of Chinese hospitals from January 3, 2019, to January 31, 2022; the last 90-day follow-up was on April 22, 2022. The included patients had an acute exacerbation of COPD and a Paco2 level greater than 45 mm Hg after receiving 6 hours of low-intensity NPPV. Interventions: Patients were randomized 1:1 to receive high-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume 10 mL/kg to 15 mL/kg of predicted body weight (n = 147) or to continue receiving low-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume of 6 mL/kg to 10 mL/kg of predicted body weight (n = 153). Patients in the low-intensity NPPV group who met the prespecified criteria for the need for endotracheal intubation were allowed to crossover to high-intensity NPPV. Main Outcomes and Measures: The primary outcome was the need for endotracheal intubation during hospitalization, which was defined by prespecified criteria. There were 15 prespecified secondary outcomes, including endotracheal intubation. Results: The trial was terminated by the data and safety monitoring board and the trial steering committee after an interim analysis of the first 300 patients. Among the 300 patients who completed the trial (mean age, 73 years [SD, 10 years]; 68% were men), all were included in the analysis. The primary outcome of meeting prespecified criteria for the need for endotracheal intubation occurred in 7 of 147 patients (4.8%) in the high-intensity NPPV group vs 21 of 153 (13.7%) in the low-intensity NPPV group (absolute difference, -9.0% [95% CI, -15.4% to -2.5%], 1-sided P = .004). However, rates of endotracheal intubation did not significantly differ between groups (3.4% [5/147] in the high-intensity NPPV group vs 3.9% [6/153] in the low-intensity NPPV group; absolute difference, -0.5% [95% CI, -4.8% to 3.7%], P = .81). Abdominal distension occurred more frequently in the high-intensity NPPV group (37.4% [55/147]) compared with the low-intensity NPPV group (25.5% [39/153]). Conclusions and Relevance: Patients with COPD and persistent hypercapnia in the high-intensity NPPV group (vs patients in the low-intensity NPPV group) were significantly less likely to meet criteria for the need for endotracheal intubation; however, patients in the low-intensity NPPV group were allowed to crossover to high-intensity NPPV, and the between-group rate of endotracheal intubation was not significantly different. Trial Registration: ClinicalTrials.gov Identifier: NCT02985918.

Association between preoperative neutrophil-to-lymphocyte ratio and the survival outcomes of esophageal cancer patients underwent esophagectomy: a systematic review and meta-analysis.

Objectives: The purpose of this study was to assess the association between preoperative neutrophil-to-lymphocyte ratio (NLR) and the survival outcomes of esophageal cancer patients who underwent esophagectomy, the latest and comprehensive systematic review performed. Methods: Related literature retrieved from PubMed, Web of Science, Embase, and Cochrane before January 2024, according to the inclusion criteria. Outcomes measured were overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). Results: Eighteen studies with 6,119 esophageal cancer patients were retained for analysis. Meta-analysis demonstrated that OS (HR: 1.47; 95% CI: 1.29, 1.67; P < 0.00001), DFS (HR: 1.62; 95% CI: 1.29, 2.05; P < 0.0001), and CSS (HR: 1.62; 95% CI: 1.29, 2.05; P < 0.0001) were significantly shorter in the high NLR group compared with the low NLR group. In addition, meta-analysis revealed a similar RFS (HR: 1.47; 95% CI: 0.92, 2.35; P = 0.10) among the two groups. Subgroup analysis of OS and DFS based on mean/median age, NLR cutoff, and region found that all subgroups remained significant difference between two groups. Conclusion: Among esophageal cancer patients who underwent esophagectomy, preoperative NLR can be used as prognostic factor independently. High-preoperative NLR is associated with poor prognosis. More large-scale, multicenter prospective clinical studies are needed to further validate the relationship between preoperative NLR and prognosis of esophageal cancer.

Evaluation of the Multidimensional Enhanced Lateral Flow Immunoassay in Point-of-Care Nanosensors.

Point-of-care (POC) nanosensors with high screening efficiency show promise for user-friendly manipulation in the ever-increasing on-site analysis demand for illness diagnosis, environmental monitoring, and food safety. Currently, inspired by the merits of integrating advanced nanomaterials, molecular biology, machine learning, and artificial intelligence, lateral flow immunoassay (LFIA)-based POC nanosensors have been devoted to satisfying the commercial demands in terms of sensitivity, specificity, and practicality. Herein, we examine the use of multidimensional enhanced LFIA in various fields over the past two decades, focusing on introducing advanced nanomaterials to improve the acquisition capability of small order of magnitude targets through engineering transformations and emphasizing interdomain fusion to collaboratively address the inherent challenges in current commercial applications, such as multiplexing, development of detectors for quantitative analysis, more practical on-site monitoring, and sensitivity enhancement. Specifically, this comprehensive review encompasses the latest advances in comprehending LFIA with an alternative signal transduction pattern, aiming to achieve rapid, ultrasensitive, and "sample-to-answer" available options with progressive applications for POC nanosensors. In summary, through the cross-collaboration development of disciplines, LFIA has the potential to break the barriers toward commercialization and achieve laboratory-level POC nanosensors, thus leading to the emergence of the next generation of LFIA.

ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish.

Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development. Defects in the process can result in severe organ mispositioning. Coiled-coil domain containing 141 (CCDC141) has been previously known as a centrosome-related gene, but its role in left-right (LR) asymmetry has not been characterized. In this study, we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects. The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways, cilia function, and Kupffer's vesicle formation. Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns, ccdc141-null mutants show no apparent abnormality, suggesting a genetic compensation response effect. In parallel, we observe a marked reduction in α-tubulin acetylation levels in the ccdc141 crispants. The treatment with histone deacetylase (HDAC) inhibitors, particularly the HDAC6 inhibitor, rescues the ccdc141 crispant phenotypes. Furthermore, exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations, with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G. Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns, identifying it as a candidate gene for laterality defects.

A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication.

The ORF9b protein, derived from the nucleocapsid's open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response. Despite its significance, the precise regulatory mechanisms underlying its function remain elusive. In the present study, we unveil that the ORF9b protein of SARS-CoV-2, including emerging mutant strains like Delta and Omicron, can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway, despite certain mutations present among these strains. Moreover, our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70 (TOM70) as a substrate receptor, bridging ORF9b with heat shock protein 90 alpha (HSP90α) and Cullin 5 (CUL5) to form a complex. Within this complex, CUL5 triggers the ubiquitination and degradation of ORF9b, acting as a host antiviral factor, while HSP90α functions to stabilize it. Notably, treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b, leading to a pronounced inhibition of SARS-CoV-2 replication. Single-cell sequencing data revealed an up-regulation of HSP90α in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90α to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90α complex as a critical regulator of ORF9b protein stability, shedding light on the intricate host-virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.

Identification of New Substrates and Inhibitors of Human CYP2A7.

CYP2A7 is one of the most understudied human cytochrome P450 enzymes and its contributions to either drug metabolism or endogenous biosynthesis pathways are not understood, as its only known enzymatic activities are the conversions of two proluciferin probe substrates. In addition, the CYP2A7 gene contains four single-nucleotide polymorphisms (SNPs) that cause missense mutations and have minor allele frequencies (MAFs) above 0.5. This means that the resulting amino acid changes occur in the majority of humans. In a previous study, we employed the reference standard sequence (called CYP2A7*1 in P450 nomenclature). For the present study, we created another CYP2A7 sequence that contains all four amino acid changes (Cys311, Glu169, Gly479, and Arg274) and labeled it CYP2A7-WT. Thus, it was the aim of this study to identify new substrates and inhibitors of CYP2A7 and to compare the properties of CYP2A7-WT with CYP2A7*1. We found several new proluciferin probe substrates for both enzyme variants (we also performed in silico studies to understand the activity difference between CYP2A7-WT and CYP2A7*1 on specific substrates), and we show that while they do not act on the standard CYP2A6 substrates nicotine, coumarin, or 7-ethoxycoumarin, both can hydroxylate diclofenac (as can CYP2A6). Moreover, we found ketoconazole, 1-benzylimidazole, and letrozole to be CYP2A7 inhibitors.

Dual-plasmonic CuS@Au heterojunctions synergistic enhanced photothermal and colorimetric dual signal for sensitive multiplexed LFIA.

Multiplexed immunodetection, which achieves qualitative and quantitative outcomes for multiple targets in a single-run process, provides more sufficient results to guarantee food safety. Especially, lateral flow immunoassay (LFIA), with the ability to offer multiple test lines for analytes and one control line for verification, is a forceful candidate in multiplexed immunodetection. Nevertheless, given that single-signal mode is incredibly vulnerable to interference, further efforts should be engrossed on the combination of multiplexed immunodetection and multiple signals. Photothermal signal has sparked significant excitement in designing immunosensors. In this work, by optimizing and comparing the amount of gold, CuS@Au heterojunctions (CuS@Au HJ) were synthesized. The dual-plasmonic metal-semiconductor hybrid heterojunction exhibits a synergistic photothermal performance by increasing light absorption and encouraging interfacial electron transfer. Meanwhile, the colorimetric property is synergistic enhanced, which is conducive to reduce the consumption of antibodies and then improve assay sensitivity. Therefore, CuS@Au HJ are suitable to be constructed in a dual signal and multiplexed LFIA (DSM-LFIA). T-2 toxin and deoxynivalenol (DON) were used as model targets for the simulated multiplex immunoassay. In contrast to colloidal gold-based immunoassay, the built-in sensor has increased sensitivity by ≈ 4.42 times (colorimetric mode) and ≈17.79 times (photothermal mode) for DON detection and by ≈ 1.75 times (colorimetric mode) and ≈13.09 times (photothermal mode) for T-2 detection. As a proof-of-concept application, this work provides a reference to the design of DSM-LFIA for food safety detection.

Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer.

Background NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2 -mutant lung cancer patients within specific subgroups. Methods A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing. Results The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2 , TERC , ATR , ZMAT3 , and SOX2 ( p < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p = 0.0459) and better overall survival. Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.

RIPK3 signaling and its role in regulated cell death and diseases.

Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines. This review summarizes the recent research progress of the regulators of the RIPK3 signaling pathway and discusses the potential role of RIPK3/necroptosis in the aetiopathogenesis of various diseases. An in-depth understanding of the mechanisms and functions of RIPK3 may facilitate the development of novel therapeutic strategies.

Fortified Dual-Spectral Overlap with Enhanced Colorimetric/Fluorescence Dual-Response Immunochromatography for On-Site Bimodal-Type Gentamicin Monitoring.

Immunochromatography (ICA) remains untapped toward enhanced sensitivity and applicability for fulfilling the nuts and bolts of on-site food safety surveillance. Herein, we report a fortified dual-spectral overlap with enhanced colorimetric/fluorescence dual-response ICA for on-site bimodal-type gentamicin (Gen) monitoring by employing polydopamine (PDA)-coated AuNPs (APDA) simultaneously serving as a colorimetric reporter and a fluorescence quencher. Availing of the enhanced colorimetric response that originated from the PDA layer, the resultant APDA exhibits less required antibody and immunoprobes in a single immunoassay, which facilitates improved antibody utilization efficiency and immuno-recognition in APDA-ICA. Further integrated with the advantageous features of fortified excitation and emission dual-spectral overlap for the Arg/ATT-AuNCs, this APDA-ICA with a "turn on/off" pattern achieves the visual limits of detection of 1.0 and 0.5 ng mL-1 for colorimetric and fluorescence patterns (25- and 50-fold lower than standard AuNPs-ICA). Moreover, the excellent self-calibration and satisfactory recovery of 79.03-118.04% were shown in the on-site visual colorimetric-fluorescence analysis for Gen in real environmental media (including real river water, an urban aquaculture water body, an aquatic product, and an animal byproduct). This work provides the feasibility of exploiting fortified dual-spectral overlap with an enhanced colorimetric/fluorescence dual response for safeguarding food safety and public health.

A systematic comparison of salt removal efficiency in washing treatment by using fly ashes from 13 MSWI plants in China.

Municipal solid waste incineration (MSWI) fly ash contains large amounts of Ca, Si, and other elements, giving it the potential to be used as a raw material for cement production. However, fly ash often contains a high content of salts, which greatly limits its blending ratio during cement production. These salts are commonly removed via water washing, but this process is affected by the nature and characteristics of fly ash. To clarify the influence of the ash characteristics on salt removal, a total of 60 fly ash samples from 13 incineration plants were collected, characterized, and washed. The ash characterization and cluster analysis showed that the incinerator type and flue gas purification technology/process significantly influenced the ash characteristics. Washing removed a high percentage of salts from fly ash, but the removal efficiencies varied significantly from each other, with the chlorine removal efficiency ranging from 73.76% to 96.48%, while the sulfate removal efficiency ranged from 6.92% to 51.47%. Significance analysis further revealed that the salt removal efficiency varied not only between the ash samples from different incinerators, but also between samples collected at different times from the same incinerator. The high variance of the 60 ash samples during salt removal was primarily ascribed to their different mineralogical and chemical characteristics. Mineralogical analysis of the raw and washed ash samples showed that the mineralogical forms and proportion of these salts in each ash sample greatly influenced their removal. The presence of less-soluble and insoluble chloride salts (e.g., CaClOH, Ca2Al(OH)6(H2O)2Cl etc.) in fly ash significantly affected the chlorine removal efficiency. This study also found that Fe, Mn, and Al in fly ash were negatively correlated with the dechlorination efficiency of fly ash. In summary, the different physical and chemical properties of fly ash caused great discrepancies in salt removal. Consequently, it is suggested to consider the potential impact of the ash source and ash generation time on salt removal to ensure a reliable treatment efficiency for engineering applications.

Precise Spectral Overlap-Based Donor-Acceptor Pair for a Sensitive Traffic Light-Typed Bimodal Multiplexed Lateral Flow Immunoassay.

Bimodal-type multiplexed immunoassays with complementary mode-based correlation analysis are gaining increasing attention for enhancing the practicability of the lateral flow immunoassay (LFIA). Nonetheless, the restriction in visually indistinguishable multitargets induced by a single fluorescent color and difficulty in single acceptor ineffectual fluorescence quenching due to the various spectra of multiple different donors impede the further execution of colorimetric-fluorescence bimodal-type multiplexed LFIAs. Herein, the precise spectral overlap-based donor-acceptor pair construction strategy is proposed by regulating the size of the nanocore, coating it with an appropriate nanoshell, and selecting a suitable fluorescence donor with distinct colors. By in situ coating Prussian blue nanoparticles (PBNPs) on AuNPs with a tunable size and absorption spectrum, the resultant APNPs demonstrate efficient fluorescence quenching ability, higher colloidal stability, remarkable colorimetric intensity, and an enhanced antibody coupling efficiency, all of which facilitate highly sensitive bimodal-type LFIA analysis. Following integration with competitive-type immunoreaction, this precise spectral overlap-supported spatial separation traffic light-typed colorimetric-fluorescence dual-response assay (coined as the STCFD assay) with the limits of detection of 0.013 and 0.152 ng mL-1 for ractopamine and clenbuterol, respectively, was proposed. This work illustrates the superiority of the rational design of a precise spectral overlap-based donor-acceptor pair, hinting at the enormous potential of the STCFD assay in the point-of-care field.

Exosomal circ_0000735 contributes to non-small lung cancer malignant progression.

Circular RNA is an important regulator for non-small cell lung cancer (NSCLC). Circ_0000735 has been found to be significantly overexpressed in NSCLC tissues. Therefore, its role and mechanism in NSCLC progression need to be further explored. The expression levels of circ_0000735, miR-345-5p and A disintegrin and metalloprotease 19 (ADAM19) were determined using quantitative real-time PCR. EdU staining, wound healing and transwell assays were utilized to detect cell proliferation and metastasis. The protein levels of metastasis markers, exosome markers and ADAM19 were determined using western blot. Animal experiments were performed to confirm the role of circ_0000735 in NSCLC tumorigenesis. The exosomes from cells and serum were identified using transmission electron microscopy and nanoparticle tracking analysis. We found that circ_0000735 was upregulated in NSCLC, and its knockdown repressed NSCLC cell proliferation and metastasis. In terms of mechanism, circ_0000735 targeted miR-345-5p to regulate ADAM19. MiR-345-5p inhibitor reversed the suppressive effect of circ_0000735 knockdown on NSCLC progression, and ADAM19 overexpression abolished the inhibition effect of miR-345-5p on NSCLC progression. Also, animal experiments showed that silencing of circ_0000735 reduced NSCLC tumorigenesis. In addition, exosomes mediated the intercellular transmission of circ_0000735, and serum exosomal circ_0000735 might be an important indicator for the diagnosis of NSCLC. In conclusion, circ_0000735 facilitated NSCLC progression via miR-345-5p/ADAM19 pathway, and serum exosomal circ_0000735 might be a potential biomarker for NSCLC diagnosis.

Single-Ion Conductive Polymer-Based Composite Electrolytes for High-Performance Solid-State Lithium Metal Batteries.

Flexible composite polymer electrolytes (CPEs) with inorganic electrolyte fillers dispersed in polymer electrolytes integrate the merits of the polymer and inorganic electrolytes and have attracted much attention in recent years. In order to increase the electrochemical performance, especially the low lithium (Li)-ion transference number in traditional dual-ion Li salt-containing CPEs, single-ion conductive CPEs are synthesized with a single-ion polymer conductor (SIPC) as the matrix and Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) particles as the active fillers. The single-ion conductive CPEs show a high Li-ion transference number (up to 0.96), high room-temperature (RT) ionic conductivity (>1.0 × 10-4 S cm-1 ), wide electrochemical stability window (>5.0 V, vs Li/Li+ ), and excellent long-term cycling stability with Li metal at RT (3200 h). Based on the SIPC-LLZTO CPE, the solid-state lithium metal batteries with LiFePO4 - and LiCoO2 -based cathodes deliver average discharge capacities of 159 mAh g-1 for 600 cycles and 119 mAh g-1 for 200 cycles at RT, respectively. This study sheds light on the design of high-performance CPEs for next-generation solid-state lithium metal batteries.

Goat anti-mouse immunoglobulin as "crosslinker" assisted signal tracer assemble with intensive antibody utilization efficiency for sensitive paper-based strip nanobiosensors.

Engineered collaborative biochemical techniques and regulated nanomaterials (NMs) offer extraordinary opportunities for improving the analysis performance of lateral flow immunoassay (LFIA). Herein, inspired by the ability of macromolecules (e.g., proteins) to assemble into new functional units and the remarkable optical performance of engineered regulated NMs, goat anti-mouse immunoglobulin (GAMI) serves as the "crosslinker" integrate with gold­manganese oxide (Au-MnOx) to assemble the "signal tracers (STs)-crosslinker-antibody (mAb)" for elevating the mAb utilization efficiency. Notably, the "STs-crosslinker-mAb" assembly shows ~13.33-folds mAb utilization efficiency enhance, which perfectly response the challenge between limited sensitivity and sufficient signal intensity in competitive-type LFIA. The black color and rough structure of Au-MnOx offer higher colorimetric brightness (~2-folds than AuNPs) and enhanced mAb coupling efficiency (up to 92.47%), which further improves sensitivity under the premise of functional assembly to intensify the competitive immunoreaction. Additionally, the convenient synthesis conditions (~13 min at room temperature) even comparable to direct purchase commercial products indicate that using Au-MnOx undoubtedly increases the cost-effectiveness. Encouragingly, the Au-MnOx-GAMI-mAb based LFIA exhibited high sensitivity (LOD: 0.063 ng mL-1 for clenbuterol (CLE) monitoring) by elevating mAb utilization efficiency with the attendant enhancing immune competition response in a cost-effective manner, which provides an invigorating reference pathway in point-of-care immunoassay.

Targeting epidermal growth factor receptor signalling pathway: A promising therapeutic option for COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously producing new variants, necessitating effective therapeutics. Patients are not only confronted by the immediate symptoms of infection but also by the long-term health issues linked to long COVID-19. Activation of epidermal growth factor receptor (EGFR) signalling during SARS-CoV-2 infection promotes virus propagation, mucus hyperproduction, and pulmonary fibrosis, and suppresses the host's antiviral response. Over the long term, EGFR activation in COVID-19, particularly in COVID-19-induced pulmonary fibrosis, may be linked to the development of lung cancer. In this review, we have summarised the significance of EGFR signalling in the context of SARS-CoV-2 infection. We also discussed the targeting of EGFR signalling as a promising strategy for COVID-19 treatment and highlighted erlotinib as a superior option among EGFR inhibitors. Erlotinib effectively blocks EGFR and AAK1, thereby preventing SARS-CoV-2 replication, reducing mucus hyperproduction, TNF-α expression, and enhancing the host's antiviral response. Nevertheless, to evaluate the antiviral efficacy of erlotinib, relevant clinical trials involving an appropriate patient population should be designed.

Nature-Derived Hollow Micron-Tubular Signal Tracers Conquering the Size Limitations for Multimodal Immunochromatographic Detection of Antibiotics.

Developing signal tracers (STAs) with large size, multifunctionality, and high retention bioaffinity is believed to be a potential solution for achieving high-performance immunochromatographic assays (ICAs). However, the size limitations of STAs on strips are always a challenge because of the serious steric hindrance. Here, based on metal-quinone coordination and further metal etching, hollow micron-tubular STAs formed by natural alizarin and Fe3+ ions (named ALIFe) are produced to break through size limitations, provide more active sites, and achieve three-mode ICAs (ALIFe STAs-ICAs). Thanks to the special tubular morphology, ALIFe can successfully pass through the strip and provide an ideal signal intensity within 7 min at low mAb and probe dosages to achieve stable ICA analysis. Importantly, ALIFe shows excellent antibody enrichment and bioaffinity retention capability. With a proof-of-concept for streptomycin, the ALIFe STAs-ICAs showed the limit of detection (LOD) at 0.39 ng mL-1 for colorimetric mode, 0.32 ng mL-1 for catalytic mode, and 0.016 ng mL-1 for photothermal mode with total recoveries ranging from 80.46 to 121.59% in mike and honey samples. We anticipate that our study will help expand the ideas for the design of high-performance STAs with large size and broaden the practical application of ICA.

Expected and Unexpected Products from the Biochemical Oxidation of Bacterial Alkylquinolones with CYP4F11.

2-Alkylquinolones are a class of microbial natural products primarily produced in the Pseudomonas and Burkholderia genera that play a key role in modulating quorum sensing. Bacterial alkylquinolones were synthesized and then subjected to oxidative biotransformation using human cytochrome P450 enzyme CYP4F11, heterologously expressed in the fission yeast Schizosaccharomyces pombe. This yielded a range of hydroxylated and carboxylic acid derivatives which had undergone ω-oxidation of the 2-alkyl chain, the structures of which were determined by analysis of NMR and MS data. Oxidation efficiency depended on chain length, with a chain length of eight or nine carbon atoms proving optimal for high yields. Homology modeling suggested that Glu233 was relevant for binding, due to the formation of a hydrogen bond from the quinolone nitrogen to Glu233, and in this position only the longer alkyl chains could come close enough to the heme moiety for effective oxidation. In addition to the direct oxidation products, a number of esters were also isolated, which was attributed to the action of endogenous yeast enzymes on the newly formed ω-hydroxy-alkylquinolones. ω-Oxidation of the alkyl chain significantly reduced the antimicrobial and antibiofilm activity of the quinolones.

Interkingdom network analyses reveal microalgae and protostomes as keystone taxa involved in nutrient cycling in large freshwater lake sediment.

Few studies have explored the role of interkingdom interactions between bacteria and microeukaryotes in nutrient cycling in lake ecosystems. We conducted sediment sampling from 40 locations covering Hongze Lake and analyzed their chemical properties. Intra- and interkingdom networks were constructed using 16S and 18S rRNA gene amplicon sequencing. Microeukaryotic intranetworks were more complex in spring than in autumn, while no clear variation in the complexity of bacterial intranetworks was found between autumn and spring. Larger and more complex bacterial-microeukaryotic bipartite networks emerged in spring than in autumn, correlated with lower carbon, nitrogen, and phosphorus levels in spring, likely resulting in intense microbial competition. Bacteria and microeukaryotes played different topological roles in interkingdom networks, with microeukaryotes contributing to the networks' greater complexity. Seven keystone modules were identified in spring and autumn nutrient cycling. Importantly, keystone taxa in these modules belonged to photoautotrophic microalgae or predatory protostomes, indicating that these organisms are key drivers in lake sediment nutrient cycling. Our results suggested that nutrient content variation in autumn and spring changes interkingdom networks' topological structure between bacteria and microeukaryotes. Microalgae and protostomes are essential in freshwater lake nutrient cycling and may be targeted to modulate nutrient cycling in large freshwater ecosystems.

Single-strain behavior predicts responses to environmental pH and osmolality in the gut microbiota.

Changes to gut environmental factors such as pH and osmolality due to disease or drugs correlate with major shifts in microbiome composition; however, we currently cannot predict which species can tolerate such changes or how the community will be affected. Here, we assessed the growth of 92 representative human gut bacterial strains spanning 28 families across multiple pH values and osmolalities in vitro. The ability to grow in extreme pH or osmolality conditions correlated with the availability of known stress response genes in many cases, but not all, indicating that novel pathways may participate in protecting against acid or osmotic stresses. Machine learning analysis uncovered genes or subsystems that are predictive of differential tolerance in either acid or osmotic stress. For osmotic stress, we corroborated the increased abundance of these genes in vivo during osmotic perturbation. The growth of specific taxa in limiting conditions in isolation in vitro correlated with survival in complex communities in vitro and in an in vivo mouse model of diet-induced intestinal acidification. Our data show that in vitro stress tolerance results are generalizable and that physical parameters may supersede interspecies interactions in determining the relative abundance of community members. This study provides insight into the ability of the microbiota to respond to common perturbations that may be encountered in the gut and provides a list of genes that correlate with increased ability to survive in these conditions. IMPORTANCE To achieve greater predictability in microbiota studies, it is crucial to consider physical environmental factors such as pH and particle concentration, as they play a pivotal role in influencing bacterial function and survival. For example, pH is significantly altered in various diseases, including cancers, inflammatory bowel disease, as well in the case of over-the-counter drug use. Additionally, conditions like malabsorption can affect particle concentration. In our study, we investigate how changes in environmental pH and osmolality can serve as predictive indicators of bacterial growth and abundance. Our research provides a comprehensive resource for anticipating shifts in microbial composition and gene abundance during complex perturbations. Moreover, our findings underscore the significance of the physical environment as a major driver of bacterial composition. Finally, this work emphasizes the necessity of incorporating physical measurements into animal and clinical studies to better understand the factors influencing shifts in microbiota abundance.