Nitrogen-cycling processes under long-term compound heavy metal(loids) pressure around a gold mine: Stimulation of nitrite reduction.

Mining and tailings deposition can cause serious heavy metal(loids) pollution to the surrounding soil environment. Soil microorganisms adapt their metabolism to such conditions, driving alterations in soil function. This study aims to elucidate the response patterns of nitrogen-cycling microorganisms under long-term heavy metal(loids) exposure. The results showed that the diversity and abundance of nitrogen-cycling microorganisms showed negative feedback to heavy metal(loids) concentrations. Denitrifying microorganisms were shown to be the dominant microorganisms with over 60% of relative abundance and a complex community structure including 27 phyla. Further, the key bacterial species in the denitrification process were calculated using a random forest model, where the top three key species (Pseudomonas stutzei, Sphingobium japonicum and Leifsonia rubra) were found to play a prominent role in nitrite reduction. Functional gene analysis and qPCR revealed that nirK, which is involved in nitrite reduction, significantly accumulated in the most metal-rich soil with the increase of absolute abundance of 63.86%. The experimental results confirmed that the activity of nitrite reductase (Nir) encoded by nirK in the soil was increased at high concentrations of heavy metal(loids). Partial least squares-path model identified three potential modes of nitrite reduction processes being stimulated by heavy metal(loids), the most prominent of which contributed to enhanced nirK abundance and soil Nir activity through positive stimulation of key species. The results provide new insights and preliminary evidence on the stimulation of nitrite reduction processes by heavy metal(loids).

Exploration for the Priority of HIV Intervention: Modelling Health Impact and Cost-Effectiveness - Six Cities, Eastern China, 2019-2028.

Introduction: In order to enhance the effectiveness of resource allocation, regions must tailor their responses to their specific epidemiological and economic situations. Methods: Utilizing Spectrum software, we projected the cost-effectiveness of 10 chosen HIV interventions in six cities in eastern China from 2019 to 2028. We assessed three scenarios - Base, Achievable, and Idealized - for each city. The analysis included the projected number of HIV infections and deaths averted, as well as the incremental cost-effectiveness ratios for each intervention in the six cities. Results: In Shijiazhuang, Wuxi, Yantai, and Zhenjiang, cities with initially low antiretroviral therapy (ART) coverage, ART showed significant effectiveness, especially for males. Conversely, in Foshan and Ningbo, where ART coverage was notably high, oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) proved effective in the Idealized scenario. MSM outreach, ART for males, and ART for females demonstrated cost-effectiveness across all six cities in both Achievable and Idealized scenarios at the predefined thresholds for each city. Discussion: Maintaining an appropriate coverage rate for outreach to MSM can lead to cost-effectiveness. In cities with low ART coverage, scaling up ART remains a crucial intervention. In regions with high ART coverage, consideration may be given to the utilization of oral PrEP for MSM individuals, requiring budget allocation.

Spatiotemporal constrained RNA-protein heterogeneous network for protein complex identification.

The identification of protein complexes from protein interaction networks is crucial in the understanding of protein function, cellular processes and disease mechanisms. Existing methods commonly rely on the assumption that protein interaction networks are highly reliable, yet in reality, there is considerable noise in the data. In addition, these methods fail to account for the regulatory roles of biomolecules during the formation of protein complexes, which is crucial for understanding the generation of protein interactions. To this end, we propose a SpatioTemporal constrained RNA-protein heterogeneous network for Protein Complex Identification (STRPCI). STRPCI first constructs a multiplex heterogeneous protein information network to capture deep semantic information by extracting spatiotemporal interaction patterns. Then, it utilizes a dual-view aggregator to aggregate heterogeneous neighbor information from different layers. Finally, through contrastive learning, STRPCI collaboratively optimizes the protein embedding representations under different spatiotemporal interaction patterns. Based on the protein embedding similarity, STRPCI reweights the protein interaction network and identifies protein complexes with core-attachment strategy. By considering the spatiotemporal constraints and biomolecular regulatory factors of protein interactions, STRPCI measures the tightness of interactions, thus mitigating the impact of noisy data on complex identification. Evaluation results on four real PPI networks demonstrate the effectiveness and strong biological significance of STRPCI. The source code implementation of STRPCI is available from https://github.com/LI-jasm/STRPCI.

AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation.

PURPOSE: Colorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response. METHODS: AKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements. RESULTS: We found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention. CONCLUSION: This study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.

Thiamethoxam-Induced Intergenerational Sublethal Effects on the Life History and Feeding Behavior of Rhopalosiphum padi.

Thiamethoxam, a second-generation neonicotinoid insecticide is widely used for controlling sap-sucking insect pests including Rhopalosiphum padi. The current study aimed to investigate the life-history parameters and feeding behavior of R. padi following treatments with sublethal concentrations of thiamethoxam. The lethal concentration 50 (LC50) value of thiamethoxam against adult R. padi was 11.458 mg L-1 after 48 h exposure. The sublethal concentrations of thiamethoxam (LC5 and LC10) significantly decreased the adult longevity, fecundity, and reproductive days in the directly exposed aphids (F0 generation). In the progeny R. padi (F1), the developmental durations and total prereproductive period (TPRP) were decreased while the adult longevity, fecundity, and reproductive days (RPd) were increased at both thiamethoxam concentrations. The demographic parameters including the net reproductive rate (R0), intrinsic rate of increase (r), and finite rate of increase (λ) were prolonged only at the LC5 of thiamethoxam. The EPG results indicated that the sublethal concentrations of thiamethoxam increases the total duration of non-probing (Np) while reducing the total duration of E2 in directly exposed aphids (F0). Interestingly, the E2 were significantly increased in the progeny generation (F1) descending from previously exposed parental aphids (F0). Overall, this study showed that thiamethoxam exhibited high toxicity against directly exposed individuals (F0), while inducing intergenerational hormetic effects on the progeny generation (F1) of R. padi. These findings provided crucial details about thiamethoxam-induced hormetic effects that might be useful in managing resurgences of this key pest.

Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Single cell RNA-sequencing reveals the cellular senescence of placental mesenchymal stem/stromal cell in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe obstetric complication closely associated with placental dysfunction. Placental mesenchymal stem/stromal cells (PMSCs) modulate placental development while PE PMSCs are excessively senescent to disturb placental function. Nevertheless, the senescence mechanism of PE PMSCs remains unclear. METHODS: PE-related single-cell RNA sequencing datasets (GSE173193), data of chip detection (GSE99007) and bulk transcriptome RNA sequencing datasets (GSE75010) were extracted from the GEO database. Firstly, the functional enrichment analyses of the differentially expressed genes (DEGs) in PMSCs were conducted. Then, the clusters of PE PMSCs were distinguished according to the expressions of senescence-related genes (SRGs) by consensus clustering analysis. Cell cycle analysis, senescence ß-galactosidase, Transwell, and tube formation were conducted. Next, the expressions of the senescence-associated secretory phenotype (SASPs) were displayed. The characteristic genes of PE were screened by the least absolute shrinkage and selection operator analysis. CTSZ was suppressed in PMSCs and the cellular senescence levels were evaluated. RESULTS: In this study, The DEGs in PMSCs were closely associated with cellular senescence. The score of SRGs was significantly higher and most of the SASPs were abnormally expressed in the senescent group. Seven characteristic genes of PE were identified, thereinto, CTSZ reduction may accelerate the senescence in PMSCs in vitro. DISCUSSION: Combined with bioinformatic analysis and lab experiments, our study emphatically revealed the abnormal cellular senescence in PE PMSCs, in which CTSZ, one of the PE characteristic genes, regulated the cellular senescence levels in PMSCs. These findings might help to deepen the understanding of the senescence mechanism of PMSCs in PE.

ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores.

Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.

Cost-effectiveness analysis of durvalumab, tremelimumab, and etoposide-platinum in first-line treatment of extensive-stage small cell lung cancer.

BACKGROUND: Durvalumab plus etoposide-platinum (DEP) showed sustained overall survival improvements in patients with extensive-stage small-cell lung cancer (ES-SCLC) compared to etoposide-platinum (EP), but adding tremelimumab to DEP (DTEP) did not significantly improve outcomes. A third-party payer perspective is taken here to evaluate the cost-effectiveness of DTEP, DEP, and EP for ES-SCLC. METHODS: The cost-effectiveness was evaluated by partitioning survival models into 3 mutually exclusive health states. In this model, clinical characteristics and outcomes were obtained from the CASPIAN. Model robustness was evaluated through 1-way deterministic and probabilistic sensitivity analyses. Outcome measurements included costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio, life-years, incremental net health benefit, and incremental net monetary benefit. The analysis was conducted with a 10-year lifetime horizon in a United States setting. RESULTS: Compared with EP, DEP, and DTEP were associated with an increment of 0.480 and 0.313 life-years, and an increment of 0.247 and 0.165 QALYs, as well as a $139,788 and $170,331 increase in cost per patient. The corresponding ICERs were $565,807/QALY and $1033,456/QALY, respectively. The incremental net health benefit and incremental net monetary benefit of DEP or DTEP were -0.685 QALYs and -$102,729, or -0.971 QALYs and -$145,608 at a willingness to pay threshold of $150,000/QALY, respectively. Compared with DTEP, DEP was dominated. DTEP and DEP were 100% unlikely to be cost-effective if the willingness to pay threshold was $150,000/QALY. DEP was cost-effective compared to EP when durvalumab was priced below $0.994/mg. Compared with EP, DEP, and DTEP were unlikely to be considered cost-effective across all subgroups. CONCLUSION: DEP and DTEP were not cost-effective options in the first-line treatment for ES-SCLC compared with EP, from the third-party payer perspective in the United States. Compared with DTEP, DEP was dominated.

EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

Effects of Aerobic Exercise Combined With Attentional Bias Modification in the Care of Male Patients With a Methamphetamine Use Disorder.

OBJECTIVE: It remains unclear which individual or combined strategies are most beneficial for methamphetamine use disorders (MUDs). We compared the effects of aerobic exercise, attentional bias modification, and combined intervention on male patients with MUD. METHOD: One hundred male patients with MUD were randomly assigned to combined intervention, aerobic exercise, attentional bias modification, or control groups (25 patients per group). The 8-week intervention protocol included three 60-minute sessions of aerobic exercises per week. Primary outcomes included high- and low-frequency heart rate variability, executive function, and cardiorespiratory fitness measured by customized software, computerized tests, and the Harvard step test, respectively. Secondary outcomes included psychiatric symptoms, drug craving, training acceptability, and persistence. RESULTS: Participant characteristics were matched between groups at baseline. Executive function, heart rate variability, cardiorespiratory fitness, drug craving, and most psychiatric symptoms had significant time-group interactions at posttest (p < .05, η2 = .08-.28). Compared with the attentional bias modification and control groups, the combined intervention and aerobic exercise groups improved significantly in executive function, heart rate variability, cardiorespiratory fitness, and most secondary outcomes. In addition, high-frequency heart rate variability and cardiorespiratory fitness in the aerobic exercise group were significantly higher than those in the combined intervention group. CONCLUSIONS: Combination strategies showed comparable efficacy to aerobic exercise alone in improving executive function, psychiatric symptoms, and drug craving and significantly exceeded other conditions. For heart rate variability and cardiorespiratory fitness, aerobic exercise alone was the most effective. For acceptability and persistence, combination strategies were preferred over single-domain training and health education intervention.

A polydopamine coating enabling the stable cycling of MnO2 cathode materials in aqueous zinc batteries.

MnO2 is a desired cathode candidate for aqueous zinc batteries. However, their cycling stability is seriously limited by active material dissolution, and pre-addition of Mn2+ salts in electrolytes is widely required to shift the dissolution equilibrium. Herein, we synthesize a polydopamine (PDA) coated MnO2 composite material (MnO2/PDA) to realize stable cycling in zinc cells without relying on pre-added Mn2+. The functional groups on PDA exhibit strong coordination ability with the Mn active material. It not only confines dissolved species within the cathode during discharge, but also enhances their deposition back to the cathode during charge to retrieve the active material. Thanks to this effect, the cathode achieves 81.1% capacity retention after 2000 cycles at 1 A g-1 in the 1 M ZnSO4 electrolyte, superior to 37.3% with the regular MnO2 cathode. This work presents an effective strategy to realize the stable cycling of manganese oxide cathode materials in aqueous zinc batteries.

Hormetic effects of thiamethoxam on Schizaphis graminum: demographics and feeding behavior.

In agroecosystems, insects contend with chemical insecticides often encountered at sublethal concentrations. Insects' exposure to these mild stresses may induce hormetic effects, which has consequences for managing insect pests. In this study, we used an electrical penetration graph (EPG) technique to investigate the feeding behavior and an age-stage, two-sex life table approach to estimate the sublethal effects of thiamethoxam on greenbug, Schizaphis graminum. The LC5 and LC10 of thiamethoxam significantly decreased longevity and fecundity of directly exposed adult aphids (F0). However, the adult longevity, fecundity, and reproductive days (RPd)-indicating the number of days in which the females produce offspring - in the progeny generation (F1) exhibited significant increase when parental aphids (F0) were treated with LC5 of the active ingredient. Subsequently, key demographic parameters such as intrinsic rate of increase (r) and net reproductive rate (R0) significantly increased at LC5 treatment. EPG recordings showed that total durations of non-probing (Np), intercellular stylet pathway (C), and salivary secretion into the sieve element (E1) were significantly increased, while mean duration of probing (Pr) and total duration of phloem sap ingestion and concurrent salivation (E2) were decreased in F0 adults exposed to LC5 and LC10. Interestingly, in the F1 generation, total duration of Np was significantly decreased while total duration of E2 was increased in LC5 treatment. Taken together, our results showed that an LC5 of thiamethoxam induces intergenerational hormetic effects on the demographic parameters and feeding behavior of F1 individuals of S. graminum. These findings have important implications on chemical control against S. graminum and highlight the need for a deeper understanding of the ecological consequences of such exposures within pest management strategies across the agricultural landscapes.

The Interaction between Human Microbes and Advanced Glycation End Products: The Role of Klebsiella X15 on Advanced Glycation End Products' Degradation.

Previous studies have shown that advanced glycation end products (AGEs) are implicated in the occurrence and progression of numerous diseases, with dietary AGEs being particularly associated with intestinal disorders. In this study, methylglyoxal-beta-lactoglobulin AGEs (MGO-ß-LG AGEs) were utilized as the exclusive nitrogen source to investigate the interaction between protein-bound AGEs and human gut microbiota. The high-resolution mass spectrometry analysis of alterations in peptides containing AGEs within metabolites before and after fermentation elucidated the capacity of intestinal microorganisms to enzymatically hydrolyze long-chain AGEs into short-chain counterparts. The 16S rRNA sequencing revealed Klebsiella, Lactobacillus, Escherichia-Shigella, and other genera as dominant microbiota at different fermentation times. A total of 187 potential strains of AGE-metabolizing bacteria were isolated from the fermentation broth at various time points. Notably, one strain of Klebsiella exhibited the most robust growth capacity when AGEs served as the sole nitrogen source. Subsequently, proteomics was employed to compare the changes in protein levels of Klebsiella X15 following cultivation in unmodified proteins and proteins modified with AGEs. This analysis unveiled a remodeled amino acid and energy metabolism pathway in Klebsiella in response to AGEs, indicating that Klebsiella may possess a metabolic pathway specifically tailored to AGEs. This study found that fermenting AGEs in healthy human intestinal microbiota altered the bacterial microbiota structure, especially by increasing Klebsiella proliferation, which could be a key factor in AGEs' role in causing diseases, particularly intestinal inflammation.

Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial.

BACKGROUND: The early-onset rectal cancer with rapidly increasing incidence is considered to have distinct clinicopathological and molecular profiles with high-risk features. This leads to challenges in developing specific treatment strategies for early-onset rectal cancer patients and questions of whether early-onset locally advanced rectal cancer (LARC) needs aggressive neoadjuvant treatment. METHODS: In this post hoc analysis of FOWARC trial, we investigated the role of preoperative radiation in early-onset LARC by comparing the clinicopathological profiles and short-term and long-term outcomes between the early-onset and late-onset LARCs. RESULTS: We revealed an inter-tumor heterogeneity of clinical profiles and treatment outcomes between the early-onset and late-onset LARCs. The high-risk features were more prevalent in early-onset LARC. The neoadjuvant radiation brought less benefits of tumor response and more risk of complications in early-onset group (pCR: OR = 3.75, 95% CI = 1.37-10.27; complications: HR = 11.35, 95% CI = 1.46-88.31) compared with late-onset group (pCR: OR = 5.33, 95% CI = 1.83-15.58; complications: HR = 5.80, 95% CI = 2.32-14.49). Furthermore, the addition of radiation to neoadjuvant chemotherapy didn't improve long-term OS (HR = 1.37, 95% CI = 0.49-3.87) and DFS (HR = 1.05, 95% CI = 0.58-1.90) for early-onset patients. CONCLUSION: Preoperative radiation plus chemotherapy may not be superior to the chemotherapy alone in the early-onset LARC. Our findings provide insight into the treatment of early-onset LARC by interrogating the aggressive treatment and alternative regimens.

2'-Fucosyllactose Promotes Colonization of Akkermansia muciniphila and Prevents Colitis In Vitro and in Mice.

Akkermansia muciniphila is a potential candidate for ulcerative colitis prevention. Considering that it utilizes 2'-fucosyllactose (2'FL) for growth, 2'FL can be used to enrich the abundance of A. muciniphila in feces. However, whether the crosswalk between 2'FL and A. muciniphila can promote the intestinal colonization of A. muciniphila remains unclear. In this study, we explored the effect and the underlying mechanism of 2'FL on the colonization of A. muciniphila in vitro and in vivo as well as its alleviating effect on colitis. Our results revealed that 2'FL can serve as a carbon source of A. muciniphila to support the growth and increase cell-surface hydrophobicity and the expression of the genes coding fibronectin-binding autotransporter adhesin to promote the adhesion to Caco2/HT29 methotrexate (MTX) cells but not of galactooligosaccharides (GOS) and glucose. Moreover, 2'FL could increase the host mucin formation to promote the adhesion of A. muciniphila to Caco2/HT29 MTX cells but not of GOS and glucose. Furthermore, 2'FL could significantly increase the colonization of A. muciniphila in the gut to alleviate colitis in mice. Overall, the interplay between A. muciniphila and 2'FL is expected to provide an advantageous ecological niche for A. muciniphila so as to confer further health benefits against colitis.

Evaluation of an algorithm-guided photoplethysmography for atrial fibrillation burden using a smartwatch.

BACKGROUND: Wearable devices based on the PPG algorithm can detect atrial fibrillation (AF) effectively. However, further investigation of its application on long-term, continuous monitoring of AF burden is warranted. METHOD: The performance of a smartwatch with continuous photoplethysmography (PPG) and PPG-based algorithms for AF burden estimation was evaluated in a prospective study enrolling AF patients admitted to Beijing Anzhen Hospital for catheter ablation from September to November 2022. A continuous Electrocardiograph patch (ECG) was used as the reference device to validate algorithm performance for AF detection in 30-s intervals. RESULTS: A total of 578669 non-overlapping 30-s intervals for PPG and ECG each from 245 eligible patients were generated. An interval-level sensitivity of PPG was 96.3% (95% CI 96.2%-96.4%), and specificity was 99.5% (95% CI 99.5%-99.6%) for the estimation of AF burden. AF burden estimation by PPG was highly correlated with AF burden calculated by ECG via Pearson correlation coefficient (R2 = 0.996) with a mean difference of -0.59 (95% limits of agreement, -7.9% to 6.7%). The subgroup study showed the robust performance of the algorithm in different subgroups, including heart rate and different hours of the day. CONCLUSION: Our results showed the smartwatch with an algorithm-based PPG monitor has good accuracy and stability in continuously monitoring AF burden compared with ECG patch monitors, indicating its potential for diagnosing and managing AF.

Transcriptomic analysis of cell envelope inhibition by prodigiosin in methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading threat to public health as it is resistant to most currently available antibiotics. Prodigiosin is a secondary metabolite of microorganisms with broad-spectrum antibacterial activity. This study identified a significant antibacterial effect of prodigiosin against MRSA with a minimum inhibitory concentration as low as 2.5 mg/L. The results of scanning electron microscopy, crystal violet staining, and confocal laser scanning microscopy indicated that prodigiosin inhibited biofilm formation in S. aureus USA300, while also destroying the structure of the cell wall and cell membrane, which was confirmed by transmission electron microscopy. At a prodigiosin concentration of 1.25 mg/L, biofilm formation was inhibited by 76.24%, while 2.5 mg/L prodigiosin significantly reduced the vitality of MRSA cells in the biofilm. Furthermore, the transcriptomic results obtained at 1/8 MIC of prodigiosin indicated that 235and 387 genes of S. aureus USA300 were significantly up- and downregulated, respectively. The downregulated genes were related to two-component systems, including the transcriptional regulator LytS, quorum sensing histidine kinases SrrB, NreA and NreB, peptidoglycan biosynthesis enzymes (MurQ and GlmU), iron-sulfur cluster repair protein ScdA, microbial surface components recognizing adaptive matrix molecules, as well as the key arginine synthesis enzymes ArcC and ArgF. The upregulated genes were mainly related to cell wall biosynthesis, as well as two-component systems including vancomycin resistance-associated regulator, lipoteichoic acid biosynthesis related proteins DltD and DltB, as well as the 9 capsular polysaccharide biosynthesis proteins. This study elucidated the molecular mechanisms through which prodigiosin affects the cell envelope of MRSA from the perspectives of cell wall synthesis, cell membrane and biofilm formation, providing new potential targets for the development of antimicrobials for the treatment of MRSA.