Trapping of deformable active particles by a periodic background potential.

The dynamic behaviors, specifically trapping and sorting, of active particles interacting with periodic substrates have garnered significant attention. This study investigates numerically the trapping of soft, deformable particles on a periodic potential substrate, which can be experimentally verified through optical tweezers. The research demonstrates that multiple factors, including the relative size of traps, self-propelled velocity, shape parameters, ratio of particles to traps, and translational diffusion, can influence the trapping effect. Within certain parameter boundaries, it is shown that all particles can be consistently trapped. The research reveals that stable trapping typically occurs at median values of the relative trap size. An increase in the self-propelled velocity, the shape parameter, and the translational diffusion coefficient tends to facilitate the escapement of the particles from the traps. It is noteworthy that particles with larger shape parameters can escape even when the restoring force exceeds the self-propelled force. In addition, as the ratio of particles to traps grows, the fraction of trapped particles steadily reduces. Notably, rigid particles are consistently divided and trapped by traps closely approximating an integer multiple of the particles' area, up until the ratio reaches the aforesaid integer value. These findings can potentially enhance the understanding of the interactive effects between active deformable particles and periodic substrates. Moreover, this work suggests a different experimental approach to sort active particles based on rigidity disparities.

The effect of ultrasonic power on the physicochemical properties and antioxidant activities of frosted figs pectin.

Ultrasound has been widely used in industry due to its high energy and efficiency. This study optimized the ultrasonic-assisted extraction (UAE) process of frosted figs pectin (FFP) using response surface methodology (RSM), and further investigated the effect of ultrasonic power on the structural characteristics and antioxidant activities of FFPs. The UAE method of FFP through RSM was optimized, and the optimal extraction process conditions, particle size of 100 mesh, pH value of 1.95, liquid-solid ratio of 47:1 (mL/g), extraction temperature of 50 °C and extraction time of 65 min, were obtained. The extraction rate of FFP under this condition was 37.97 ± 2.56 %. Then, the four FFPs modified by ultrasound were obtained by changing the ultrasonic power. Research had found that ultrasonic power had little effect on the monosaccharide composition, Zeta potential, as well as the thermal stability and appearance structure of the four FFPs. However, ultrasonic power had a significant impact on other properties of FFP: as the ultrasonic power increased, the DM% and particle size decreased continuously, while the total carbohydrate content increased. Meanwhile, ultrasonic power also had a significant impact on antioxidant activities of FFPs. From the research results, it could be seen that different ultrasonic power had certain changes in its spatial structure and properties, and the structural changes also affected the biological activity of FFP. The study of the effects of ultrasonic power on the physicochemical properties and biological activity of FFP lays the foundation for the development and application of FFP in food additives and natural drug carriers.

Transmissible gastroenteritis virus induces inflammatory responses via RIG-I/NF-κB/HIF-1α/glycolysis axis in intestinal organoids and in vivo.

Transmissible gastroenteritis virus (TGEV)-induced enteritis is characterized by watery diarrhea, vomiting, and dehydration, and has high mortality in newborn piglets, resulting in significant economic losses in the pig industry worldwide. Conventional cell lines have been used for many years to investigate inflammation induced by TGEV, but these cell lines may not mimic the actual intestinal environment, making it difficult to obtain accurate results. In this study, apical-out porcine intestinal organoids were employed to study TEGV-induced inflammation. We found that apical-out organoids were susceptible to TGEV infection, and the expression of representative inflammatory cytokines was significantly upregulated upon TGEV infection. In addition, retinoic acid-inducible gene I (RIG-I) and the nuclear factor-kappa B (NF-κB) pathway were responsible for the expression of inflammatory cytokines induced by TGEV infection. We also discovered that the transcription factor hypoxia-inducible factor-1α (HIF-1α) positively regulated TGEV-induced inflammation by activating glycolysis in apical-out organoids, and pig experiments identified the same molecular mechanism as the ex vivo results. Collectively, we unveiled that the inflammatory responses induced by TGEV were modulated via the RIG-I/NF-κB/HIF-1α/glycolysis axis ex vivo and in vivo. This study provides novel insights into TGEV-induced enteritis and verifies intestinal organoids as a reliable model for investigating virus-induced inflammation. IMPORTANCE: Intestinal organoids are a newly developed culture system for investigating immune responses to virus infection. This culture model better represents the physiological environment compared with well-established cell lines. In this study, we discovered that inflammatory responses induced by TGEV infection were regulated by the RIG-I/NF-κB/HIF-1α/glycolysis axis in apical-out porcine organoids and in pigs. Our findings contribute to understanding the mechanism of intestinal inflammation upon viral infection and highlight apical-out organoids as a physiological model to mimic virus-induced inflammation.

Unraveling the Nature of Spin Coupling in a Metal-Free Diradical: Theoretical Distinction of Ferromagnetic and Antiferromagnetic Interactions.

Metal-free diradicals based on polycyclic aromatic hydrocarbons are promising candidates for organic spintronics due to their stable magnetism and tunable spin coupling. However, distinguishing and elucidating the origins of ferromagnetic and antiferromagnetic interactions in these systems remain challenging. Here, we investigate the 2-OS diradical molecule sandwiched between gold electrodes using a combined density functional theory and hierarchical equations of motion approach. We find that the dihedral angle between the radical moieties controls the nature and strength of the intramolecular spin coupling, transitioning smoothly from antiferromagnetic to ferromagnetic as the angle increases. Distinct features in the inelastic electron tunneling spectra are identified that can discern the two coupling regimes, including spin excitation steps whose energies directly reveal the exchange coupling constant. Mechanical stretching of the junction is predicted to modulate the spectral line shapes by adjusting the hybridization of the molecular radicals with the electrodes. Our work elucidates the electronic origin of tunable spin interactions in 2-OS and provides spectroscopic fingerprints for characterizing magnetism in metal-free diradicals.

High-efficient separation of deoxyribonucleic acid from pathogenic bacteria by hedgehog-inspired magnetic nanoparticles microextraction.

Efficient separation of deoxyribonucleic acid (DNA) through magnetic nanoparticles (MN) is a widely used biotechnology. Hedgehog-inspired MNs (HMN) possess a high-surface-area due to the distinct burr-like structure of hedgehog, but there is no report about the usage of HMN for DNA extraction. Herein, to improve the selection of MN and illustrate the performance of HMN for DNA separation, HMN and silica-coated Fe3O4 nanoparticles (Fe3O4@SiO2) were fabricated and compared for the high-efficient separation of pathogenic bacteria of DNA. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) are typical Gram-negative and Gram-positive bacteria and are selected as model pathogenic bacteria. To enhance the extraction efficiency of two kinds of MNs, various parameters, including pretreatment, lysis, binding and elution conditions, have been optimized in detail. In most separation experiments, the DNA yield of HMN was higher than that of Fe3O4@SiO2. Therefore, a HMN-based magnetic solid-phase microextraction (MSPE) and quantitative real-time PCR (qPCR) were integrated and used to detect pathogenic bacteria in real samples. Interestingly, the HMN-based MSPE combined qPCR strategy exhibited high sensitivity with a limit of detection of 2.0 × 101 CFU mL-1 for E. coli and 4.0 × 101 CFU mL-1 for S. aureus in orange juice, and 2.8 × 102 CFU mL-1 for E. coli and 1.1 × 102 CFU mL-1 for S. aureus in milk, respectively. The performance of the proposed strategy was significantly better than that of commercial kit. This work could prove that the novel HMN could be applicable for the efficient separation of DNA from complex biological samples.

Unconventional Surface Doping Effect on the Spin State of an Adsorbed Magnetic Molecule.

Magnetic molecules adsorbed on two-dimensional (2D) substrates have attracted broad attention because of their potential applications in quantum device applications. Experimental observations have demonstrated substantial alteration in the spin excitation energy of iron phthalocyanine (FePc) molecules when adsorbed on nitrogen-doped graphene substrates. However, the underlying mechanism responsible for this notable change remains unclear. To shed light on this, we employ an embedding method and ab initio quantum chemistry calculations to investigate the effects of surface doping on molecular properties. Our study unveils an unconventional chemical bonding at the interface between the FePc molecule and the N-doped graphene. This bonding interaction, stronger than non-covalent interactions, significantly modifies the magnetic anisotropy energy of the adsorbed molecule, consistent with experimental observations. These findings provide valuable insights into the electronic and magnetic properties of molecules on 2D substrates, offering a promising pathway for precise manipulation of molecular spin states.

Hypoxia inducible factor-1α facilitates transmissible gastroenteritis virus replication by inhibiting type I and type III interferon production.

Transmissible gastroenteritis virus (TGEV) is characterized by watery diarrhea, vomiting, and dehydration and is associated with high mortality especially in newborn piglets, causing significant economic losses to the global pig industry. Hypoxia inducible factor-1α (HIF-1α) has been identified as a key regulator of TGEV-induced inflammation, but understanding of the effect of HIF-1α on TGEV infection remains limited. This study found that TGEV infection was associated with a marked increase in HIF-1α expression in ST cells and an intestinal organoid epithelial monolayer. Furthermore, HIF-1α was shown to facilitate TGEV infection by targeting viral replication, which was achieved by restraining type I and type III interferon (IFN) production. In vivo experiments in piglets demonstrated that the HIF-1α inhibitor BAY87-2243 significantly reduced HIF-1α expression and inhibited TGEV replication and pathogenesis by activating IFN production. In summary, we unveiled that HIF-1α facilitates TGEV replication by restraining type I and type III IFN production in vitro, ex vivo, and in vivo. The findings from this study suggest that HIF-1α could be a novel antiviral target and candidate drug against TGEV infection.

Amphiphilic α-Peptoid-deoxynojirimycin Conjugate-based Multivalent Glycosidase Inhibitor for Hypoglycemic Effect and Fluorescence Imaging.

Multivalent glycosidase inhibitors based on 1-deoxynojirimycin derivatives against α-glucosidases have been rapidly developed. Nonetheless, the mechanism based on self-assembled multivalent glucosidase inhibitors in living systems needs to be further studied. It remains to be determined whether the self-assembly possesses sufficient stability to endure transit through the small intestine and subsequently bind to the glycosidases located therein. In this paper, two amphiphilic compounds, 1-deoxynojirimycin and α-peptoid conjugates (LP-4DNJ-3C and LP-4DNJ-6C), were designed. Their self-assembling behaviors, multivalent α-glucosidase inhibition effect, and fluorescence imaging on living organs were studied. LP-4DNJ-6C exhibited better multivalent α-glucosidase inhibition activities in vitro. Moreover, the self-assembly of LP-4DNJ-6C could effectively form a complex with Nile red. The complex showed fluorescence quenching effect upon binding with α-glucosidases and exhibited potent fluorescence imaging in the small intestine. This result suggests that a multivalent hypoglycemic effect achieved through self-assembly in the intestine is a viable approach, enabling the rational design of multivalent hypoglycemic drugs.

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice.

Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Visible-Light Induced Radical Addition-Elimination Reaction for Constructing Allylic Sulfones from Sulfonyl Chlorides and Allyl Bromides.

Allyl sulfones are commonly present in bioactive compounds and organic building blocks. This work introduces a photocatalytic radical addition-elimination reaction involving readily accessible sulfonyl chlorides and allyl bromides. It delivers structurally diverse allylic sulfones in moderate to excellent yields, showcasing a high tolerance to functional groups. Notably, this method operates under mild reaction conditions without the need for oxidants, stoichiometric reducing metals, or additives.

Coexistence of Ferromagnetism and Ferroelectricity in Cu-Intercalated Bilayer CrI3.

Design of two-dimensional (2D) multiferroic materials with two or more ferroic orders in one structure is highly desired in view of the development of next-generation electronic devices. Unfortunately, experimental or theoretical discovery of 2D intrinsic multiferroic materials is rare. Using first-principles calculation methods, we report the realization of multiferroics that couple ferromagnetism and ferroelectricity by intercalating Cu atoms in bilayer CrI3, Cux@bi-CrI3 (x = 0.03, 0.06, and 0.25). Our results show that the intercalation of Cu atoms leads to the inversion symmetry breaking of bilayer CrI3 and produces intercalation density-dependent out-of-plane electric polarization, around 18.84-90.31 pC·cm-2. Moreover, the switch barriers of Cux@bi-CrI3 in both polarization states are small, ranging from 0.31 to 0.69 eV. Furthermore, the magnetoelectric coupling properties of Cux@bi-CrI3 can be modulated via varying the metal ion intercalation density, and half-metal to semiconductor transition can be occurred by decreasing the intercalation density of metal ions. Our work paves a practical path for 2D magnetoelectron coupling devices.

Vagus nerve stimulation as a promising neuroprotection for ischemic stroke via α7nAchR-dependent inactivation of microglial NLRP3 inflammasome.

Ischemic stroke is a major cause of disability and death worldwide, and its management requires urgent attention. Previous studies have shown that vagus nerve stimulation (VNS) exerts neuroprotection in ischemic stroke by inhibiting neuroinflammation and apoptosis. In this study, we evaluated the timing for VNS intervention in ischemic stroke, and the underlying mechanisms  of VNS-induced neuroprotection. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min. The left vagus nerve at cervical level was exposed and attached to an electrode connected to a low-frequency electrical stimulator. Vagus nerve stimulation (VNS) was given for 60 min before, during and after tMCAO (Pre-VNS, Dur-VNS, Post-VNS). Neurological function was assessed 24 h after reperfusion. We found that all the three VNS significantly protected against the tMCAO-induced injury evidenced by improved neurological function and reduced infarct volume. Moreover, the Pre-VNS was the most effective against the ischemic injury. We found that tMCAO activated microglia in the ischemic core and penumbra regions of the brain, followed by the NLRP3 inflammasome activation-induced neuroinflammation, which finally triggered neuronal death. VNS treatment preserved α7nAChR expression in the penumbra regions, inhibited NLRP3 inflammasome activation and ensuing neuroinflammation, rescuing cerebral neurons. The role of α7nAChR in microglial NLRP3 inflammasome activation in ischemic stroke was further validated using genetic manipulations, including Chrna7 knockout mice and microglial Chrna7 overexpression mice, as well as pharmacological interventions using the α7nAChR inhibitor methyllycaconitine and agonist PNU-282987. Collectively, this study demonstrates the potential of VNS as a safe and effective strategy to treat ischemic stroke, and presents a new approach targeting microglial NLRP3 inflammasome, which might be therapeutic for other inflammation-related diseases.

Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes.

OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. METHODS: We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. RESULTS: The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. CONCLUSIONS: Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

Alkaloids from Fritillaria przewalskii Bulbs and Their Anti-Alzheimer's Disease Activities.

Three undescribed isosteroidal alkaloids, przewalskines A-C (1-3), as well as seven known alkaloids (4-10) were obtained from Fritillaria przewalskii bulbs. Their structures were deduced by extensive HRESIMS, 1D NMR, and 2D NMR analyses, and their bioactivities were evaluated involving the anti-inflammatory and inhibitory potencies on AChE, BChE, and Aß aggregation. Compound 4 revealed the potent effect on inhibiting Aß aggregation activity with IC50 value of 33.1 µM, AChE activity with IC50 value of 6.9 µM, and also showed NO release inhibitory acitivity with IC50 value of 32.6 µM. These findings contribute new multi-.target anti-AD agents and embody the chemical diversity of F. przewalskii.

Marbofloxacin combined with heavy rare-earth ions makes better candidates for veterinary drugs: crystal structure and bio-activity studies.

Marbofloxacin (MB) is a newly developed fluoroquinolone antibiotic used especially as a veterinary drug. It may be regarded as the improved version of enrofloxacin owing to its antibacterial activity, enhanced bioavailability, and pharmacokinetic-pharmacodynamic (PK-PD) properties. In this study, nine heavy rare-earth ions (Y, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu) were selected in light of their potential antibacterial activity and satisfactory biosafety to afford the corresponding rare-earth metal complexes of MB: the MB-Ln series. Their chemical structures and coordination patterns were characterized using IR spectroscopy, HRMS, TGA, and X-ray single-crystal diffraction analysis. Our results confirmed that all the MB-Ln complexes yielded the coincident coordination modes with four MB ligands coordinating to the Ln(III) center. In vitro antibacterial screening on five typical bacteria strains revealed that the MB-Ln complexes exhibited antibacterial activities comparable with MB, as indicated by the MIC/MBC values, in which Escherichia coli and Salmonella typhi were the most sensitive ones to MB-Ln. Furthermore, the MB-Ln complexes were found to be much less toxic in vivo than MB, as suggested by the evaluated LD50 (50% lethal dose) values. All the MB-Ln series complexes fell in the LD50 range of 5000-15 000 mg kg-1, while the LD50 value of MB was only 1294 mg kg-1. Furthermore, MB-Lu, as the selected representative of MB-Ln, could effectively inhibit the activity of DNA gyrase, the same as MB, suggesting the primary antibacterial mechanism of the MB-Ln series. The results demonstrated the good prospects and potential of metal-based veterinary drugs with better drug performance.

Generalized system-bath entanglement theorem for Gaussian environments.

The entanglement between system and bath often plays a pivotal role in complex systems spanning multiple orders of magnitude. A system-bath entanglement theorem was previously established for Gaussian environments in J. Chem. Phys. 152, 034102 (2020) regarding linear response functions. This theorem connects the entangled responses to the local system and bare bath properties. In this work, we generalize it to correlation functions. Key steps in derivations involve using the generalized Langevin dynamics for hybridizing bath modes and the Bogoliubov transformation that maps the original finite-temperature reservoir to an effective zero-temperature vacuum by employing an auxiliary bath. The generalized theorem allows us to evaluate the system-bath entangled correlations and the bath mode correlations in the total composite space, as long as we know the bare-bath statistical properties and obtain the reduced system correlations. To demonstrate the cross-scale entanglements, we utilize the generalized theorem to calculate the solvation free energy of an electron transfer system with intramolecular vibrational modes.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.

Effects of alcohol on the composition and metabolism of the intestinal microbiota among people with HIV: a cross-sectional study.

OBJECTIVES: Alcohol consumption is not uncommon among people with HIV (PWH) and may exacerbate HIV-induced intestinal damage, and further lead to dysbiosis and increased intestinal permeability. This study aimed to determine the changes in the faecal microbiota and its association with alcohol consumption in HIV-infected patients. METHODS: A cross-sectional survey was conducted between November 2021 and May 2022, and 93 participants were recruited. To investigate the alterations of alcohol misuse on fecal microbiology in HIV-infected individuals, we performed 16s rDNA gene sequencing on fecal samples from the low to moderate drinking (n=21) and non-drinking (n=72) groups. RESULTS: Comparison between groups using alpha and beta diversity showed that the diversity of stool microbiota in the low to moderate drinkinge group did not differ from that of the non-drinking group (all P>0.05). The Linear discriminant Analysis effect size (LEfSe) algorithm was to determine the bacterial taxa associated with alcohol consumption, and the results showed altered fecal bacterial composition in HIV-infected patients who consumed alcohol, with Coprobacillus, Pseudobutyrivibrio and Peptostreptococcaceae enriched, and Pasteurellaceae and Xanthomonadaceae were depleted. In addition, by using the Kyoto Encyclopedia of Genes and Genomes (KEGG) functional microbiome features were also found to be altered in the low to moderate drinking group, showing a reduction in metabolic pathways (P=0.036) and cardiovascular disease pathway (P=0.006). CONCLUSION: Low to moderate drinking will change the composition, metabolism and cardiovascular disease pathway of the gut microbiota of HIV-infected patients.