The Potentiation Activity of Azithromycin in Combination with Colistin or Levofloxacin Against Pseudomonas aeruginosa Biofilm Infection.

Objective: Pseudomonas aeruginosa (PA) often displays drug resistance and biofilm-mediated adaptability. Here, we aimed to evaluate the antibiofilm efficacy of azithromycin-based combination regimens. Methods: Minimum inhibitory concentrations (MICs), minimal biofilm eradication concentrations (MBECs), and MBEC-combination of azithromycin, colistin, amikacin, and levofloxacin to bioluminescent strain PAO1 and carbapenem-resistant PAO1 (CRPAO1) were assessed. An animal biofilm infection model was established and detected using a live animal bio-photonic imaging system. Results: In vitro, PAO1 and CRPAO1 were susceptible to colistin, amikacin, and levofloxacin, while they were unsusceptible to azithromycin. The combinations based on azithromycin have no synergistic effect on biofilm in vitro. In vivo, azithromycin plus colistin or levofloxacin could shorten the PAO1 biofilm eradication time, which totally eradicates the biofilm in all mice on the 8th or 6th day, while monotherapy only eradicate biofilm in 70% or 80% mice on the 8th day. For CRPAO1 biofilm, only azithromycin-colistin combination and colistin monotherapy eradicated the bacteria in 60% and 40% of mice at the 6th day. Conclusion: Azithromycin-based combinations containing levofloxacin or colistin had no synergistic effect in vitro, and they are promising for clinical applications due to the good synergistic activity against PAO1 biofilms in vivo.

Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells.

Background: The tumor microenvironment (TME) plays a pivotal role in the progression and metastasis of lung adenocarcinoma (LUAD). However, the detailed characteristics of LUAD and its associated microenvironment are yet to be extensively explored. This study aims to delineate a comprehensive profile of the immune cells within the LUAD microenvironment, including CD8+ T cells, CD4+ T cells, and myeloid cells. Subsequently, based on marker genes of exhausted CD8+ T cells, we aim to establish a prognostic model for LUAD. Method: Utilizing the Seurat and Scanpy packages, we successfully constructed an immune microenvironment atlas for LUAD. The Monocle3 and PAGA algorithms were employed for pseudotime analysis, pySCENIC for transcription factor analysis, and CellChat for analyzing intercellular communication. Following this, a prognostic model for LUAD was developed, based on the marker genes of exhausted CD8+ T cells, enabling effective risk stratification in LUAD patients. Our study included a thorough analysis to identify differences in TME, mutation landscape, and enrichment across varying risk groups. Moreover, by integrating risk scores with clinical features, we developed a new nomogram. The expression of model genes was validated via RT-PCR, and a series of cellular experiments were conducted, elucidating the potential oncogenic mechanisms of GALNT2. Results: Our study developed a single-cell atlas for LUAD from scRNA-seq data of 19 patients, examining crucial immune cells in LUAD's microenvironment. We underscored pDCs' role in antigen processing and established a Cox regression model based on CD8_Tex-LAYN genes for risk assessment. Additionally, we contrasted prognosis and tumor environments across risk groups, constructed a new nomogram integrating clinical features, validated the expression of model genes via RT-PCR, and confirmed GALNT2's function in LUAD through cellular experiments, thereby enhancing our understanding and approach to LUAD treatment. Conclusion: The creation of a LUAD single-cell atlas in our study offered new insights into its tumor microenvironment and immune cell interactions, highlighting the importance of key genes associated with exhausted CD8+ T cells. These discoveries have enabled the development of an effective prognostic model for LUAD and identified GALNT2 as a potential therapeutic target, significantly contributing to the improvement of LUAD diagnosis and treatment strategies.

Advances in Engineered Macrophages: A New Frontier in Cancer Immunotherapy.

Macrophages, as pivotal cells within the tumour microenvironment, significantly influence the impact of and reactions to treatments for solid tumours. The rapid evolution of bioengineering technology has revealed the vast potential of engineered macrophages in immunotherapy, disease diagnosis, and tissue engineering. Given this landscape, the goal of harnessing and innovating macrophages as a novel strategy for solid tumour immunotherapy cannot be overstated. The diverse strategies for engineered macrophages in the realm of cancer immunotherapy, encompassing macrophage drug delivery systems, chimeric antigen receptor macrophage therapy, and synergistic treatment approaches involving bacterial outer membrane vesicles and macrophages, are meticulously examined in this review. These methodologies are designed to enhance the therapeutic efficacy of macrophages against solid tumours, particularly those that are drug-resistant and metastatic. Collectively, these immunotherapies are poised to supplement and refine current solid tumour treatment paradigms, thus heralding a new frontier in the fight against malignant tumours.

LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.

Recent advancements in mogrosides: A review on biological activities, synthetic biology, and applications in the food industry.

Mogrosides are low-calorie, biologically active sweeteners that face high production costs due to strict cultivation requirements and the low yield of monk fruit. The rapid advancement in synthetic biology holds the potential to overcome this challenge. This review presents mogrosides exhibiting antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and liver protective activities, with their efficacy in diabetes treatment surpassing that of Xiaoke pills (a Chinese diabetes medication). It also discusses the latest elucidated biosynthesis pathways of mogrosides, highlighting the challenges and research gaps in this field. The critical and most challenging step in this pathway is the transformation of mogrol into a variety of mogrosides by different UDP-glucosyltransferases (UGTs), primarily hindered by the poor substrate selectivity, product specificity, and low catalytic efficiency of current UGTs. Finally, the applications of mogrosides in the current food industry and the challenges they face are discussed.

Self-propulsion of a droplet induced by combined diffusiophoresis and Marangoni effects.

Chemically active droplets display complex self-propulsion behavior in homogeneous surfactant solutions, often influenced by the interplay between diffusiophoresis and Marangoni effects. Previous studies have primarily considered these effects separately or assumed axisymmetric motion. To understand the full hydrodynamics, we investigate the motion of a two-dimensional active droplet under their combined influences using weakly nonlinear analysis and numerical simulations. The impact of two key factors, the Péclet number ( P e $Pe$ ) and the mobility ratio between diffusiophoretic and Marangoni effects ( m $m$ ), on droplet motion is explored. We establish a phase diagram in the P e - m $Pe-m$ space, categorizing the boundaries between four types of droplet states: stationary, steady motion, periodic/quasi-periodic motion, and chaotic motion. We find that the mobility ratio does not affect the critical P e $Pe$ for the onset of self-propulsion, but it significantly influences the stability of high-wavenumber modes as well as the droplet's velocity and trajectory. Scaling analysis reveals that in the high P e $Pe$ regime, the Marangoni and diffusiophoresis effects lead to distinct velocity scaling laws: U ∼ P e - 1 / 2 $U\sim Pe^{-1/2}$ and U ∼ P e - 1 / 3 $U\sim Pe^{-1/3}$ , respectively. When these effects are combined, the velocity scaling depends on the sign of the mobility ratio. In cases with a positive mobility ratio, the Marangoni effect dominates the scaling, whereas the negative diffusiophoretic effect leads to an increased thickness of the concentration boundary layer and a flattened scaling of the droplet velocity.

DFT Study of Metal (Ag, Au, Pt)-Modified SnS2 for Adsorption of SF6 Decomposition Gases in Gas-Insulated Switchgear.

In this study, the gas-sensitive response of metal (Ag, Au, Pt)-modified SnS2 toward SF6 decomposition gases (SOF2, SO2F2, SO2, H2S) in gas-insulated switchgear was studied by analyzing the adsorption structure, band structure, charge transfer, and density of states based on density functional theory. The results show that the adsorption of the four target gases on pristine SnS2 belongs to weak physical adsorption. Compared with the pristine SnS2, the adsorption energy of the transition metal atom-modified SnS2 monolayer has been improved to a certain extent and the adsorption capacity of these four gases on the transition metal atom-modified SnS2 monolayer has obviously improved. Moreover, the recovery time of Ag-SnS2/SOF2, Ag-SnS2/SO2F2, Au-SnS2/SOF2, Au-SnS2/SO2F2, and Pt-SnS2/SO2F2 is too short, indicating that these conditions have poor adsorption capacity and sensitivity to SF6 decomposition gases and are not suitable as detection materials for these gases. According to the different changes in conductivity during adsorption, it provides a feasible solution to detect each SF6 decomposition gas. This theoretical study effectively explained the adsorption and sensing properties between the metal-modified monolayers and gases.

Recent Progress in Flexible Surface Acoustic Wave Sensing Technologies.

In this work, the major methods for implementing flexible sensing technology-flexible surface acoustic wave (SAW) sensors-are summarized; the working principles and device characteristics of the flexible SAW sensors are introduced; and the latest achievements of the flexible SAW sensors in the selection of the substrate materials, the development of the piezoelectric thin films, and the structural design of the interdigital transducers are discussed. This paper focuses on analyzing the research status of physical flexible SAW sensors such as temperature, humidity, and ultraviolet radiation, including the sensing mechanism, bending strain performance, device performance parameters, advantages and disadvantages, etc. It also looks forward to the development of future chemical flexible SAW sensors for gases, the optimization of the direction of the overall device design, and systematic research on acoustic sensing theory under strain. This will enable the manufacturing of multifunctional and diverse sensors that better meet human needs.

Structural basis of Acinetobacter type IV pili targeting by an RNA virus.

Acinetobacters pose a significant threat to human health, especially those with weakened immune systems. Type IV pili of acinetobacters play crucial roles in virulence and antibiotic resistance. Single-stranded RNA bacteriophages target the bacterial retractile pili, including type IV. Our study delves into the interaction between Acinetobacter phage AP205 and type IV pili. Using cryo-electron microscopy, we solve structures of the AP205 virion with an asymmetric dimer of maturation proteins, the native Acinetobacter type IV pili bearing a distinct post-translational pilin cleavage, and the pili-bound AP205 showing its maturation proteins adapted to pilin modifications, allowing each phage to bind to one or two pili. Leveraging these results, we develop a 20-kilodalton AP205-derived protein scaffold targeting type IV pili in situ, with potential for research and diagnostics.

Targeting neutrophils: Mechanism and advances in cancer therapy.

BACKGROUND: Cancer is a thorny problem which cannot be conquered by mankind at present and recent researchers have put their focus on tumor microenviroment. Neutrophils, the prominent leukocytes in peripheral blood that accumulate in tumours, serves as frontline cells in response to tumour progression owing to the rapid development of micro biotechnology. Hence, targeted therapy with these neutrophils has made targeting treatment a promising field in cancer therapy. MAIN BODY: We broadly summarise some studies on the phenotypes and functions of tumour-associated neutrophils as well as the unique web-like products of neutrophils that play a role in cancer progression-neutrophil extracellular traps-and the interactions between neutrophils and the tumour microenvironment. Moreover, several targeted neutrophils therapeutic studies have made some progress and provided potential strategies for the treatment of cancer. CONCLUSION: This review aims to offer a holistic perspective on therapeutic interventions targeting neutrophils to further inspire more researches on cancer therapies.

A specific dual-locked fluorescence probe to visualize the dynamic changes of lipid droplets and hypochlorous acid in inflammation.

Inflammation is a key factor leading to the occurrence and development of many diseases, both lipid droplets (LDs) and hypochlorous acid (HClO/ClO-) are regarded as the important biomarkers of inflammation. Therefore, it is of great significance to develop an efficient single chemical sensor that can simultaneously detect these two biomarkers. To achieve the goal, we developed a dual-locked fluorescence probe (TPA-DNP) by fusing two targets activated reporting system, its implementation was achieved by turning-on the fluorescence of TPA-DNP through LDs and HClO/ClO- simultaneously. In simulated LDs environment, TPA-DNP displayed excellent selectivity to HClO/ClO-, high sensitivity (LOD = 0.527 µM) and strong anti-interference ability. In addition, cell and zebrafish imaging experiments showed that TPA-DNP could be utilized to visualize exogenous/endogenous HClO/ClO- in LDs environment, and could also be used to observe the impact of LDs changes on the HClO/ClO- detection. On the basis, TPA-DNP served as a favorable tool to achieve visualization of inflammatory dynamic changes.

Pivotal role of intracellular oxidation by HOCl in simultaneously removing antibiotic resistance genes and enhancing dewaterability during conditioning of sewage sludge using Fe2+/Ca(ClO)2.

Pre-acidification has been shown to be crucial in attenuating antibiotic resistance genes (ARGs) during the conditioning of sewage sludge. However, it is of great significance to develop alternative conditioning approaches that can effectively eliminate sludge-borne ARGs without relying on pre-acidification. This is due to the high investment costs and operational complexities associated with sludge pre-acidification. In this study, the effects of Fe2+/Ca(ClO)2 conditioning treatment on the enhancement of sludge dewaterability and the removal of ARGs were compared with other conditioning technologies. The dose effect and the associated mechanisms were also investigated. The findings revealed that Fe2+/Ca(ClO)2 conditioning treatment had the highest potential, even surpassing Fenton treatment with pre-acidification, in terms of eliminating the total ARGs. Moreover, the effectiveness of the treatment was found to be dose-dependent. This study also identified that the •OH radical reacted with extracellular polymeric substance (EPS) and extracellular ARGs, and the HOCl, the production of which was positively correlated with the dose of Fe2+/Ca(ClO)2, could infiltrate the EPS layer and diffuse into the cell of sludge flocs, inducing the oxidation of intracellular ARGs. Furthermore, this study observed a significant decrease in the predicted hosts of ARGs and MGEs in sludge conditioned with Fe2+/Ca(ClO)2, accompanied by a significant downregulation of metabolic pathways associated with ARG propagation, thereby contributing to the attenuation of sludge-borne ARGs. Based on these findings, it can be concluded that Fe2+/Ca(ClO)2 conditioning treatment holds great potential for the removal of sludge-borne ARGs while also enhancing sludge dewaterability, which mainly relies on the intracellular oxidation by HOCl.

Enhanced Carbon-Carbon Coupling at Interfaces with Abrupt Coordination Number Changes.

Cu-catalyzed electrochemical CO2 reduction reaction (CO2RR) produces multi-carbon (C2+) chemicals with considerable selectivities and activities, yet required high overpotentials impede its practical application. Here, we design interfaces with abrupt coordination number (CN) changes that greatly reduce the applied potential for achieving high C2+ Faradaic efficiency (FE). Encouraged by the mechanistic finding that the coupling between *CO and *CO(H) is the most probable C-C bond formation path, we use Cu2O- and Cu-phthalocyanine-derived Cu (OD-Cu and PD-Cu) to build the interface. Using operando X-ray absorption spectroscopy (XAS), we find that the Cu CN of OD-Cu is ~11, favoring CO* adsorption, while the PD-Cu has a COH*-favorable CN of ~4. Operando Raman spectroscopy revealed that the interfaces with abrupt CN changes promote *OCCOH formation. As a result, the designed catalyst achieves a C2+ FE of 85±2 % at 220 mA cm-2 in a zero-gap CO2 electrolyzer. An improvement of C2+ FE by 3 times is confirmed at the low potential regime where the current density is 60-140 mA cm-2, compared to bare OD-Cu. We report a 45-h stable CO2RR operation at 220 mA cm-2, producing a C2+ product FE of ~80 %.

Ru- and Co-Catalyzed Intermolecular Carbonyl-Alkyne Metathesis Reactions of 1H-Indene-1,2,3-triones with Internal Alkynes.

The catalyst-dependent intermolecular carbonyl-alkyne metathesis (CAM) reaction of 1H-indene-1,2,3-triones with internal alkynes was realized using Ru and Co catalysts. 2-(2-Oxo-1,2-diphenylethylidene)-1H-indene-1,3(2H)-dione derivatives were obtained using a Ru catalyst, whereas S-alkyl 2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)-2-phenylethanethioates were prepared using a Co catalyst. These transformations led to the synthesis of α,ß-unsaturated carbonyl compounds with a broad substrate scope, excellent regiocontrol, and gram-scale amenability. This catalytic strategy using a Co or Ru catalyst has rarely been described for other established CAM catalysts.

TGF-ß-activated circRYK drives glioblastoma progression by increasing VLDLR mRNA expression and stability in a ceRNA- and RBP-dependent manner.

BACKGROUND: The TGF-ß signalling pathway is intricately associated with the progression of glioblastoma (GBM). The objective of this study was to examine the role of circRNAs in the TGF-ß signalling pathway. METHODS: In our research, we used transcriptome analysis to search for circRNAs that were activated by TGF-ß. After confirming the expression pattern of the selected circRYK, we carried out in vitro and in vivo cell function assays. The underlying mechanisms were analysed via RNA pull-down, luciferase reporter, and RNA immunoprecipitation assays. RESULTS: CircRYK expression was markedly elevated in GBM, and this phenotype was strongly associated with a poor prognosis. Functionally, circRYK promotes epithelial-mesenchymal transition and GSC maintenance in GBM. Mechanistically, circRYK sponges miR-330-5p and promotes the expression of the oncogene VLDLR. In addition, circRYK could enhance the stability of VLDLR mRNA via the RNA-binding protein HuR. CONCLUSION: Our findings show that TGF-ß promotes epithelial-mesenchymal transition and GSC maintenance in GBM through the circRYK-VLDLR axis, which may provide a new therapeutic target for the treatment of GBM.

Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors.

The voltage-gated calcium channel CaV1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of CaV1.2 are involved in brain and heart diseases. Pharmacological inhibition of CaV1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of CaV1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6II, S6III, and S6IV helices and forms extensive hydrophobic interactions with CaV1.2. Our structure elucidates that benidipine is located in the DIII-DIV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5DIII, S6DIII, and S6DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.

A DFT study on regulating the active center of v-Ti2XT2 MXene through surface modification for efficient nitrogen fixation.

The electrochemical conversion of nitrogen to ammonia provides an encouraging method to substitute the traditional Haber-Bosch process, owing to its high efficiency and mild reaction conditions. The search for high-performance catalysts and comprehension of catalytic mechanisms remains significant challenges. Herein, we conduct a systematic theoretical calculation of the NRR performance and mechanism of 24 Ti2XT2 (X = B, C, N; T = F, Cl, Br, I, O, S, Se, Te) MXenes with a T-vacancy to explore the influence of surface functional terminations and non-metallic center elements. Our findings demonstrate that surface functionalization significantly reduces the limiting potential by altering the rate-determining step. This change ranges from -1.24 V (Ti2NF2) to -0.21 V (Ti2BSe2), signifying the remarkable efficacy of modification of the surrounding environment of the exposed transition metal active center in promoting electrocatalytic performance. Detailed investigation of the charge density difference and orbital interaction reveals that the different NRR performance originates from the surface termination and non-metallic atoms regulate the electronic properties of the active Ti atoms. We also introduce the free energy change of *NNH2 (ΔG*NNH2) as a descriptor to predict the performance of NRR, which exhibits satisfactory linear relationship with free energy change of different intermediates and displays favourable volcano plot with limiting potential. Moreover, we highlight the pivotal role of work function in tuning the energy barrier of the rate-determining step, which can be regulated through the surface modification of MXenes. Our study not only offers a comprehensive understanding of the crucial impact of surface modification on the catalytic activities of defective MXenes, but also provides a rational perspective for designing efficient NRR catalysts.

Group-based sleep trajectories in children and adolescents: A systematic review.

Sleep is crucial for health and development. Evidence indicates that sleep changes over time and distinct subgroups may experience different longitudinal patterns. This study systematically reviewed the studies that used latent trajectory modeling to investigate sleep trajectories of children and adolescents aged 0-18 years, and summarized the associated determinants and health-related outcomes. We searched PubMed, Embase, CENTRAL, PsycINFO, and Web of Science, identifying 46 articles that met our criteria. To ensure the reliability of the review, only studies rated as good or fair in terms of methodological quality were included, resulting in a total of 36 articles. Group-based trajectories were identified on several sleep dimensions (i.e., sleep duration, general and specific sleep problems, and bed-sharing behavior) and three or four trajectories were reported in most studies. There was a convergence trend across sleep duration trajectories during the first six years of life. Studies on specific sleep problem (i.e., insomnia, night-waking, and sleep-onset difficulties) typically identified two trajectories: consistent, minimal symptoms or chronic yet fluctuating symptoms. Lower socioeconomic status, maternal depression, and night feeding behaviors were the most frequently reported determinants of sleep trajectories. Membership in a group with certain adverse patterns (e.g., persistent short sleep duration) was associated with increased risks of multiple negative health-related conditions, such as obesity, compromised immunity, neurological problems, substance use, or internalizing/externalizing symptoms. Generally, there is potential to improve the quality of studies in this field. Causality is hard to be inferred within the current body of literature. Future studies could emphasize early life sleep, incorporate more assessment timepoints, use objective measures, and employ experimental design to better understand changes of and mechanisms behind the various sleep trajectories and guide targeted interventions for at-risk subpopulations.

Erdr1 Drives Macrophage Programming via Dynamic Interplay with YAP1 and Mid1.

Erythroid differentiation regulator 1 (Erdr1) is a stress-induced, widely expressed, highly conserved secreted factor found in both humans and mice. Erdr1 is linked with the Hippo-YAP1 signaling. Initially identified as an inducer of hemoglobin synthesis, Erdr1 emerged as a multifunctional protein, especially in immune cells. Although Erdr1 has been implicated in regulating T cells and NK cell function, its role in macrophage remains unclear. This study explored the function and mechanism of Erdr1 in macrophage inflammatory response. The data demonstrated that Erdr1 could promote anti-inflammatory cytokine production, a function that also has been reported by previous research. However, I found Erdr1 also could play a proinflammatory role. The function of Erdr1 in macrophages depends on its dose and cell density. I observed that Erdr1 expression was inhibited in M1 macrophages but was upregulated in M2 macrophages compared with unpolarized macrophages. I hypothesized that Erdr1 balances the inflammatory response by binding with distinct adaptors dependent on varying concentrations. Mechanistically, I demonstrated YAP1 and Mid1 as the two adaptor proteins of Erdr1. The Erdr1-YAP1 interaction promotes anti-inflammatory cytokine production when Erdr1 levels are elevated, whereas the Erdr1-Mid1 interaction induces proinflammatory cytokine production when Erdr1 levels are decreased. This study highlights the effects of Erdr1 on regulating cytokine production from polarized macrophages potentially by regulating YAP1 in the nonclassical Hippo pathway.