Intermittent pulses of methylprednisolone with low-dose prednisone attenuate lupus symptoms in B6.MRL-Faslpr/J mice with fewer glucocorticoid side effects.

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Novel bioactive nanospheres show effective antibacterial effect against multiple endodontic pathogens.

Aim: The current study evaluated the antibacterial activity of a newly developed quaternary ammonium polymethacrylate (QAPM)-containing bioactive glasses (BGs) via a two-step method by our group, namely BGs-HAEMB, and explored its cytotoxicity and biocompatibility. Methods: The antibacterial effects of the BGs-HAEMB against planktonic bacteria, bacterial biofilm formation, and experimental root canal biofilms of persistent pathogens (Enterococcus faecalis, Streptococcus sanguis and Porphyromonas endodontalis) associated with endodontic infection were evaluated in vitro by agar diffusion tests, direct contact tests and live/dead staining. The cytotoxicity and biocompatibility of BGs-HAEMB were evaluated by CCK-8 assays in vitro and a skin implantation model in vivo. Results: Compared to three clinically used endodontic sealers (Endofill, AH Plus, and iRoot SP), BGs-HAEMB exhibited the relatively strongest antibacterial effect against E. faecalis, S. sanguis and P. endodontalis after sitting for 14 and 28 days (P < 0.01). SEM images and CLSM images also showed that for each tested bacteria, BGs-HAEMB killed the most microorganism among all the experimental groups, regardless of treatment for 7 days or 28 days (P < 0.05). Besides, the BGs-HAEMB-treated groups showed a relatively low cytotoxicity (RGRs ranging from 88.6% to 102.9%) after 1, 3, and 7 days of exposure. Meanwhile, after 28 days of implantation, the inflammatory grade in BGs-HAEMB treated group was assessed as Grade I, in which the average numbers of inflammatory cells (6.7 ± 2.1) were less than 25. Conclusions: BGs-HAEMB exerted a long-term and stable antibacterial effect. The remarkable biocompatibility of BGs-HAEMB in vitro and in vivo confirmed its possible clinical application as a potential alternative in the development of the next generation of endodontic sealers.

A magnetic beads-based ligand fishing method for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from Hunteria zeylanica.

In this study, a novel magnetic bead-based ligand fishing method was developed for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from natural products. In order to improve the screening efficiency, two different magnetic beads, i.e. amine and carboxyl terminated magnetic beads, were comprehensively compared in terms of their ability to immobilize monoamine oxidase A (MAOA), biocatalytic activity and specific adsorption rates for affinity ligands. Carboxyl terminated magnetic beads performed better for MAOA immobilization and demonstrated superior performance in ligand fishing. The MAOA immobilized magnetic beads were applied to screen novel monoamine oxidase inhibitors in an alkaloid-rich plant, Hunteria zeylanica. Twelve MAOA affinity ligands were screened out, and ten of them were identified as monoterpene indole alkaloids by HPLC-Obitrap-MS/MS. Among them, six ligands, namely geissoschizol, vobasinol, yohimbol, dihydrocorynanthenol, eburnamine and (+)-isoeburnamine which exhibited inhibitory activity against MAOA with low IC50 values. To further explore their inhibitory mechanism, enzyme kinetic analysis and molecular docking studies were conducted.

Prognostic value of the fibrinogen-to-albumin ratio (FAR) in patients with chronic heart failure across the different ejection fraction spectrum.

The ratio of fibrinogen to albumin (FAR) is considered a new inflammatory biomarker and a predictor of cardiovascular disease risk. However, its prognostic value for patients with chronic heart failure (CHF) with different ejection fractions (EFs) remains unclear. A total of 916 hospitalized patients with CHF from January 2017 to October 2021 in the First Affiliated Hospital of Kunming Medical University were included in the study. Death occurred in 417 (45.5%) patients out of 916 patients during a median follow-up time of 750 days. Among these patients, 381 patients suffered from HFrEF (LVEF <40%) and 535 patients suffered from HFpEF or HFmrEF (HFpEF plus HFmrEF, LVEF ≥ 40%). Patients were categorized into high-level FAR (FAR-H) and low-level FAR (FAR-L) groups based on the optimal cut-off value of FAR (9.06) obtained from receiver operating characteristic (ROC) curve analysis. Upon analysing the Kaplan - Meier plots, the incidence of death was significantly higher in all patients with FAR-H and patients in both HF subgroups (p < 0.001). The multivariate Cox proportional hazard analyses indicated that the FAR was an independent predictor of all-cause mortality, regardless of heart failure subtype. (HR 1.115, 95% CI 1.089-1.142, p < 0.001; HFpEF plus HFmrEF, HR 1.109, 95% CI 1.074-1.146, p < 0.0001; HFrEF, HR 1.138, 95% CI 1.094-1.183, p < 0.0001) The optimal cut-off value of FAR in predicting all-cause mortality was 9.06 with an area under the curve value of 0.720 (95% CI: 0.687-0.753, p < 0.001), a sensitivity of 68.8% and a specificity of 65.6%. After adjusting for the traditional indicators (LVEF, Lg BNP, etc.), the new model with the FAR had better prediction ability in patients with CHF. Elevated FAR is an independent predictor of death in CHF and is not related to the HF subtype.

Clinical prognostic impact of C-NLR in heart failure patients with different ejection fractions: a retrospective study.

OBJECTION: Inflammatory conditions and immune disorders may worsen the prognosis of chronic heart failure (CHF) patients. The aim of this study was to evaluate the prognostic value of a new indicator, C-NLR, composed of C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), for the risk of all-cause mortality in HF patients with different ejection fractions. METHODS: A total of 1221 CHF patients admitted to the First Affiliated Hospital of Kunming Medical University from January 2017 to October 2021 were enrolled in this study. All patients were divided into 2 groups according to the median C-NLR. Kaplan-Meier survival curves were used to compare the all-cause mortality among CHF patients with different ejection fractions. Cox proportional hazards analysis was used to evaluate the relationships between variables and mortality. The predictive value of the C-NLR was assessed by using receiver operating characteristic (ROC) analyses. RESULTS: We collected data from 1192 patients with CHF. Kaplan-Meier survival analysis revealed that patients with low LCR levels had better overall survival (OS). After multivariate adjustment Cox proportional hazards analysis, the level of C-NLR was still independently related to mortality. CONCLUSIONS: C-NLR was a competent independent predictor in HF with different ejection fractions, and routine measurement of C-NLR would help clinical doctors identify patients with a poor prognosis.

Realize Generative Yet Complete Latent Representation for Incomplete Multi-View Learning.

In multi-view environment, it would yield missing observations due to the limitation of the observation process. The most current representation learning methods struggle to explore complete information by lacking either cross-generative via simply filling in missing view data, or solidative via inferring a consistent representation among the existing views. To address this problem, we propose a deep generative model to learn a complete generative latent representation, namely Complete Multi-view Variational Auto-Encoders (CMVAE), which models the generation of the multiple views from a complete latent variable represented by a mixture of Gaussian distributions. Thus, the missing view can be fully characterized by the latent variables and is resolved by estimating its posterior distribution. Accordingly, a novel variational lower bound is introduced to integrate view-invariant information into posterior inference to enhance the solidative of the learned latent representation. The intrinsic correlations between views are mined to seek cross-view generality, and information leading to missing views is fused by view weights to reach solidity. Benchmark experimental results in clustering, classification, and cross-view image generation tasks demonstrate the superiority of CMVAE, while time complexity and parameter sensitivity analyses illustrate the efficiency and robustness. Additionally, application to bioinformatics data exemplifies its practical significance.

Uncovering the substituted-position effect on excited-state evolution of benzophenone-phenothiazine dyads.

Photofunctional materials based on donor-acceptor molecules have drawn intense attention due to their unique optical properties. Importantly, Systematic investigation of substitution effects on excited-state charge transfer dynamics of donor-acceptor molecules is a powerful approach for identifying application-relevant design principles. Here, by coupling phenothiazine (PTZ) at the ortho-, meta-, and para-positions of the benzene ring of benzophenone (BP), three regioisomeric BP-PTZ dyads were designed to understand the relationship between substituted positions and excited-state evolution channels. Ultrafast transient absorption is used to detect and trace the transient species and related evolution channels of BP-PTZ dyads at excited state. In a non-polar solvent, BP-o-PTZ undergoes the through-space charge transfer process to produce a singlet charge-transfer (1CT) state, which subsequently proceeds the intersystem crossing process and transforms into a triplet charge-transfer (3CT) state; BP-m-PTZ experiences intramolecular charge transfer (ICT) process to generate the 1CT state, which subsequently transforms into the 3CT state by the intersystem crossing (ISC) and finally converts into the local-excited triplet (3LE) state; as for BP-p-PTZ, only 3LE states can be detected after the ISC process from the 1CT state. On the other hand, the twisted ICT states are generated via twisted motion between the donor and acceptor for all BP-PTZ dyads or planarization of the PTZ unit in high polar solvents. The excited-state theoretical calculations unveil that the features of ICT and intramolecular interaction between the three dyads play a decisive role in determining the through-bond charge transfer and through-space charge transfer processes. Also, these results demonstrate that the excited-state evolution channels of PTZ derivatives could be modified by tuning the substituted positions of the donor-acceptor dyads. This study provides a deep perspective for the substitute-position effect on donor-acceptor-type PTZ derivatives.

Childhood-onset systemic lupus erythematosus: characteristics and the prospect of glucocorticoid pulse therapy.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development. High dose oral glucocorticoid (GC) has become the rule for treating moderate to severe cSLE activity. However, GC-related side effects and potential toxicities are problems that cannot be ignored. Recent studies have suggested that GC pulse therapy can achieve disease remission rapidly and reduce GC-related side effects with a reduction in oral prednisone doses. This article reviews characteristics, including pathogenesis and manifestations of cSLE, and summarized the existing evidence on GC therapy, especially on GC pulse therapy in cSLE, followed by our proposal for GC therapy according to the clinical effects and pathogenesis.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Pathogenic Gene Spectrum and Clinical Implication in Chinese Patients with Lupus Nephritis.

BACKGROUND: Lupus nephritis is a rare immunological disorder. Genetic factors are considered important in its causation. We aim to systematically investigate the rare pathogenic gene variants in patients with lupus nephritis. METHODS: Whole-exome sequencing was used to screen pathogenic gene variants in 1886 probands with lupus nephritis. Variants were interpreted on the basis of known pathogenic variants or the American College of Medical Genetics and Genomics guidelines and studied by functional analysis, including RNA sequencing, quantitative PCR, cytometric bead array, and Western blotting. RESULTS: Mendelian form of lupus nephritis was confirmed in 71 probands, involving 63 variants in 39 pathogenic genes. The detection yield was 4%. The pathogenic genes enriched in nuclear factor kappa-B (NF-κB), type I interferon, phosphatidylinositol-3-kinase/serine/threonine kinase Akt (PI3K/AKT), Ras GTPase/mitogen-activated protein kinase (RAS/MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Clinical manifestation patterns were diverse among different signaling pathways. More than 50% of the pathogenic gene variants were reported to be associated with lupus or lupus nephritis for the first time. The identified pathogenic gene variants of lupus nephritis overlapped with those of autoinflammatory and immunodeficiency diseases. Inflammatory signatures, such as cytokine levels of IL-6, IL-8, IL-1 ß , IFN α , IFN γ , and IP10 in serum and transcriptional levels of interferon-stimulated genes in blood, were significantly higher in patients with pathogenic gene variants compared with controls. The overall survival rate of patients with pathogenic gene variants was lower than those without pathogenic gene variants. CONCLUSIONS: A small fraction of patients with lupus nephritis had identifiable pathogenic gene variants, primarily in NF-κB, type I interferon, PI3K/AKT, JAK/STAT, RAS/MAPK, and complement pathways.

Small molecule II-6s synergises with fluconazole against Candida albicans.

BACKGROUND: Candida albicans (C. albicans) is the most common opportunistic fungal species in the oral cavity. The emergence of drug resistance of C. albicans has necessitated the development of novel antifungal agents. OBJECTIVES: This study evaluated the antifungal activity of a previously developed antimicrobial small molecule, namely II-6s, and explored its potential synergism with fluconazole against C. albicans and the underlying mechanisms. METHODS: The antifungal effects of II-6s against C. albicans were evaluated with microdilution and time-killing assays. Synergism of II-6s with fluconazole was determined by calculating the fractional inhibitory concentration index (FICI). The effects of II-6s on efflux pump, mitochondrial function and energy metabolism were examined to investigate the underlying mechanism of synergism. The antifungal mechanism of II-6s against C. albicans was further explored with RNA-seq and validated with specific mutant strains. RESULTS: II-6s exhibited a fungicidal effect against C. albicans with a minimum fungicidal concentration of 31.25 µg/mL. II-6s also inhibited C. albicans biofilm with a sessile minimum inhibitory concentration at 500 µg/mL. More importantly, II-6s showed a synergistic effect with fluconazole against a fluconazole-resistant strain of C. albicans, which expressed elevated levels of CDR1 (FICI < 0.5). II-6s inhibited the efflux pump activity of C. albicans. Consistently, II-6s inhibited energy metabolism of C. albicans by reducing the mitochondrial membrane potential and ATP generation, and inhibited utilisation of the non-fermentable carbon source. II-6s also inhibited the mitogen-activated protein kinase signal pathway, particularly HOG1, which may explain its antifungal activity against C. albicans. CONCLUSION: The small molecule II-6s inhibits the growth of C. albicans by targeting HOG1. II-6s also synergises with fluconazole by inhibiting the drug efflux pump, representing a promising antifungal agent for the control of candidiasis.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Novel loss-of-function mutations in TNFAIP3 gene in patients with lupus nephritis.

Background: Heterozygous loss-of-function mutations in the tumour necrosis factor alpha induced protein 3 (TNFAIP3) gene cause an early-onset auto-inflammatory disease named haploinsufficiency of A20 (HA20). Here we describe three unrelated patients with autoimmune lupus nephritis (LN) phenotypes carrying three novel mutations in the TNFAIP3 gene. Methods: Whole-exome sequencing (WES) was used to identify the causative mutations in three biopsy-proven LN patients. Sanger sequencing and quantitative polymerase chain reaction (qPCR) were used to validate the mutations identified by WES. RNA sequencing, qPCR and cytometric bead array was used to detect inflammatory signatures in the patients. Results: The patients predominantly presented with an autoimmune phenotype, including autoimmune haemolytic anaemia, multipositive autoantibodies and LN. Additionally, novel phenotypes of allergy and pericardial effusion were first reported. WES identified three novel heterozygous mutations in the TNFAIP3 gene, including a novel splicing mutation located in the canonical splicing site (c.634+2T>C) resulting in an intron 4 insertion containing a premature stop codon, a de novo novel copy number variation (exon 7-8 deletion) and a novel nonsense mutation c.1300_1301delinsTA causing a premature stop codon. We further identified hyperactivation signatures of nuclear factor- kappa B and type I IFN signalling and overproduction of pro-inflammatory cytokines in the blood. This report expanded the phenotype to a later age, as two girls were diagnosed at age 3 years and one man at age 29 years. Conclusions: Kidney involvement may be the main feature of the clinical spectrum of HA20, even in adults. Genetic screening should be considered for early-onset LN patients.

Temporal Changes in Fecal Unabsorbed Carbohydrates Relative to Perturbations in Gut Microbiome of Neonatal Calves: Emerging of Diarrhea Induced by Extended-Spectrum ß-lactamase-Producing Enteroaggregative Escherichia coli.

Early gut microbiota development and colonization are crucial for the long-term health and performance of ruminants. However, cognition among these microbiota is still vague, particularly among the neonatal dairy calves. Here, extended-spectrum ß-lactamase-producing enteroaggregative E. coli (ESBL-EAEC)-induced temporal changes in diversity, stability, and composition of gut microbiota were investigated among the neonatal female calves, with the view of discerning potential biomarkers of this arising diarrhea cases in local pastures. Nearly, 116 newborn calves were enrolled in this time period study during their first 2 weeks of life, and a total of 40 selected fecal samples from corresponding calves were used in this study. The results revealed that differentiated gut microbiome and metabolome discerned from neonatal calves were accompanied by bacterial infections over time. Commensal organisms like Butyricicoccus, Faecalibacterium, Ruminococcus, Collinsella, and Coriobacterium, as key microbial markers, mainly distinguish "healthy" and "diarrheic" gut microbiome. Random forest machine learning algorithm indicated that enriched fecal carbohydrates, including rhamnose and N-acetyl-D-glucosamine, and abundant short-chain fatty acids (SCFAs) existed in healthy ones. In addition, Spearman correlation results suggested that the presence of Butyricicoccus, Faecalibacterium, Collinsella, and Coriobacterium, key commensal bacteria of healthy calves, is positively related to high production of unabsorbed carbohydrates, SCFAs, and other prebiotics, and negatively correlated to increased concentrations of lactic acid, hippuric acid, and α-linolenic acid. Our data suggested that ESBL-EAEC-induced diarrhea in female calves could be forecasted by alterations in the gut microbiome and markedly changed unabsorbed carbohydrates in feces during early lives, which might be conducive to conduct early interventions to ameliorate clinical symptoms of diarrhea induced by the rising prevalence of ESBL-EAEC.

Assembling CdSe Quantum Dots into Polymeric Micelles Formed by a Polyethylenimine-Based Amphiphilic Polymer to Enhance Efficiency and Selectivity of CO2-to-CO Photoreduction in Water.

Colloidal quantum dots (QDs) as photocatalysts enable catalysis of CO2-to-CO conversion in the presence of electron donors. The surface and/or interfacial chemical environment of the QDs is essential for the activity and selectivity of the CO2 photoreduction. Various strategies, including exposing active metal sites or anchoring functional organic ligands, have been applied to tune the QDs' surface chemical environment and thus to improve both activity and selectivity of CO2 photoreduction, which occurs at surface of the QDs. However, the efficient and selective photocatalytic CO2 reduction with QD photocatalysts in water is still a challenging task due to low CO2 solubility and robust competing reaction of proton reduction in water. Different from state-of-the-art QDs' surface manipulation, we proposed to ameliorate the interfacial chemical environment of CdSe QDs via assembling the QDs into functional polymeric micelles in water. Herein, CdSe@PEI-LA assemblies were constructed by loading CdSe QDs into polymeric micelles formed by PEI-LA, a polyethylenimine (PEI)-based functional amphiphilic polymer. Due to self-assembly and high CO2 adsorption capacity of PEI-LA in water, the photocatalytic CO2-to-CO conversion efficiency and selectivity of the CdSe@PEI-LA assemblies in water were dramatically improved to 28.0 mmol g-1 and 87.5%, respectively. These two values increased 57 times and 1.5 times, respectively, compared with those of the pristine CdSe QDs. Mechanism studies revealed that CdSe QDs locate in polymeric micelles of high CO2 local concentration and the photoinduced electron transfer from the conduction band of CdSe QDs to Cd-CO2* species is thermodynamically and kinetically improved in the presence of PEI-LA. The CdSe@PEI-LA system represents a successful example of using a functionalized amphiphilic polymer to ameliorate interfacial microenvironments of nanocrystal photocatalysts and realizing efficient and selective CO2 photoreduction in water.

Gut microbiota-derived ursodeoxycholic acid from neonatal dairy calves improves intestinal homeostasis and colitis to attenuate extended-spectrum ß-lactamase-producing enteroaggregative Escherichia coli infection.

BACKGROUND: Antimicrobials are often used to prevent and treat diarrhea induced by enteroaggregative Escherichia coli (EAEC) in young ruminants. However, drug overuse or misuse accelerates the spread of multidrug-resistant extended-spectrum ß-lactamase (ESBL)-producing E. coli. Thus, supplementary foods as alternatives to antibiotics are needed to prevent colibacillus diarrhea in neonatal dairy calves. Ursodeoxycholic acid (UDCA), a therapeutic bile acid, helps alleviate colitis. However, how UDCA helps alleviate ESBL-EAEC-induced clinical symptoms and colitis remains unclear. RESULTS: We investigated the microbial profiles and metabolites of healthy and diarrheic neonatal calves to determine microbial and metabolite biomarkers in early-life development. Both the gut microbiota communities and their associated metabolites differed between healthy and diarrheic calves. Commensal Butyricicoccus, Faecalibacterium, Ruminococcus, Collinsella, and Coriobacterium were key microbial markers that distinguished healthy and diarrheic gut microbiomes. Random forest machine-learning algorithm and Spearman correlation results indicated that enriched UDCA, short-chain fatty acids (SCFAs), and other prebiotics were strongly positively correlated with these five bacterial genera. We explored the effect of ursodiol on bacterial growth, cell adherence, and lipopolysaccharide-treated Caco-2 cells. Adding ursodiol induced direct antibacterial effects, suppressed proinflammatory effects, and reduced cell integrity damage. Oral ursodiol delivery to neonatal mice exhibited significant antibacterial effects and helped maintain colonic barrier integrity in mouse models of peritonitis sepsis and oral infection. UDCA supplementation attenuated colitis and recovered colonic SCFA production. To validate this, we performed fecal microbiota transplantations to inoculate ESBL-EAEC-infected neonatal mice. Microbiotas from UDCA-treated neonatal mice ameliorated colitis and hindgut commensal bacterial damage compared with that of the microbiotas from the control and placebo mice, as evidenced by colonization of abundant bacteria, including Oscillospiraceae, Ruminococcaceae, Lachnospiraceae, and Clostridia_UCG-014, and upregulated SCFA production. CONCLUSIONS: This study provided the first evidence that UDCA could confer diarrhea resistance in ESBL-EAEC-infected newborn dairy calves. UDCA blocked bacterial growth and invasion both in vitro and in vivo, alleviated commensal bacterial dysbiosis during ESBL-EAEC infection in neonatal mouse models of sepsis and colitis via the TGR5-NF-κB axis, and upregulated SCFA production in the hindgut digesta. Our findings provide insight into the UDCA-mediated remission of ESBL-EAEC infections and the potential role of UDCA as an antibiotic alternative. Video abstract.

Ultrafast study of substituted-position-dependent excited-state evolution in benzophenone-carbazole dyads.

Donor and acceptor (D-A) compounds based on benzophenone (BP) and carbazole (Cz) were recently reported to exhibit an extraordinary long afterglow phosphorescence in the solid state. However, the BP derivatives' mechanism of long afterglow phosphorescence is obscure. BP-o-Cz, BP-m-Cz, and BP-p-Cz were designed by coupling Cz at the ortho-, meta- and para-positions of the BP's benzene ring to uncover the excited-state evolution of BP-Cz molecules. Femtosecond and nanosecond transient absorption and excited-state theoretical calculations were carried out to detect and trace the photophysical process of BP-Cz dyads. After the excitation, all dyads experience intramolecular charge transfer (ICT) and intersystem crossing (ISC) processes. The resulting charge-transfer (1CT and 3CT) state of BP-o-Cz will decay to the ground state directly and quickly via the fast charge recombination (CR) process, which may be caused by through-space D-A interaction due to the enforced proximity between BP and Cz. In contrast, for BP-m-Cz and BP-p-Cz dyads, the complete separation of HOMOs and LUMOs leads to extended ICT and slow CR processes, producing an obvious Cz cation radical intermediate and an ultralong-lived triplet state species after the 3CT. Herein, we demonstrated that the excited-state evolution channels could be modified by tuning the substituted positions of D-A dyads. This may pave the way for designing efficient D-A type luminescent materials.

Blue or Near-Infrared Light-Triggered Release of Halogens via Blebbistatin Photocage.

Photocages can provide spatial and temporal control to accurately release the various chemicals and bioactive groups when excited by light. Although the absorption spectra of most photocages are in the ultraviolet absorption region, only a few absorb in the visible or near-infrared region. Blebbistatin (Bleb) would release a hydroxyl radical under blue one-photon or two-photon near-infrared light (800 nm) irradiation. In this work, typical chlorine and bromine as leaving groups substituted hydroxyl compounds (Bleb-Cl, Bleb-Br) are synthesized to evaluate the photocage's capability of Bleb's platform. Driven by the excited-state charge transfer, Bleb-Cl and Bleb-Br show good photolysis quantum yield to uncage the halogen anion and the uncaging process would be accelerated in water solution. The photochemical reaction, final product's analysis, and femtosecond transient absorption studies on Bleb-Cl/Bleb-Br demonstrate that Bleb can act as a photocage platform to release the halogen ion via heterolytic reaction when irradiated by blue or near-infrared light. Therefore, Bleb can be a new generation of visible or near-infrared light-triggered photocage.

The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases.

Oral microbial dysbiosis is the major causative factor for common oral infectious diseases including dental caries and periodontal diseases. Interventions that can lessen the microbial virulence and reconstitute microbial ecology have drawn increasing attention in the development of novel therapeutics for oral diseases. Antimicrobial small molecules are a series of natural or synthetic bioactive compounds that have shown inhibitory effect on oral microbiota associated with oral infectious diseases. Novel small molecules, which can either selectively inhibit keystone microbes that drive dysbiosis of oral microbiota or inhibit the key virulence of the microbial community without necessarily killing the microbes, are promising for the ecological management of oral diseases. Here we discussed the research progress in the development of antimicrobial small molecules and delivery systems, with a particular focus on their antimicrobial activity against typical species associated with oral infectious diseases and the underlying mechanisms.

Low-Threshold Blue Quasi-2D Perovskite Laser through Domain Distribution Control.

Quasi-2D perovskites, composed of self-organized quantum well structures, are emerging as gain materials for laser applications. Here we investigate the influence of domain distribution on the laser emission of CsPbCl1.5Br1.5-based quasi-2D perovskites. The use of 2,2-diphenylethylammonium bromide (DPEABr) as a ligand enables the formation of quasi-2D film with a large-n-dominated narrow domain distribution. Due to the reduced content of small-n domains, the incomplete energy transfer from small-n to large-n domains can be greatly addressed. Moreover, the photoinduced carriers can be concentrated on most of the large-n domains to reduce the local carrier density, thereby suppressing the Auger recombination. By controlling the domain distribution, we achieve blue amplified spontaneous emission and single-mode vertical-cavity surface-emitting lasing with low thresholds of 6.5 and 9.2 µJ cm-2, respectively. This work provides a guideline to design the domain distribution to realize low-threshold multicolor perovskite lasers.