Bioengineering and management for efficient and sustainable utilization of phosphorus in crops.

Phosphorus (P) is an essential macronutrient for plant growth, but low P availability in soils is also a primary constraint to crop production. To meet the increasing demands for food, P fertilizer applications have been increased, causing the accumulation of surplus P in soils, which has led to the frequency and magnitude of associated risk effects on agroecosystems. Finding solutions for efficient and sustainable crop P utilization is, therefore, an urgent priority. This review summarizes recent progress in bioengineering approaches to improving crop P efficiency and highlights that modifying root architecture in P-deficient soils and reducing P accumulation in grains in soils with P surplus could offer a way forward for improving P use efficiency.

Correlative Effects of Carbon Support Structures and Surface Properties on ORR Catalytic Activities of Loaded Catalysts.

As a complex three-phase heterogeneous catalyst, the oxygen reduction reaction (ORR) catalyst activity is determined by the interfacial and surface structures and chemical state of the catalyst support. As a typical biomass carbon-based support, rice husk-based porous carbon (RHPC) has natural unique hierarchical porous structures, which easily regulate the microstructure and surface properties. This study explored the correlative effects of RHPC structure and surface properties on ORR catalytic activity through the typical modification methods, namely, alkali etching, high temperature, oxidation, and ball milling. The various factors for the joint effects are defined as the specific surface area, oxygen-containing functional groups, graphite edge defects, resistivity, and contact angle. The analysis of such joint influences is difficult to quantitatively evaluate due to the large number of experimental factors and small sample sizes. Partial least-squares (PLS) can better deal with such problems. Therefore, a PLS regression model was established to evaluate the relative weight of each factor on the catalytic activity for the RHPC-based support catalysts. The results reveal that the regression coefficients of four factors yield similar magnitude for the effect of the half-wave potential (E1/2). However, graphite edge defects had a more significant impact on the limiting diffusion current density (J) and electron transfer number (n). Furthermore, an optimal support named BM-RHPC-3 was prepared with more defects and oxygen-containing functional groups, which prepared Fe-NS/BM-RHPC-3 presenting the best ORR catalytic activity (E1/2 = 0.880 V, J of 5.15 mA cm-2), superior to Pt/C (E1/2 = 0.844 V, J of 4.99 mA cm-2). The statistical regression model is validated with a relative error of less than 5% between predicted and true values for analyzing RHPC-based ORR catalysts' catalytic performance. It shows the feasibility of experiment-informed learning for data-driven material discovery and design.

ParalichenysinDY4, a novel bacteriocin-like substance, is employed to control Clostridium perfringens.

Clostridium perfringens (C. perfringens) is an important pathogen that contributes to human and animal disease. At present, antibiotic therapy is one of the most effective strategies for C. perfringens. However, with the rise of antibacterial resistance, new agents with novel mechanisms of action are urgently needed. Bacteriocins are recognized as a viable alternative to antibiotics. In this study, the bacteriocin-like substance ParalichenysinDY4, derived from the Bacillus paralicheniformis (B. paralicheniformis) DY4 strain, is investigated as a potential alternative for combating Clostridium perfringens. The substance was isolated from B. paralicheniformis DY4 fermentation broth through a series of purification steps including methanol extraction, gel filtration, and high-performance liquid chromatography. Mass spectrometry analysis of ParalichenysinDY4 revealed that the detected peptide sequences did not match any previously known bacteriocins, indicating it is a novel bacteriocin-like substance. The novel bacteriocin-like substance exhibits effective antibacterial activity and broad antimicrobial spectrum against C. perfringens. Subsequent analyses utilizing methodologies including flow cytometry and scanning electron microscopy suggest that its mechanism of action is linked to its effects on the cell membrane. At the same time, due to its exceptional stability, safety, and efficient ability to remove pathogens both in vitro and in vivo, ParalichenysinDY4 holds promise as a valuable natural antimicrobial agent.

Prevalence of and factors associated with cognitive frailty in elderly patients with chronic obstructive pulmonary disease: A cross-sectional study.

The status of cognitive frailty in elderly patients with chronic obstructive pulmonary disease (COPD) and its influencing factors in China remains unclear. This study aimed to investigate the prevalence of and factors associated with cognitive frailty in elderly patients with COPD. This cross-sectional study enrolled elderly patients with stable COPD between May and November 2022 from the Respiratory Department of the First Affiliated Hospital of Zhengzhou University and the Fifth Affiliated Hospital of Zhengzhou University. Convenience sampling method was adopted. Frailty Phenotype scale, Montreal Cognitive Assessment scale, Geriatric Depression Scale, and Clinical Dementia Rating scale were used to assess the prevalence of cognitive frailty in elderly patients with COPD. Multivariable logistic regression analysis was used to explore the associated factors. A total of 406 valid questionnaires were collected, and 173 patients (35.6%) had cognitive frailty. Binary logistic regression analysis showed that sex (odds ratio [OR] = 0.009; 95%CI: 0.001-0.770; P = .038), depression (OR = 17.780; 95%CI: 1.092-289.478; P = .043), modified Medical Research Council grade 1-3 (OR = 28.394-4095.683; 95%CI: 1.086-4,592,652.211; P < .05), global initiative for chronic obstructive lung disease grade 2 and 3 (OR = 32.508-282.072; 95%CI: 1.101-12,516.874; P < .05), and frequencies of acute exacerbations of COPD and hospitalizations within 1 year of 2 times (OR = 21.907; 95%CI: 4.587-104.622; P < .001) were independently associated with cognitive frailty. The prevalence of cognitive frailty in elderly patients with stable COPD was high. Female, depression, modified Medical Research Council grade, global initiative for chronic obstructive lung disease grade, and frequencies of acute exacerbations of COPD and hospitalizations within 1 year might be the factors independently associated with cognitive frailty, educational level might be a protective associated factor for cognitive frailty.

Theoretical study on the mechanisms, kinetics and risk assessment of OH radicals and Cl atom initiated transformation of HCFC-235fa in the atmosphere.

Hydrochlorofluorocarbons (HCFCs) are important greenhouse gases and ozone-depleting substances. Thus, a thorough understanding of their atmospheric fate is essential for preventing and controlling atmospheric pollution. Herein, the atmospheric transformation mechanism of CF3CH2CClF2 (HCFC-235fa) by the OH radical and the Cl atom was carried out at the dual-level of CCSD(T)/aug-cc-pVTZ//M06-2X/6-311+G(d,p). The reaction rate coefficients were calculated using the multistructural canonical variational transition state theory with small curvature tunneling (MS-CVT/SCT) at 200-1000 K. The kMS-CVT/SCT(CF3CH2CClF2 + OH) and kMS-CVT/SCT(CF3CH2CClF2 + Cl) values are 9.05 × 10-15 and 1.95 × 10-17 cm3 molecule-1 s-1 at 297 K, respectively. The results show that the role of OH is more important than Cl in the degradation of CF3CH2CClF2. The atmospheric lifetimes (83 days-77.93 years), ozone destruction potential (0.001-0.023), and global warming potentials (GWP100 = 21.06-5157.35) of CF3CH2CClF2 were assessed, and these results indicate that CF3CH2CClF2 is atmospherically persistent and environmentally unfriendly. The evolution mechanisms of CF3C·HCClF2, CF3C(OO˙)HCClF2, and CF3C(O˙)HCClF2 in the presence of O2, HO2˙, and NO were investigated and discussed. The resulting products of CF3CH2CClF2 are mostly highly oxidized multi-functional compounds in the forms of aldehydes, ketones, and organic nitrates. A computational assessment of acute and chronic toxicities was performed at three levels of nutrition in order to improve the understanding of the potential toxicity of CF3CH2CClF2 and its degradation products to the aquatic environment. The acidification potential of CF3CH2CClF2 was calculated to be 1.141 and presumed to contribute to the formation of acid rain. The results may contribute to describing HCFCs' atmospheric fate, persistence, and environmental risks.

Polypharmacological Drug Design Guided by Integrating Phenotypic and Restricted Fragment Docking Strategies.

Polypharmacological drugs are of great value for treating complex human diseases by the combinative modulation of several biological targets. However, multitarget drug design with more than two targets is challenging and generally discovered by serendipity. Herein, a restricted fragment docking (RFD) computational method combined with a phenotypic discovery approach was developed for rational polypharmacological drug design. Via genetic and drug combination studies in a microglial phenotype, we first identified novel synergistic effects by triple target modulation toward RIPK1, MAP4K4, and ALK. Drawing on the RFD method to explore virtual chemical spaces in three target pockets, we identified a lead compound, LP-10d, that precisely modulated RIPK1/MAP4K4/ALK for synergistic microglial protection with low nanomolar potency. LP-10d showed polypharmacology against multiple neuropathologies in the 3xTg Alzheimer's disease mouse model. Our study revealed a potential application of the RFD method, which is valuable to further polypharmacological drug discovery involved in clinical studies for treating complex human diseases.

Circ_001653 alleviates sepsis associated-acute kidney injury by recruiting BUD13 to regulate KEAP1/NRF2/HO-1 signaling pathway.

BACKGROUND: The kidney is exceptionally vulnerable during sepsis, often resulting in sepsis-associated acute kidney injury (SA-AKI), a condition that not only escalates morbidity but also significantly raises sepsis-related mortality rates. Circular RNA circ_001653 has been previously reported to be upregulated in the serum of SA-AKI patients, while the role and underlying mechanism of circ_001653 in SA-AKI remains unknown. In this study, we aimed to explore the functional role and the molecular mechanism of circ_001653 in the pathogenesis of SA-AKI. METHODS: LPS-stimulated HK-2 cells and ligation and perforation of cecum (CLP)-induced rats were used as in vitro and in vivo models of SA-AKI. The target gene expression levels were measured using qRT-PCR and western blot. Renal function (BUN, sCr, uNGAL, and uKIM-1), and renal pathological changes were detected in septic mice. TUNEL and EdU assays were conducted to measure apoptosis and proliferation rates in vitro. DCFH-DA staining was used to detect ROS levels in vitro and in vivo. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), and inflammation markers (IL-1ß, IL-6, and TNF-α) were determined using commercial kits both in vitro and in vivo. Additionally, gain-and-loss-of-function assays and mechanistic experiments were conducted to explore the regulatory role of circ_001653 in SA-AKI pathogenesis. RESULTS: Data showed that circ_001653 expression was high in LPS-stimulated HK-2 cells and CLP-induced rat renal tissue and was mainly localized in the cytoplasm. Notably, circ_001653 silencing alleviated SA-AKI by reducing apoptosis and alleviating oxidative stress and inflammation in HK-2 cells and renal tissue of rats. Mechanistically, it was found that circ_001653 alleviated SA-AKI by recruiting BUD13 to activate the KEAP1/Nrf2/HO-1 signaling pathway. CONCLUSIONS: To summarize, our study is the first to reveal elevated expression of circ_001653 in sepsis-associated AKI, and its downregulation effectively attenuates AKI by reducing apoptosis, inflammation, and oxidative stress. Mechanistically, circ_001653 exerts its effects by recruiting BUD13 to activate the KEAP1/Nrf2/HO-1 signaling pathway. These findings suggest circ_001653 as a potential therapeutic target for the drug development of sepsis-associated AKI.

Causal associations between frailty and low back pain: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Previous observational studies have revealed a potentially robust bidirectional relationship between frailty and low back pain (LBP). However, the precise causal relationship remains unclear. METHODS: To examine the potential causal association between frailty and LBP, we conducted bidirectional two-sample Mendelian randomization analysis (MR) study. Genetic data on frailty index (FI) and LBP were acquired from publicly available genome-wide association studies (GWAS). Various MR methodologies were utilized, such as inverse variance weighting (IVW), weighted median, and MR-Egger, to evaluate causality. Additionally, sensitivity analyses were conducted to evaluate the robustness of the findings. RESULTS: Genetically predicted higher FI (IVW, odds ratio [OR] = 1.66, 95% CI 1.17-2.36, p = 4.92E-03) was associated with a higher risk of LBP. As for the reverse direction, genetic liability to LBP showed consistent associations with a higher FI (IVW, OR = 1.13, 95% CI 1.07-1.19, p = 2.67E-05). The outcomes from various MR techniques and sensitivity analyses indicate the robustness of our findings. CONCLUSION: Our research findings provide additional evidence bolstering the bidirectional causal relationship between frailty and LBP.

Pumpless microfluidic sweat sensing yarn.

Textile sweat sensors possess immense potential for non-invasive health monitoring. Rapid in-situ sweat capture and prevention of its evaporation are crucial for accurate and stable real-time monitoring. Herein, we introduce a unidirectional, pump-free microfluidic sweat management system to tackle this challenge. A nanofiber sheath layer on micrometer-scale sensing filaments enables this pumpless microfluidic design. Utilizing the capillary effect of the nanofibers allows for the swift capture of sweat, while the differential configuration of the hydrophilic and hydrophobic properties of the sheath and core yarns prevents sweat evaporation. The Laplace pressure difference between the cross-scale fibers facilitates the management system to ultimately expulse sweat. This results in microfluidic control of sweat without the need for external forces, resulting in rapid (<5 s), sensitive (19.8 nA µM-1), and stable (with signal noise and drift suppression) sweat detection. This yarn sensor can be easily integrated into various fabrics, enabling the creation of health monitoring smart garments. The garments maintain good monitoring performance even after 20 washes. This work provides a solution for designing smart yarns for high-precision, stable, and non-invasive health monitoring.

Unveiling the seroprevalence of human papillomavirus in Guangdong, China: Implications for vaccination strategies.

Seroepidemiological characteristics of human papillomavirus (HPV) in community residents reflect natural infection and can guide the reform of vaccination programs. A population-based serological survey was conducted in Guangdong Province. Serum anti-HPV IgG antibody levels were determined by an ELISA. Neutralizing antibodies against HPV6, 11, 16, and 18 were detected via a pseudovirus-based neutralization assay (PBNA). A total of 5122 serum samples were collected from community residents, including 1989 males and 3133 females, in three cities of Guangdong Province. The rate of HPV IgG antibody positivity in females was 5.39% (95% CI: 4.6-6.2), which was greater than that in males (2.36%; 95% CI: 1.7-3.1). HPV IgG antibodies were more frequently detected in females aged 51-60 years (11.30%; 95% CI: 7.6-16.0), whereas in males, the detection increased with age and reached 4.94% (95% CI: 2.8-6.9) in the group aged ≥71 years. The seropositivity of neutralizing antibodies against HPV6 and 11 was greater than that against HPV16 and 18. The serum neutralizing antibody titers in individuals who received three doses of a vaccine were 7- to 12-fold greater than those in individuals who did not receive the vaccine. The neutralizing antibody titers slightly decreased within 40 months and ranged from 0.038 to 0.057 log ED50 per month. A moderate consistency between the HPV ELISA and PBNA results was observed (Kappa score = 0.49, r = 0.249, 0.635, 0.382, and 0.466 for HPV6, 11, 16, and 18, respectively). The HPV seropositivity rate among healthy residents of Guangdong Province was found to be low among children and adolescents and to increase with age. The serum neutralizing antibody titers were significantly greater in the vaccine group than that in the control group, and this difference persisted over time, which indicated promising protection against HPV infection.

Farmed fur animals harbour viruses with zoonotic spillover potential.

Animals such as raccoon dogs, mink and muskrats are farmed for fur and are sometimes used as food or medicinal products1,2, yet they are also potential reservoirs of emerging pathogens3. Here we performed single-sample metatranscriptomic sequencing of internal tissues from 461 individual fur animals that were found dead due to disease. We characterized 125 virus species, including 36 that were novel and 39 at potentially high risk of cross-species transmission, including zoonotic spillover. Notably, we identified seven species of coronaviruses, expanding their known host range, and documented the cross-species transmission of a novel canine respiratory coronavirus to raccoon dogs and of bat HKU5-like coronaviruses to mink, present at a high abundance in lung tissues. Three subtypes of influenza A virus-H1N2, H5N6 and H6N2-were detected in the lungs of guinea pig, mink and muskrat, respectively. Multiple known zoonotic viruses, such as Japanese encephalitis virus and mammalian orthoreovirus4,5, were detected in guinea pigs. Raccoon dogs and mink carried the highest number of potentially high-risk viruses, while viruses from the Coronaviridae, Paramyxoviridae and Sedoreoviridae families commonly infected multiple hosts. These data also reveal potential virus transmission between farmed animals and wild animals, and from humans to farmed animals, indicating that fur farming represents an important transmission hub for viral zoonoses.

Near-infrared and multifunctional fluorescent probe enabled by cyanopyridine cyanine dye for bisulfite recognition and biological imaging.

SO2 derivatives, sulfite/bisulfite, are widely employed in both the food processing and drug synthesis industries. Despite their widespread application, excessive levels of sulfite/bisulfite can negatively impact human health. Most probes for detecting sulfite/bisulfite are restricted by their fluorescence within the visible spectrum range and poor solubility in aqueous solution, which limit their use in food testing and biological imaging. Herein, a near-infrared probe comprising of the cyanopyridine cyanine skeleton, 4-((Z)-2-((E)-2-chloro-3-(2-cyano-2-(1-methylpyridine-4(1H)-ylidene)ethylidene)cyclohex-1-en-1-yl)-1-cyanovinyl)-1-methylpyridin-1-ium (abbreviated as CCP), was developed. This probe enables precise quantification of bisulfite (HSO3-) in almost pure buffered solutions, showing a near-infrared fluorescence emission at 784 nm with an impressively low detection limit of 0.32 µM. The probe stands out for its exceptional selectivity, minimal susceptibility to interference, and strong adaptability. The probe CCP utilizes the CC bond to trigger a near-infrared fluorescence quenching reaction with HSO3- via nucleophilic addition, which effectively disrupts the large delocalization within the molecule for accurate HSO3- identification. Moreover, the probe has been successfully applied in detecting HSO3- in various food products and living cells, simplifying the measurement of HSO3- content in water samples. This advancement not only enhances the analytical capabilities but also contributes to ensuring food safety and environmental protection. ENVIRONMENTAL IMPLICATION: SO2 derivatives including sulfite/bisulfite, serving dual roles as preservatives and antioxidants, have widespread application across various sectors including food preservation, water sanitation, and the pharmaceutical industry. Despite their widespread application, excessive levels of sulfite/bisulfite can affect human health. Developing methods for precisely and sensitively detecting sulfite/bisulfite in food products and biological samples is important for ensuring food safety and environmental protection. Here, a sensitive near-infrared and multifunctional fluorescent probe in a 99.9 % buffered solution, along with water gel encapsulation, has been successfully applied for the detection of bisulfite in food, authentic water samples, and biological cells.

Cancer immunotherapy and its facilitation by nanomedicine.

Cancer immunotherapy has sparked a wave of cancer research, driven by recent successful proof-of-concept clinical trials. However, barriers are emerging during its rapid development, including broad adverse effects, a lack of reliable biomarkers, tumor relapses, and drug resistance. Integration of nanomedicine may ameliorate current cancer immunotherapy. Ultra-large surface-to-volume ratio, extremely small size, and easy modification surface of nanoparticles enable them to selectively detect cells and kill cancer cells in vivo. Exciting synergistic applications of the two approaches have emerged in treating various cancers at the intersection of cancer immunotherapy and cancer nanomedicine, indicating the potential that the combination of these two therapeutic modalities can lead to new paradigms in the treatment of cancer. This review discusses the status of current immunotherapy and explores the possible opportunities that the nanomedicine platform can make cancer immunotherapy more powerful and precise by synergizing the two approaches.

An adaptive cycle resilience perspective to understand the regime shifts of social-ecological system interactions over the past two millennia in the Tarim River Basin.

Socio-ecological systems (SESs) in arid regions have experienced multiple transformations throughout history due to human activities and natural forces. However, few studies have used the resilience cycle model to explain the resilience status and determinants of SESs over the past two millennia. This study proposes the adaptive cycle resilience (ACR) perspective to investigate regime shifts of socio-ecological system interactions in the Tarim River Basin (TRB) over the past two millennia. An ACR framework combining a piecewise linear regression model (PLR), ACR theory, and physical resilience models has been built to assess and quantify socio-ecological system resilience. Key indicators such as climate variability, settlement numbers, war frequency, glacier accumulation, and oasis area changes are identified and quantified to evaluate SESs adaptability and transformability. Glacier accumulation serves as a proxy for long-term climate change, while oasis area changes reflect the direct impact of human activities and environmental feedback on ecosystem productivity. Population and war indicators provide insights into social system stability and the impact of conflicts on SESs dynamics. The findings reveal that the 7th century and 1850s are critical points of regime shifts in the ACR. 200s BC-350s AD and 700s AD-900s AD are in the forward loop (r-K) period of the ACR. 350s AD-700s AD and 900s AD-1850s AD are the adaptive resilience backward loop (Ω-α) phase. Assessing the historical socio-ecological system resilience and identifying key transition points can inform proactive measures to mitigate potential regime shifts. Combining historical data with resilience theory provides a deep understanding of the ACR of SESs and their driving factors. This enriches the theoretical understanding of SESs and offers a robust case study for future resilience assessments and scenario analyses in arid regions.

Resuscitation Promotion Factor: A Pronounced Bacterial Cytokine in Propelling Bacterial Resuscitation.

While confronted with unfavorable growth conditions, bacteria may transform into the dormant state, such as viable but nonculturable (VBNC) state, which is a reversible state characterized by low metabolic activity and lack of division. These dormant cells can be reactivated through the influence of the resuscitation promoting factor (Rpf) family, which are classified as autocrine growth factors and possess peptidoglycan hydrolase activities. To date, with the significant resuscitation or growth promotion ability of Rpf, it has been extensively applied to increasing bacterial diversity and isolating functional microbial species. This review provides a comprehensive analysis of the distribution, mode of action, and functional mechanisms of Rpf proteins in various bacterial species. The aim is to create opportunities for decoding microbial communities and extracting microbial resources from real samples across different research fields.

How Identity Impacts Bystander Responses to Workplace Mistreatment.

Integrating a social identity approach with Cortina's (2008) theorizing about selective incivility as modern discrimination, we examine how identification-with an organization, with one's gender, and as a feminist-shapes bystanders' interpretations and responses to witnessed incivility (i.e., interpersonal acts of disrespect) and selective incivility (i.e., incivility motivated by targets' social group membership) toward women at work. We propose that bystanders with stronger organizational identification are less likely to perceive incivility toward female colleagues as discrimination and intervene, but female bystanders with stronger gender identification are more likely to do so. Results from two-wave field data in a cross-lagged panel design (Study 1, N = 336) showed that organizational identification negatively predicted observed selective incivility 1 year later but revealed no evidence of an effect of female bystanders' gender identification. We replicated and extended these results with a vignette experiment (Study 2, N = 410) and an experimental recall study (Study 3, N = 504). Findings revealed a "dark side" of organizational identification: strongly identified bystanders were less likely to perceive incivility as discrimination, but there were again no effects of women's gender identification. Study 3 also showed that bystander feminist identification increased intervention via perceived discrimination. These results raise doubts that female bystanders are more sensitive to recognizing other women's mistreatment as discrimination, but more strongly identified feminists (male or female) were more likely to intervene. Although strongly organizationally identified bystanders were more likely to overlook women's mistreatment, they were also more likely to intervene once discrimination was apparent.

Role of Lactobacillus plantarum-Derived Extracellular Vesicles in Regulating Alcohol Consumption.

Alcohol Use Disorder (AUD), characterized by repeated alcohol consumption and withdrawal symptoms, poses a significant public health issue. Alcohol-induced impairment of the intestinal barrier results in alterations in intestinal permeability and the composition of the intestinal microbiota. Such alterations lead to a reduced relative abundance of intestinal lactic acid bacteria. However, the role of gut microbiota in alcohol consumption is not yet fully understood. In this study, we explore the mechanism by which gut microbiota regulates alcohol consumption, specifically using extracellular vesicles derived from Lactobacillus plantarum (L-EVs). L-EVs were administered to Sprague-Dawley rats either through intraperitoneal injection or microinjection into the ventral tegmental area (VTA), resulting in a significant reduction in alcohol consumption 72 hours after withdrawal. The observed reduction was akin to the effect of an intra-VTA microinjection of Brain-Derived Neurotrophic Factor (BDNF). Intriguingly, the microinjection of K252a (a Trk B antagonist) into the VTA blocked the reducing effect of L-EVs on alcohol consumption. The intraperitoneal injection of L-EVs restored the diminished BDNF expression in the VTA of alcohol-dependent rats. Furthermore, L-EVs rescued the low BDNF expression in alcohol-incubated PC12 cells. In conclusion, our study demonstrates that L-EVs attenuated alcohol consumption by enhancing BDNF expression in alcohol-dependent rats, thus suggesting the significant therapeutic potential of L-EVs in preventing excessive alcohol consumption.

Interplay between gut microbiota and tryptophan metabolism in type 2 diabetic mice treated with metformin.

Tryptophan (TRP) metabolites have been identified as potent biomarkers for complications of type 2 diabetes mellitus (T2DM). However, it remains unclear whether the therapeutic effect of metformin in T2DM is related to the modulation of TRP metabolic pathway. This study aims to investigate whether metformin affects TRP metabolism in T2DM mice through the gut microbiota. A liquid chromatography-tandem mass spectrometry method was established to determine 16 TRP metabolites in the serum, colon content, urine, and feces of T2DM mice, and the correlations between metabolites and the T2DM mice gut microbiota were performed. The method demonstrated acceptable linearity (R2 > 0.996), with the limit of quantification ranging from 0.29 to 69.444 nmol/L for 16 analytes, and the limit of detection ranging from 0.087 to 20.833 nmol/L. In T2DM mice, metformin treatment effectively restored levels of indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), and the ILA/IPA ratio, along with several aryl hydrocarbon receptor ligands in the serum, with a notable impact in the colon but not in the urine. This restoration was accompanied by a shift in the relative abundance of Dubosiella, Turicibacter, RF39, Clostridia_UCG-014, and Alistipes. Spearman's correlation analysis revealed positive correlations between Turicibacter and Alistipes with IPA and indole-3-acetic acid. Conversely, these genera displayed negative correlations with ILA and kynurenine. In addition, our study revealed the presence of endogenous indole pathway in germ-free mice, and the impact of metformin on endogenous TRP metabolism in T2DM mice cannot be disregarded. Further research is needed to investigate the regulation of TRP metabolism by metformin. IMPORTANCE: This study provides valuable insights into the interrelationship between metformin administration, changes in the tryptophan (TRP) metabolome, and gut microbiota in type 2 diabetes mellitus (T2DM) mice. Indole-3-lactic acid (ILA)/indole-3-propionic acid (IPA) emerges as a potential biomarker for the development of T2DM and prediction of therapeutic response. While the indole metabolic pathway has long been associated exclusively with the gut microbiome, recent research has demonstrated the ability of host interleukin-4-induced-1 to metabolize TRP. The detection of indole derivatives in the serum of germ-free mice suggests the existence of inherent endogenous indole metabolic pathways. These findings deepen our understanding of metformin's efficacy in correcting TRP metabolic disorders and provide valuable directions for further investigation. Moreover, this knowledge may pave the way for the development of targeted treatment strategies for T2DM, focusing on the gut microbiome and restoration of associated TRP metabolism.

ADAM8 deficiency in macrophages promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway.

INTRODUCTION: A disintegrin and metalloproteinase 8 (ADAM8), a crucial regulator in macrophages, is closely associated with cardiovascular disease progression. OBJECTIVES: This study aimed to explore how ADAM8 regulates macrophage function to inhibit cardiac repair after myocardial infarction (MI). METHODS: Macrophage-specific ADAM8 knockout mice (ADAM8flox/flox, Lyz2-Cre, KO) and corresponding control mice (ADAM8flox/flox, Flox) were established using the CRISPR/Cas9 system. Bone marrow transplantation was performed, and macrophage-specific ADAM8-overexpressing adeno-associated virus (AAV6-CD68-Adam8) was produced. Finally, proteomics, RNA sequencing, and co-immunoprecipitation/mass spectrometry (COIP/MS) were used to explore the underlying mechanisms involved. RESULTS: ADAM8 was highly expressed in the plasma of patients with acute myocardial infarction (AMI) and in cardiac macrophages derived from AMI mice. ADAM8 KO mice exhibited enhanced angiogenesis, suppressed inflammation, reduced cardiac fibrosis, and improved cardiac function during AMI, which were reversed by overexpressing macrophage-specific ADAM8 and intervention with the clinical anti-angiogenic biologic bevacizumab. Bone marrow transplantation experiments produced ADAM8 KO phenotypes. RNA sequencing showed that autophagy was activated in bone marrow-derived macrophages (BMDMs) with ADAM8 KO, which was confirmed via p-mTOR Ser2448/mTOR, p62, and LC3II/I detection. Autophagy inactivation suppressed angiogenic factor release and promoted inflammation in BMDMs with ADAM8 KO. Mechanistically, ADAM8 could bind to ANXA2 and promote phosphorylation of the ANXA2 Ser26 site. ADAM8 KO impeded ANXA2 phosphorylation, inhibited mTOR Ser2448 site phosphorylation, and activated autophagy, which were demonstrated using the activation or inactivation of ANXA2 phosphorylation. CONCLUSIONS: ADAM8 was increased in cardiac macrophages after AMI. The ADAM8-ANXA2-mTOR-autophagy axis in macrophages is responsible for regulating angiogenesis and inflammation following MI. Thus, ADAM8 may be a new target in MI treatment.

Aptamer-Loop DNA Nanoflower Recognition and Multicolor Fluorescent Carbon Quantum Dots Labeling System for Multitarget Living Cell Imaging.

Visualization of multiple targets in living cells is important for understanding complex biological processes, but it still faces difficulties, such as complex operation, difficulty in multiplexing, and expensive equipment. Here, we developed a nanoplatform integrating a nucleic acid aptamer and DNA nanotechnology for living cell imaging. Aptamer-based recognition probes (RPs) were synthesized through rolling circle amplification, which were further self-assembled into DNA nanoflowers encapsulated by an aptamer loop. The signal probes (SPs) were obtained by conjugation of multicolor emission carbon quantum dots with oligonucleotides complementary to RPs. Through base pairing, RPs and SPs were hybridized to generate aptamer sgc8-, AS1411-, and Apt-based imaging systems. They were used for individual/simultaneous imaging of cellular membrane protein PTK7, nucleolin, and adenosine triphosphate (ATP) molecules. Fluorescence imaging and intensity analysis showed that the living cell imaging system can not only specifically recognize and efficiently bind their respective targets but also provide a 5-10-fold signal amplification. Cell-cycle-dependent distribution of nucleolin and concentration-dependent fluorescence intensity of ATP demonstrated the utility of the system for tracking changes in cellular status. Overall, this system shows the potential to be a simple, low-cost, highly selective, and sensitive living cell imaging platform.