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Abstract Crohn’s disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease.

Abstract The concept of Yin-Yang, originating in ancient Chinese philosophy, symbolizes two opposing but complementary forces or principles found in all aspects of life. This concept can be quite fitting in the context of extracellular vehicles (EVs) and inflammatory diseases. Over the past decades, numerous studies have revealed that EVs can exhibit dual sides, acting as both pro- and anti-inflammatory agents, akin to the concept of Yin-Yang theory (i.e., two sides of a coin). This has enabled EVs to serve as potential indicators of pathogenesis or be manipulated for therapeutic purposes by influencing immune and inflammatory pathways. This review delves into the recent advances in understanding the Yin-Yang sides of EVs and their regulation in specific inflammatory diseases. We shed light on the current prospects of engineering EVs for treating inflammatory conditions. The Yin-Yang principle of EVs bestows upon them great potential as, therapeutic, and preventive agents for inflammatory diseases. Graphical Abstract

IntroductionThe type VI secretion system (T6SS) is a crucial virulence factor in the nosocomial pathogen Acinetobacter baumannii. However, its association with drug resistance is less well known. Notably, the roles that different T6SS components play in the process of antimicrobial resistance, as well as in virulence, have not been systematically revealed.MethodsThe importance of three representative T6SS core genes involved in the drug resistance and virulence of A. baumannii, namely, tssB, tssD (hcp), and tssM was elucidated.ResultsA higher ratio of the three core genes was detected in drug-resistant strains than in susceptible strains among our 114 A. baumannii clinical isolates. Upon deletion of tssB in AB795639, increased antimicrobial resistance to cefuroxime and ceftriaxone was observed, alongside reduced resistance to gentamicin. The ΔtssD mutant showed decreased resistance to ciprofloxacin, norfloxacin, ofloxacin, tetracycline, and doxycycline, but increased resistance to tobramycin and streptomycin. The tssM-lacking mutant showed an increased sensitivity to ofloxacin, polymyxin B, and furazolidone. In addition, a significant reduction in biofilm formation was observed only with the ΔtssM mutant. Moreover, the ΔtssM strain, followed by the ΔtssD mutant, showed decreased survival in human serum, with attenuated competition with Escherichia coli and impaired lethality in Galleria mellonella.DiscussionThe above results suggest that T6SS plays an important role, participating in the antibiotic resistance of A. baumannii, especially in terms of intrinsic resistance. Meanwhile, tssM and tssD contribute to bacterial virulence to a greater degree, with tssM being associated with greater importance.

ABSTRACTMessenger RNA (mRNA) therapeutics have recently demonstrated high clinical potential with the accelerated approval of SARS-CoV-2 vaccines. To fulfill the promise of unprecedented mRNA-based treatments, the development of safe and efficient carriers is still necessary to achieve effective delivery of mRNA. Herein, we prepared mRNA-loaded nanocarriers for enhanced in vivo delivery using biocompatible block copolymers having functional amino acid moieties for tunable interaction with mRNA. The block copolymers were based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) modified with glycine (Gly), leucine (Leu) or tyrosine (Tyr) via ester bonds to generate block catiomers. Moreover, the amino acids can be gradually detached from the block copolymers after ester bond hydrolyzation, avoiding cytotoxic effects. When mixed with mRNA, the block catiomers formed narrowly distributed polymeric micelles with high stability and enhanced delivery efficiency. Particularly, the micelles based on tyrosine-modified PEG-PG (PEG-PGTyr), which formed a polyion complex (PIC) and π–π stacking with mRNA, displayed excellent stability against polyanions and promoted mRNA integrity in serum. PEG-PGTyr-based micelles also increased the cellular uptake and the endosomal escape, promoting high protein expression both in vitro and in vivo. Furthermore, the PEG-PGTyr-based micelles significantly extended the half-life of the loaded mRNA after intravenous injection. Our results highlight the potential of PEG-PGTyr-based micelles as safe and effective carriers for mRNA, expediting the rational design of polymeric materials for enhanced mRNA delivery.

The modified carbapenem inactivation method (mCIM) recommended by the Clinical and Laboratory Standards Institute is not applicable for detecting carbapenemases in Acinetobacter baumannii. Four currently reported phenotypic detection methods, namely, the modified Hodge test, the mCIM, the adjusted mCIM, and the simplified carbapenem inactivation method (sCIM), did not perform well in our 90 clinical A. baumannii isolates. Thus, the minimal inhibitory concentrations (MICs) of carbapenems and the existence and expression of carbapenemase-encoding genes were detected to explain the results. According to the E-test, which was more accurate than the VITEK 2 system, 80.0 and 41.1% were resistant to imipenem (IPM) and meropenem (MEM), respectively, and 14.4 and 53.3% exhibited intermediate resistance, respectively. Five β-lactamase genes were found, of which blaOXA-51-like, blaTEM, and blaOXA-23-like were detected more frequently in 85 non-susceptible strains. The expression of blaOXA-23-like was positively correlated with the MIC values of IPM and MEM. Therefore, an improved approach based on the mCIM, designated the optimized CIM (oCIM), was developed in this study to detect carbapenemases more accurately and reproducibly. The condition was improved by evaluating the factors of A. baumannii inoculum, incubation broth volume, and MEM disk incubation time. Obvious high sensitivity (92.94%) and specificity (100.00%) were obtained using the oCIM, which was cost-effective and reproducible in routine laboratory work.

The C−C coupling of methane (CH4) and carbon dioxide (CO2) to generate acetic acid (CH3COOH) represents a highly atom‐efficient chemical conversion, fostering the comprehensive utilization of greenhouse gases. However, the inherent thermodynamic stability and kinetic inertness of CH4 and CO2 present obstacles to achieving efficient and selective conversion at room temperature. Our study reveals that hydroxyl radicals (⋅OH) and hydrated electrons (eaq−) produced by water radiolysis can effectively activate CH4 and CO2, yielding methyl radicals (⋅CH3) and carbon dioxide radical anions(⋅CO2−) that facilitate the production of CH3COOH at ambient temperature. The introduction of radiation‐synthesized CuO‐anchored TiO2 bifunctional catalyst could further enhance reaction efficiency and selectivity remarkably by boosting radiation absorption and radical stability, resulting in a concentration of 7.1 mmol ⋅ L−1 of CH3COOH with near‐unity selectivity (>95 %). These findings offer valuable insights for catalyst design and implementation in radiation‐induced chemical conversion. [ABSTRACT FROM AUTHOR]

The C−C coupling of methane (CH4) and carbon dioxide (CO2) to generate acetic acid (CH3COOH) represents a highly atom‐efficient chemical conversion, fostering the comprehensive utilization of greenhouse gases. However, the inherent thermodynamic stability and kinetic inertness of CH4 and CO2 present obstacles to achieving efficient and selective conversion at room temperature. Our study reveals that hydroxyl radicals (⋅OH) and hydrated electrons (eaq−) produced by water radiolysis can effectively activate CH4 and CO2, yielding methyl radicals (⋅CH3) and carbon dioxide radical anions(⋅CO2−) that facilitate the production of CH3COOH at ambient temperature. The introduction of radiation‐synthesized CuO‐anchored TiO2 bifunctional catalyst could further enhance reaction efficiency and selectivity remarkably by boosting radiation absorption and radical stability, resulting in a concentration of 7.1 mmol ⋅ L−1 of CH3COOH with near‐unity selectivity (>95 %). These findings offer valuable insights for catalyst design and implementation in radiation‐induced chemical conversion. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata (AA) is mainly a T cell-medicated autoimmune disease with non-scarring hair loss and limited treatment options. Of these, the patchy-type alopecia areata (AAP) is the most common and relatively easy to treat due to smaller areas of the scalp affected. To understand the pathogenesis of AAP and explore the therapeutic target, we focus on the molecular signatures by comparing AAP and normal subjects. Methods: The gene expression profile (GSE68801) was obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified between AAP patients and normal controls using the GEO2R. Then the Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein interaction (PPI) network analysis were performed for DEGs. Results: A total of 185 DEGs were identified, including 45 up-regulated genes and 140 down-regulated genes. The up-regulated DEGs were related to the immune response and chemokine signaling pathway. Meanwhile, down-regulated DEGs were enriched in keratin filament and intermediate filament. Subsequently, the top 10 hub genes were picked out in the PPI network, among them, CD2 showed the highest connectivity degree and central roles. Conclusion: Our data suggest that the CD2 may be a new therapeutic target for AAP. Further study is needed to explore the value of CD2 in the treatment of alopecia areata.

ABSTRACT Acinetobacter baumannii is an important nosocomial pathogen that can develop various resistance mechanisms to many antibiotics. However, little is known about how it evolves from an antibiotic sensitive to a resistant phenotype. In this study, we investigated the transition of outer membrane proteins (OMPs) under antibiotic stress and identified YiaD as an OMP marker involved in the development of adaptive resistance to meropenem (MEM) in A. baumannii. Following stimulation of a carbapenem-sensitive strain AB5116 with sub-MIC of MEM, yiaD showed significantly decreased expression, and this decrease continued with prolonged stimulation for 8 h. The downregulation of yiaD was not only observed in clinically sensitive strains but also in 45 carbapenem-resistant isolates that produced the β-lactamases TEM and OXA-23. However, the extent of the reduction of yiaD expression in resistant strains was less than that in sensitive strains. Lack of yiaD resulted in a 4-fold increase in the MIC of AB5116 to MEM. The same level of depressed susceptibility induced by yiaD deletion was observed in both a growth curve test and a survival rate assay. Moreover, the colony shape became enlarged and irregular after loss of yiaD, and the biofilm formation ability of A. baumannii was influenced by YiaD. These results suggest that YiaD could respond to the stimulus of MEM in A. baumannii with a downregulation trend that kept pace with the prolonged stimulation time, indicating that it participates in various routes to benefit MEM resistance evolution in both carbapenem-sensitive and -resistant A. baumannii strains. IMPORTANCE Acinetobacter baumannii can develop various resistance mechanisms to carbapenems. However, the factors involved in the evolutionary process that leads from transition to the sensitive to resistant phenotype are not clear. The outer membrane protein YiaD of A. baumannii was downregulated under the stress of meropenem (MEM), and its expression level was continuously reduced with prolonged stimulation time. The downregulation of yiaD was not only observed in sensitive strains but also in carbapenem-resistant isolates producing the β-lactamases TEM and OXA-23. However, the extent of yiaD reduction was less in resistant strains than in sensitive strains. Lack of yiaD resulted in an increased MEM MIC, enlarged and irregular colonies, and decreased biofilm formation ability. These results suggest that YiaD responds to MEM stimulus in A. baumannii and participates in the adaptive resistance of MEM in both carbapenem-sensitive and -resistant strains.

Ultrasound/microwave assisted extraction (UMAE) of flavonoid compounds from Eucommia ulmoides leaves was studied and the extraction conditions were optimized by the Plackett-Burman design (PBD) method combined with the Box-Behnken design (BBD). The antioxidant and antibacterial activities of the flavonoid extract were investigated. The results show that the optimal conditions were an ethanol concentration of 41%, microwave power of 178 W and an ultrasound extraction time of 26 min. Under these conditions, the yield of the flavonoid compounds was 2.454%±0.230%, which was higher than that after direct solvent extraction, ultrasound extraction and microwave extraction. The results of in vitro antioxidant assays showed that the flavonoid extract had scavenging capacity for DPPH, ABTS and hydroxyl radicals, with corresponding IC50 values of 30.76 mg/L, 21.09 mg/L, 248.4 mg/L, respectively. In addition, this extract exhibited strong antibacterial activity on Escherichia coli, Staphylococcus aureus and Salmonella typhimurium.

Abstract Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.