Tethered cord syndrome from pediatric and adult perspectives: a comprehensive systematic review of 6135 cases.

OBJECTIVE: This study aimed to investigate the differences in clinical features, diagnostic examination, treatment, and pathological results between adult-onset and pediatric-onset tethered cord syndrome (TCS). METHODS: The authors searched the PubMed, Embase, and Cochrane Library databases through January 2023 for reports on TCS, extracting information on clinical features, imaging data, treatment modalities, prognosis, and pathological research results. A total of 6135 cases from 246 articles were included in the analysis. This review was conducted in accordance with the 2020 PRISMA guidelines and registered on PROSPERO. RESULTS: The most common adult clinical manifestations were pain, urinary symptoms, and numbness; in children, they were urinary symptoms, skin lesions, bowel symptoms, and unspecific motor deficits. Surgical treatment was the primary approach for both adults and children, with a higher clinical improvement rate observed in adults. However, adults also had a higher rate of surgical complications than children. TCS pathological studies have not yet identified the differences between adults and children, and the pathogenesis of adult-onset TCS requires further investigation. CONCLUSIONS: Adult-onset and pediatric-onset TCS exhibit certain differences in clinical characteristics, diagnostic examinations, and treatments. However, significant differences have not been found in current pathological studies between adults and children. Systematic review registration no.: CRD42023479450 (www.crd.york.ac.uk/prospero).

Associations between genetically predicted TIMP-3 levels and risk of venous thromboembolism: A two sample Mendelian randomization study.

TIMP metallopeptidase inhibitor 3 (TIMP-3) may contribute to the pathogenesis of venous thromboembolism (VTE). However, few studies have investigated the effect of TIMP-3 on VTE. Therefore, a two-sample Mendelian randomization (MR) analysis was conducted to investigate the association between TIMP-3 levels and VTE. Seven independent single-nucleotide polymorphisms (SNPs) for TIMP-3 levels were obtained from a published genome-wide association study (the KORA Consortium, including 997 Europeans). We obtained outcome datasets for VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) from the FinnGen Consortium. The primary analytical method used in the MR analysis was the inverse variance weighted (IVW) method. To enhance the robustness of the MR results, some other MR methods including weighted median, MR-Egger, and MR-PRESSO were conducted. Moreover, several sensitivity analyses were performed to identify potential horizontal pleiotropy and heterogeneity. In primary IVW MR analyses, per log increase in genetically predicted TIMP-3 levels were positively associated with the incidence of VTE (odds ratio [OR], 1.03; 95 % confidence interval (CI), 1.01, 1.06; P = 0.010), PE (OR, 1.04; 95 % CI, 1.01, 1.08; P = 0.009), and DVT (OR, 1.06; 95 % CI, 1.02, 1.10; P= 0.003). The results of the weighted median, MR-Egger, and MR-PRESSO were similar to the main findings. No unbalanced pleiotropy or heterogeneity was observed. The study suggests that genetically predicted high levels of TIMP-3 may be associated with an increased risk of VTE. These findings indicate that strategies targeting TIMP-3 may provide a basis for the prevention and treatment of VTE. Further investigation is required to clarify this potential mechanism.

Identification of nuclear membrane SUN proteins and components associated with wheat fungal stress responses.

In eukaryotes, the nuclear membrane that encapsulates genomic DNA is composed of an inner nuclear membrane (INM), an outer nuclear membrane (ONM), and a perinuclear space. SUN proteins located in the INM and KASH proteins in the ONM form the SUN-KASH NM-bridge, which functions as the junction of the nucleocytoplasmic complex junction. Proteins containing the SUN domain showed the highest correlation with differentially accumulated proteins (DAPs) in the wheat response to fungal stress. To understand the characteristics of SUN and its associated proteins in wheat responding to pathogen stress, here we investigated and comprehensive analyzed SUN- and KASH-related proteins among the DAPs under fungi infection based on their conserved motifs. In total, four SUN proteins, one WPP domain-interacting protein (WIP), four WPP domain-interacting tail-anchored proteins (WIT), two WPP proteins and one Ran GTPase activating protein (RanGAP) were identified. Following transient expression of Nicotiana benthamiana, TaSUN2, TaRanGAP2, TaWIT1 and TaWIP1 were identified as nuclear membrane proteins, while TaWPP1 and TaWPP2 were expressed in both the nucleus and cell membrane. RT-qPCR analysis demonstrated that the transcription of TaSUN2, TaRanGAP2 and TaWPP1 were strongly upregulated in response to fungal infection. Furthermore, using the bimolecular fluorescence complementation, the luciferase complementation and a nuclear and split-ubiquitin-based membrane yeast two-hybrid systems, we substantiated the interaction between TaSUN2 and TaWIP1, as well as TaWIP1/WIT1 and TaWPP1/WPP2. Silencing of TaSUN2, TaRanGAP2 and TaWPP1 in wheat leaves promoted powdery mildew infection and hyphal growth, and reduced the expression of TaBRI1, TaBAK1 and Ta14-3-3, indicating that these NM proteins play a positive role in resistance to fungal stress. Our study reveals the characteristics of NM proteins and propose the preliminary construction of SUN-WIP-WPP-RanGAP complex in wheat, which represents a foundation for detail elucidating their functions in wheat in future.

Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine (PC), and sphingolipid (SL) derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids (SFA-PC) and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) and Ceramide Synthase 5 (CERS5) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSION: In conclusion, our study elucidates the metabolic reprogramming gnature of lipid metabolism in HCC, identifies prognostic markers, and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Self-supervised Adversarial Training of Monocular Depth Estimation against Physical-World Attacks.

Monocular Depth Estimation (MDE) plays a vital role in applications such as autonomous driving. However, various attacks target MDE models, with physical attacks posing significant threats to system security. Traditional adversarial training methods, which require ground-truth labels, are not directly applicable to MDE models that lack ground-truth depth. Some self-supervised model hardening techniques (e.g., contrastive learning) overlook the domain knowledge of MDE, resulting in suboptimal performance. In this work, we introduce a novel self-supervised adversarial training approach for MDE models, leveraging view synthesis without the need for ground-truth depth. We enhance adversarial robustness against real-world attacks by incorporating L0-norm-bounded perturbation during training. We evaluate our method against supervised learning-based and contrastive learning-based approaches specifically designed for MDE. Our experiments with two representative MDE networks demonstrate improved robustness against various adversarial attacks, with minimal impact on benign performance. Our code: https://github.com/Bob-cheng/DepthModelHardening.

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis.

Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.

Coverage-sensitive mechanism of electrochemical NO reduction on the SrTiO3(001) surface: a DFT investigation.

Due to its adverse environmental and human health hazards, addressing the elimination of nitric oxide (NO) has become a pressing concern for modern society. Currently, electrochemical NO reduction provides a new alternative to traditional selective catalytic reduction technology under mild reaction conditions. However, the complexity and variability of products make the coverage of NO an influencing factor that needs to be investigated. Hence, this study delves into the coverage-sensitive mechanism of electrochemical NO reduction on cost-effective perovskite catalysts, using SrTiO3 as an example, through density functional theory calculations. Phase diagrams analysis reveals that the coverage range from 0.25 to 1.00 monolayer (ML) coverage is favorable for NO adsorption. Gibbs free energy results indicate that the selectivity is significantly influenced by NO coverage. NH3 is likely to be generated at low coverage, while N2O and N2 are more likely to be produced at high coverage through a dimer mechanism. Charge analysis suggests that the charge transfer and Ti-O bond strength between reactants and catalysts are crucial factors. This work not only provides deep insights into coverage-sensitive reaction mechanisms but also is a guideline towards further rational design of high-performance perovskite catalysts.

Decreased Left Ventricular Mass is Associated with Sarcopenia and its Severity in Elderly Inpatients.

Objective: Skeletal muscle mass and cardiac structure change with age. It is unclear whether the loss of skeletal muscle mass (SMM) is accompanied by a decrease in heart mass loss. The aim of this study is to investigate the relationship of left ventricular mass (LVM) with sarcopenia and its severity in elderly inpatients. Methods: Seventy-one sarcopenia subjects and 103 non-sarcopenia controls were enrolled in this study. Bioelectrical impedance analysis, handgrip strength, and 5-time chair stand test were used to evaluate SMM, muscle strength, and physical performance, respectively. Myocardial structure and function were assessed by echocardiography. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria 2019. Results: Sarcopenic patients had smaller left ventricular sizes and LVM than non-sarcopenic controls. Severe sarcopenic patients had smaller left ventricular sizes and LVM than non-severe sarcopenic patients. In univariate regression analysis, body mass index (BMI), cardiac size, and LVM were positively correlated with SMM or SMI. In multivariate regression analysis, BMI and LVM were independently correlated with SMM and SMI. The combined measurement of LVM and BMI predicts sarcopenia with 66.0% sensitivity and 88.7% specificity (AUC: 0.825; 95% CI: (0.761, 0.889); p < 0.001). Conclusion: In hospitalized elderly patients, decreased left ventricular mass is associated with sarcopenia and its severity, and the combined measurement of LVM and BMI has a predictive value for sarcopenia.

The cerebroprotection and prospects of FNDC5/irisin in stroke.

Stroke, the leading cause of disability and cognitive impairment, is also the second leading cause of death worldwide. The drugs with multi-targeted brain cytoprotective effects are increasingly being advocated for the treatment of stroke. Irisin, a newly discovered myokine produced by cleavage of fibronectin type III domain 5, has been shown to regulate glucose metabolism, mitochondrial energy, and fat browning. A large amount of evidence indicated that irisin could exert anti-inflammatory, anti-apoptotic, and antioxidant properties in a variety of diseases such as myocardial infarction, inflammatory bowel disease, lung injury, and kidney or liver disease. Studies have found that irisin is widely distributed in multiple brain regions and also plays an important regulatory role in the central nervous system. The most common cause of a stroke is a sudden blockage of an artery (ischemic stroke), and in some circumstances, a blood vessel rupture can also result in a stroke (hemorrhagic stroke). After a stroke, complicated pathophysiological processes lead to serious brain injury and neurological dysfunction. According to recent investigations, irisin may protect elements of the neurovascular unit by acting on multiple pathological processes in stroke. This review aims to outline the currently recognized effects of irisin on stroke and propose possible directions for future research.

Emerging trends in CDs@hydrogels composites: from materials to applications.

Carbon dots (CDs) are nanoscale carbon materials with unique optical properties and biocompatibility. Their applications are limited by their tendency to aggregate or oxidize in aqueous environments. Turning weakness to strengths, CDs can be incorporated with hydrogels, which are three-dimensional networks of crosslinked polymers that can retain large amounts of water. Hydrogels can provide a stable and tunable matrix for CDs, enhancing their fluorescence, stability, and functionality. CDs@hydrogels, known for their ease of synthesis, strong binding capabilities, and rich surface functional groups, have emerged as promising composite materials. In this review, recent advances in the synthesis and characterization of CDs@hydrogels, composite materials composed of CDs and various types of natural or synthetic hydrogels, are summarized. The potential applications of CDs@hydrogels in fluorescence sensing, adsorption, drug delivery, antibacterial activity, flexible electronics, and energy storage are also highlighted. The current challenges and future prospects of CDs@hydrogels systems for the novel functional materials are discussed.

Metal Hydrogen-Bonded Organic Frameworks as Open Lewis Acid Catalysts for Two Types of CO2 Transformations.

Efficient and multiple CO2 utilization into high-value-added chemicals holds significant importance in carbon neutrality and industry production. However, most catalysis systems generally exhibit only one type of CO2 transformation with the efficiency to be improved. The restricted abundance of active catalytic sites or an inefficient utilization rate of these sites results in the constraint. Consequently, we designed and constructed two metal hydrogen-bonded organic frameworks (M-HOFs) {[M3(L3-)2(H2O)10]·2H2O}n (M = Co (1), Ni (2); L = 1-(4-carboxyphenyl)-1H-pyrazole-3,5-dicarboxylic acid) in this research. 1 and 2 are well-characterized, and both show excellent stability. The networks connected by multiple hydrogen bonds enhance the structural flexibility and create accessible Lewis acidic sites, promoting interactions between the substrates and catalytic centers. This enhancement facilitates efficient catalysis for two types of CO2 transformations, encompassing both cycloaddition reactions with epoxides and aziridines to afford cyclic carbonates and oxazolidinones. The catalytic activities (TON/TOF) are superior compared with those of most other catalysts. These heterogeneous catalysts still exhibited high performance after being reused several times. Mechanistic studies indicated intense interactions between the metal sites and substrates, demonstrating the reason for efficient catalysis. This marks the first instance on M-HOFs efficiently catalyzing two types of CO2 conversions, finding important significance for catalyst design and CO2 utilization.

Impact of soil physicochemical factors and heavy metals on co-occurrence pattern of bacterial in rural simple garbage dumping site.

Rural waste accumulation leads to heavy metal soil pollution, impacting microbial communities. However, knowledge gaps exist regarding the distribution and occurrence patterns of bacterial communities in multi-metal contaminated soil profiles. In this study, high-throughput 16 S rRNA gene sequencing technology was used to explore the response of soil bacterial communities to various heavy metal pollution in rural simple waste dumps in karst areas of Southwest China. The study selected three habitats in the center, edge, and uncontaminated areas of the waste dump to evaluate the main factors driving the change in bacterial community composition. Pollution indices reveal severe contamination across all elements, except for moderately polluted lead (Pb); contamination severity ranks as follows: Mn > Cd > Zn > Cr > Sb > V > Cu > As > Pb. Proteobacteria, Actinobacteria, Chloroflexi, and Acidobacteriota predominate, collectively constituting over 60% of the relative abundance. Analysis of Chao and Shannon indices demonstrated that the waste dump center boasted the greatest bacterial richness and diversity. Correlation data indicated a predominant synergistic interaction among the landfill's bacterial community, with a higher number of positive associations (76.4%) compared to negative ones (26.3%). Network complexity was minimal at the dump's edge. RDA analysis showed that Pb(explained:46%) and Mn(explained:21%) were the key factors causing the difference in bacterial community composition in the edge area of the waste dump, and AK(explained:42.1%) and Cd(explained:35.2%) were the key factors in the center of the waste dump. This study provides important information for understanding the distribution patterns, co-occurrence networks, and environmental response mechanisms of bacterial communities in landfill soils under heavy metal stress, which helps guide the formulation of rural waste treatment and soil remediation strategies.

Advances in Mechanism of HIV-1 Immune Reconstitution Failure: Understanding Lymphocyte Subpopulations and Interventions for Immunological Nonresponders.

In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.

Depletion of protective microbiota promotes the incidence of fruit disease.

Plant-associated microbiomes play important roles in plant health and productivity. However, despite fruits being directly linked to plant productivity, little is known about the microbiomes of fruits and their potential association with fruit health. Here, by integrating 16S rRNA gene, ITS high-throughput sequencing data, and microbiological culturable approaches, we reported that roots and fruits (pods) of peanut, a typical plant that bears fruits underground, recruit different bacterial and fungal communities independently of cropping conditions and that the incidence of pod disease under monocropping conditions is attributed to the depletion of Bacillus genus and enrichment of Aspergillus genus in geocarposphere. On this basis, we constructed a synthetic community (SynCom) consisting of three Bacillus strains from geocarposphere soil under rotation conditions with high culturable abundance. Comparative transcriptome, microbiome profiling, and plant phytohormone signaling analysis reveal that the SynCom exhibited more effective Aspergillus growth inhibition and pod disease control than individual strain, which was underpinned by a combination of molecular mechanisms related to fungal cell proliferation interference, mycotoxins biosynthesis impairment, and jasmonic acid-mediated plant immunity activation. Overall, our results reveal the filter effect of plant organs on the microbiome and that depletion of key protective microbial community promotes the fruit disease incidence.

Beyond inhibition against the PD-1/PD-L1 pathway: development of PD-L1 inhibitors targeting internalization and degradation of PD-L1.

Tumor cells hijack the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway to suppress the immune response through overexpressing PD-L1 to interact with PD-1 of T cells. With in-depth ongoing research, tumor-intrinsic PD-L1 is found to play important roles in tumor progression without interaction with PD-1 expressed on T cells, which provides an additional important target and therapeutic approach for development of PD-L1 inhibitors. Existing monoclonal antibody (mAb) drugs against the PD-1/PD-L1 pathway generally behave by conformationally blocking the interactions of PD-1 with PD-L1 on the cell surface. Beyond general inhibition of the protein-protein interaction (PPI), inhibitors targeting PD-L1 currently focus on the functional inhibition of the interaction between PD-1/PD-L1 and degradation of tumor-intrinsic PD-L1. This perspective will clarify the evolution of PD-L1 inhibitors and provide insights into the current development of PD-L1 inhibitors, especially targeting internalization and degradation of PD-L1.

The potentiality of bacteria to drive SARS-CoV-2 mutation.

A recent study published in mBio by Cao et al. revealed the crucial roles of bacteria in benefitting SARS-CoV-2 mutations (B. Cao, X. Wang, W. Yin, Z. Gao, and B. Xia, mBio e3187-23, 2024, https://doi.org/10.1128/mbio.03187-23). Understanding the underlying mechanisms driving the evolution of SARS-CoV-2 is crucial for predicting the future trajectory of the COVID-19 pandemic and developing preventive and treatment strategies. This study provides important insights into the rapid and complex evolution of viruses facilitated by bacterial-virus interactions.

Delineating molecular regulatory network of meat quality of longissimus dorsi indicated by transcriptomic, proteomic, and metabolomics analysis in rabbit.

This study aims to investigate the potential regulatory network responsible for the meat quality using multi-omics to help developing better varieties. Slaughter performance and meat quality of Shuxing No.1 rabbit outperformed IRA rabbit according to the tested rabbit parameters. Differentially expressed genes (DEGs) and differentially abundance proteins (DAPs) were involved in meat quality-related pathways, such as PI3K - Akt and MAPK signaling pathways. Only SMTNL1 and PM20D2 shared between DEGs and DAPs. Olfactory-sensitive undecanal, a differentially abundant metabolite (DAM) in volatilomics (vDAMs), correlated with all of the remaining 11 vDAMs, and most of 12 vDAMs were associated with amino acid metabolism. Integration revealed that 829 DEGs/DAPs were associated with 15 DAMs in four KEGG pathways, such as melatonin (a DAM in widely targeted metabolomics) was significantly positively correlated with ALDH and negatively correlated with RAB3D and CAT in the tryptophan metabolism pathway. This study sheds light on the potential mechanisms that contribute to the improved meat quality and flavor. SIGNIFICANCE: Shuxing No.1 rabbit is a new breed of meat rabbit in the Chinese market. In meat marketing, meat quality usually determines the purchase intention of consumers. Determining the biological and molecular mechanisms of meat quality in meat rabbit is essential for developing strategies to improve meat quality. According to the tested rabbit parameters, this study ascertained that the slaughter performance and meat quality of Shuxing No.1 rabbit surpasses that of IRA rabbit. The present study profiled the transcriptome, proteome, widely targeted metabolome, and volatilome of longissimus dorsi from Shuxing No.1 rabbit and IRA rabbit. The study found that meat quality and flavor-related tryptophan metabolism pathway is enriched with many DEGs/DAPs (including ALDH, RAB3D, and CAT), as well as a DAM, melatonin. This study sheds light on the potential mechanisms that contribute to the improved meat quality and flavor.

Association of single-point insulin sensitivity estimator index (SPISE) with future cardiovascular outcomes in patients with type 2 diabetes.

AIMS: To investigate the association of single-point insulin sensitivity estimator (SPISE) index with future cardiovascular outcomes in patients with type 2 diabetes. MATERIALS AND METHODS: SPISE index (= 600 × high-density lipoprotein cholesterol [mg/dL]0.185/triglycerides [mg/dL]0.2 × body mass index [kg/m2]1.338) was calculated in 10 190 participants. Cox proportional hazard regression models were applied to evaluate the association between SPISE index and future cardiovascular outcomes. Restricted cubic spline analyses and two-piecewise linear regression models were employed to explore the nonlinear association and to determine the threshold value. Subgroup and interaction analyses were conducted to test the robustness of the results. RESULTS: After fully adjusting for well-established metabolic confounders, higher SPISE index was significantly associated with lower risk of future cardiovascular outcomes in patients with type 2 diabetes (major adverse cardiovascular event [MACE]): hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.90-0.98, p = 0.0026; overall mortality: HR 0.90, 95% CI 0.86-0.93, p < 0.0001; cardiovascular disease [CVD] mortality: HR 0.85, 95% CI 0.79-0.92, p < 0.0001; congestive heart failure (CHF): HR 0.72, 95% CI 0.67-0.78, p < 0.0001; major coronary events: HR 0.91, 95% CI 0.87-0.95, p < 0.0001. There was a nonlinear association between SPISE index and future cardiovascular outcomes (the threshold value was 5.68 for MACE, 5.71 for overall mortality, 4.64 for CVD mortality, 4.48 for CHF, and 6.09 for major coronary events, respectively). CONCLUSIONS: Higher SPISE index was independently associated with lower risk of future cardiovascular outcomes in type 2 diabetes patients after full adjustment for well-established metabolic confounders.

Mucin alleviates colonic barrier dysfunction by promoting spermine accumulation through enhanced arginine metabolism in Limosilactobacillus mucosae.

Dietary fiber deprivation is linked to probiotic extinction, mucus barrier dysbiosis, and the overgrowth of mucin-degrading bacteria. However, whether and how mucin could rescue fiber deprivation-induced intestinal barrier defects remains largely unexplored. Here, we sought to investigate the potential role and mechanism by which exogenous mucin maintains the gut barrier function. The results showed that dietary mucin alleviated fiber deprivation-induced disruption of colonic barrier integrity and reduced spermine production in vivo. Importantly, we highlighted that microbial-derived spermine production, but not host-produced spermine, increased significantly after mucin supplementation, with a positive association with upgraded colonic Lactobacillus abundance. After employing an in vitro model, the microbial-derived spermine was consistently dominated by both mucin and Lactobacillus spp. Furthermore, Limosilactobacillus mucosae was identified as an essential spermine-producing Lactobacillus spp., and this isolated strain was responsible for spermine accumulation, especially after adhering to mucin in vitro. Specifically, the mucin-supplemented bacterial supernatant of Limosilactobacillus mucosae was verified to promote intestinal barrier functions through the increased spermine production with a dependence on enhanced arginine metabolism. Overall, these findings collectively provide evidence that mucin-modulated microbial arginine metabolism bridged the interplay between microbes and gut barrier function, illustrating possible implications for host gut health. IMPORTANCE: Microbial metabolites like short-chain fatty acids produced by dietary fiber fermentation have been demonstrated to have beneficial effects on intestinal health. However, it is essential to acknowledge that certain amino acids entering the colon can be metabolized by microorganisms to produce polyamines. The polyamines can promote the renewal of intestinal epithelial cell and maintain host-microbe homeostasis. Our study highlighted the specific enrichment by mucin on promoting the arginine metabolism in Limosilactobacillus mucosae to produce spermine, suggesting that microbial-derived polyamines support a significant enhancement on the goblet cell proliferation and barrier function.

Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.