Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

EGF-driven EGFR/miR-27b-3p/FOXO1 promotes rat FSH synthesis and secretion.

The adenopituitary secretes follicle-stimulating hormone (FSH), which plays a crucial role in regulating the growth, development, and reproductive functions of organisms. Investigating the process of FSH synthesis and secretion can offer valuable insights into potential areas of focus for reproductive research. Epidermal growth factor (EGF) is a significant paracrine/autocrine factor within the body, and studies have demonstrated its ability to stimulate FSH secretion in animals. However, the precise mechanisms that regulate this action are still poorly understood. In this research, in vivo and in vitro experiments showed that the activation of epidermal growth factor receptor (EGFR) by EGF induces the upregulation of miR-27b-3p and that miR-27b-3p targets and inhibits Foxo1 mRNA expression, resulting in increased FSH synthesis and secretion. In summary, this study elucidates the precise molecular mechanism through which EGF governs the synthesis and secretion of FSH via the EGFR/miR-27b-3p/FOXO1 pathway.

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

GnRH-driven FTO-mediated RNA m6A modification promotes gonadotropin synthesis and secretion.

BACKGROUND: Gonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear. RESULTS: Herein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion. CONCLUSIONS: Overall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction.

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Self-Assembled Integrated Nanozyme Cascade Biosensor with Dual Catalytic Activity for Portable Urease Analysis.

In this work, a novel nanozyme (Cu@Zr) with all-in-one dual enzyme and fluorescence properties is designed by simple self-assembly. A nanozyme cascade sensor with disodium phenyl phosphate (PPDS) as substrate was first established by exploiting the dual enzymatic activities of phosphatase and laccase. Specifically, phosphatase cleaves the P-O bond of PPDS to produce colorless phenol, which is then oxidized by laccase and complexed with the chromogenic agent 4-aminoantipyrine (4-AP) to produce red quinoneimine (QI). Strikingly, the NH3 produced by the urease hydrolysis of urea can interact with Cu@Zr, accelerating the electron transfer rate and ultimately leading to a significantly improved performance of the cascade reaction. Moreover, the fluorescence at 440 nm of Cu@Zr is further quenched by the inner filter effect (IFE) of QI. Thus, the colorimetric and fluorescence dual-mode strategy for sensitive urease analysis with LODs of 3.56 and 1.83 U/L was established by the proposed cascade sensor. Notably, a portable swab loaded with Cu@Zr was also prepared for in situ urease detection with the aid of a smartphone RGB readout. It also provides a potentially viable analytical avenue for environmental and biological analysis.

Intrinsic microbial temperature sensitivity and soil organic carbon decomposition in response to climate change.

Soil microbes are essential for regulating carbon stocks under climate change. However, the uncertainty surrounding how microbial temperature responses control carbon losses under warming conditions highlights a significant gap in our climate change models. To address this issue, we conducted a fine-scale analysis of soil organic carbon composition under different temperature gradients and characterized the corresponding microbial growth and physiology across various paddy soils spanning 4000 km in China. Our results showed that warming altered the composition of organic matter, resulting in a reduction in carbohydrates of approximately 0.026% to 0.030% from humid subtropical regions to humid continental regions. These changes were attributed to a decrease in the proportion of cold-preferring bacteria, leading to significant soil carbon losses. Our findings suggest that intrinsic microbial temperature sensitivity plays a crucial role in determining the rate of soil organic carbon decomposition, providing insights into the temperature limitations faced by microbial activities and their impact on soil carbon-climate feedback.

Community assembly of organisms regulates soil microbial functional potential through dual mechanisms.

Unraveling the influence of community assembly processes on soil ecosystem functioning presents a major challenge in the field of theoretical ecology, as it has received limited attention. Here, we used a series of long-term experiments spanning over 25 years to explore the assembly processes of bacterial, fungal, protist, and nematode communities using high-throughput sequencing. We characterized the soil microbial functional potential by the abundance of microbial genes associated with carbon, nitrogen, phosphorus, and sulfur cycling using GeoChip-based functional gene profiling, and determined how the assembly processes of organism groups regulate soil microbial functional potential through community diversity and network stability. Our results indicated that balanced fertilization (NPK) treatment improved the stochastic assembly of bacterial, fungal, and protist communities compared to phosphorus-deficient fertilization (NK) treatment. However, there was a nonsignificant increase in the normalized stochasticity ratio of the nematode community in response to fertilization across sites. Our findings emphasized that soil environmental factors influenced the assembly processes of the biotic community, which regulated soil microbial functional potential through dual mechanisms. One mechanism indicated that the high phosphorus levels and low soil nutrient stoichiometry may increase the stochasticity of bacterial, fungal, and protist communities and the determinism of the nematode community under NPK treatment, ultimately enhancing soil microbial functional potential by reinforcing the network stability of the biotic community. The other mechanism indicated that the low phosphorus levels and high soil nutrient stoichiometry may increase the stochastic process of the bacterial community and the determinism of the fungal, protist, and nematode communities under NK treatment, thereby enhancing soil microbial functional potential by improving the ß-diversity of the biotic community. Taken together, these results provide valuable insights into the mechanisms underlying the assembly processes of the biotic community that regulate ecosystem functioning.

Corrosion Properties and Passive Film Interface of Inconel 718 in NaNO3 Solution for Laser-Assisted Electrochemical Machining.

Laser-assisted electrochemical machining (ECM) is an ideal manufacturing method for Inconel 718 (IN718) because of the method's high efficiency and good surface quality, and the basis for and key to laser-assisted ECM is its anodic electrochemical dissolution behavior. In this study, IN718 in a 10 wt % NaNO3 solution was subjected to innovative electrochemical testing and laser-assisted ECM experiments to investigate its corrosion properties and the passive film characteristics formed on its surface. The passivation-related behaviors and structures of the passive film were investigated based on open-circuit potentials, dynamic polarization, potentiostatic polarization, and electrochemical impedance spectroscopy. It was found that there was obvious active-passive-transpassive transition behavior, and the structure of the passive film in laser-assisted ECM exhibited pores and defects, resulting in weak corrosion resistance, compared with IN718 under ECM without laser irradiation. The chemical composition of the passive film was obtained by X-ray photoelectron spectroscopy. The results showed that the passive film was composed mainly of a mixture of NiO, Ni(OH)2, Cr2O3, CrO3, Fe2O3, α-Fe2O3, α-FeOOH, Nb2O5, NbO, MoO3, MoO2, and TiO2. The passive film formed by laser-assisted ECM was rich in NiO and TiO2 and lacked Cr2O3 and MoO3, which validated its pores and defect structures. A corresponding schematic model was also proposed to characterize the interface structure between the IN718 substrate and the passive film. Laser-assisted ECM tests were performed under different current densities and machining times, and the corrosion morphology of IN718 was identified. Corrosion pits and a loose product layer appeared on the machined surface at low current densities, and the dissolution mechanism was pitting. The quantity and depth of the corrosion pits dispersed on the machined surface clearly decreased as the current density increased. Finally, a quantitative corrosion model was established to characterize the dissolution behavior of IN718 in NaNO3 solution during laser-assisted ECM.

Identification and biological characteristics of Enterococcus casseliflavus TN-47 isolated from Monochamus alternatus.

With the widespread use of antibiotics, the incidence of antibiotic resistance in microorganisms has increased. Monochamus alternatus is a trunk borer of pine trees. This study aimed to investigate the in vitro antimicrobial and biological characteristics of Enterococcus casseliflavus TN-47 (PP411196), isolated from the gastrointestinal tract of M. alternatus in Jilin Province, PR China. Among 13 isolates obtained from the insects, five were preliminarily screened for antimicrobial activity. E. casseliflavus TN-47, which exhibited the strongest antimicrobial activity, was identified. E. casseliflavus TN-47 possessed antimicrobial activity against Staphylococcus aureus USA300 and Salmonella enterica serovar Pullorum ATCC 19945. Furthermore, E. casseliflavus TN-47 was sensitive to tetracyclines, penicillins (ampicillin, carbenicillin, and piperacillin), quinolones and nitrofuran antibiotics, and resistant to certain beta-lactam antibiotics (oxacillin, cefradine and cephalexin), macrolide antibiotics, sulfonamides and aminoglycosides. E. casseliflavus TN-47 could tolerate low pH and pepsin-rich conditions in the stomach and grow in the presence of bile acids. E. casseliflavus TN-47 retained its strong auto-aggregating ability and hydrophobicity. This strain did not exhibit any haemolytic activity. These results indicate that E. casseliflavus TN-47 has potential as a probiotic. This study provides a theoretical foundation for the future applications of E. casseliflavus TN-47 and its secondary metabolites in animal nutrition and feed.

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

Single-Cell Transcriptional Profile Construction of Rat Pituitary Glands before and after Sexual Maturation and Identification of Novel Marker Spp1 in Gonadotropes.

The mammalian pituitary gland drives highly conserved physiological processes such as somatic cell growth, pubertal transformation, fertility, and metabolism by secreting a variety of hormones. Recently, single-cell transcriptomics techniques have been used in pituitary gland research. However, more studies have focused on adult pituitary gland tissues from different species or different sexes, and no research has yet resolved cellular differences in pituitary gland tissue before and after sexual maturation. Here, we identified a total of 15 cell clusters and constructed single-cell transcriptional profiles of rats before and after sexual maturation. Furthermore, focusing on the gonadotrope cluster, 106 genes were found to be differentially expressed before and after sexual maturation. It was verified that Spp1, which is specifically expressed in gonadotrope cells, could serve as a novel marker for this cell cluster and has a promotional effect on the synthesis and secretion of follicle-stimulating hormone. The results provide a new resource for further resolving the regulatory mechanism of pituitary gland development and pituitary hormone synthesis and secretion.

Targeting ferroptosis in cardio-metabolic-diseases: Mechanisms and therapeutic prospects.

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.

Coupling temperature-dependent spatial turnover of microbes and plants using the metabolic theory of ecology.

There is an urgent need to understand the coupled relationship between belowground microbes and aboveground plants in response to temperature under climate change. The metabolic theory of ecology (MTE) provides a way to predict the metabolic rate and species diversity, but the spatial scale dependence and connections between plants and microorganisms are still unclear. Here, we used two independent datasets to address this question. One is from comprehensive sampling of paddy fields targeting bacteria and microbial functional genes, and the other is a global metadata of spatial turnover for microorganisms (bacteria, fungi and archaea, n = 139) and plants (n = 206). Results showed that spatial turnover of bacterial communities and microbial functional genes increased with temperature and fitted MTE. Through meta-analysis, the temperature-dependent spatial scale pattern was further extended to the global scale, with the spatial turnover of microorganisms and plants being consistent with MTE. Belowground microorganisms and aboveground plants were closely linked with each other even when controlling for temperature, suggesting that factors other than shared relationships with temperature also contribute to their linkages. These results implied a broad application of MTE in biology and have important implications for predicting the ecological consequences of future climate warming.

Drivers of microbially and plant-derived carbon in topsoil and subsoil.

Plant- and microbially derived carbon (C) are the two major sources of soil organic matter (SOM), and their ratio impacts SOM composition, accumulation, stability, and turnover. The contributions of and the key factors defining the plant and microbial C in SOM along the soil profile are not well known. By leveraging nuclear magnetic resonance spectroscopy and biomarker analysis, we analyzed the plant and microbial C in three soil types using regional-scale sampling and combined these results with a meta-analysis. Topsoil (0-40 cm) was rich in carbohydrates and lignin (38%-50%), whereas subsoil (40-100 cm) contained more proteins and lipids (26%-60%). The proportion of plant C increases, while microbial C decreases with SOM content. The decrease rate of the ratio of the microbially derived C to plant-derived C (CM:P ) with SOM content was 23%-30% faster in the topsoil than in the subsoil in the regional study and meta-analysis. The topsoil had high potential to stabilize plant-derived C through intensive microbial transformations and microbial necromass formation. Plant C input and mean annual soil temperature were the main factors defining CM:P in topsoil, whereas the fungi-to-bacteria ratio and clay content were the main factors influencing subsoil CM:P . Combining a regional study and meta-analysis, we highlighted the contribution of plant litter to microbial necromass to organic matter up to 1-m soil depth and elucidated the main factors regulating their long-term preservation.

Comprehensive analysis of differences in N6-methyladenosine RNA methylomes in the rat adenohypophysis after GnRH treatment.

N6-methyladenosine is considered to be the most common and abundant internal chemical modification among the more than 150 identified chemical RNA modifications. It is involved in most biological processes and actively participates in the regulation of animal reproduction. However, the potential function of m6 A in the pituitaries of mammals is not yet clear. It is also unknown whether m6 A is involved in the secretion and regulation of FSH by GnRH, which in turn affects mammalian reproduction. In this study, rats were treated with gonadorelin to simulate physiological GnRH-mediated regulation of FSH synthesis and secretion, and m6 A-seq was used to analyze the differential m6 A modification of the rat pituitary after gonadorelin treatment. A whole-transcriptome map of m6 A in the rat pituitary gland before and after gonadorelin treatment was successfully created. A total of 6413 differential peaks were identified, of which 3764 m6 A peaks were upregulated and 2649 m6 A peaks were downregulated. Among the 709 differentially expressed genes, 250 genes were discovered with differential methylation modifications. Intriguingly, the altered m6 A peaks within mRNAs were enriched in steroid biosynthetic processes and responses to cAMP. The results of the study will lay a foundation for further exploration of the potential role of m6 A modification in the regulation of reproductive hormone secretion and provide a theoretical basis for the application of GnRH analogs in mammalian artificial reproduction.

Phosphorus Fertilization Boosts Mineral-Associated Soil Organic Carbon Formation Associated with Phagotrophic Protists.

Long-term fertilization affects soil organic C accumulation. A growing body of research has revealed critical roles of bacteria in soil organic C accumulation, particularly through mineral-associated organic C (MAOC) formation. Protists are essential components of soil microbiome, but the relationships between MAOC formation and protists under long-term fertilization remain unclear. Here, we used cropland soil from a long-term fertilization field trial and conducted two microcosm experiments with 13C-glucose addition to investigate the effects of N and P fertilizations on MAOC formation and the relationships with protists. The results showed that long-term fertilization (especially P fertilization) significantly (P < 0.05) increased 13C-MAOC content. Compared with P-deficient treatment, P replenishment enriched the number of protists (mainly Amoebozoa and Cercozoa) and bacteria (mainly Acidobacteriota, Bacteroidota, and Gammaproteobacteria), and significantly (P < 0.001) promoted the abundances of bacterial functional genes controlling C, N, P, and S metabolisms. The community composition of phagotrophic protists prominently (P < 0.001) correlated with the bacterial community composition, bacterial functional gene abundance, and 13C-MAOC content. Co-occurrence networks of phagotrophic protists and bacteria were more connected in soil with the N inoculum added than in soil with the NP inoculum added. P replenishment strengthened bacterial 13C assimilation (i.e., 13C-phospholipid fatty acid content), which negatively (P < 0.05) correlated with the number and relative abundance of phagotrophic Cercozoa. Together, these results suggested that P fertilization boosts MAOC formation associated with phagotrophic protists. Our study paves the way for future research to harness the potential of protists to promote belowground C accrual in agroecosystems.

Bacteria-Virus Interactions Are More Crucial in Soil Organic Carbon Storage than Iron Protection in Biochar-Amended Paddy Soils.

Iron oxides supposedly provide physicochemical protection for soil organic carbon (SOC) under anoxic conditions. Likewise, biochar can modulate the composition of soil microbial communities. However, how Fe oxides and microbial communities influence the fate of SOC with biochar amendment remains unresolved, especially the effect of the bacteria-virus interaction on SOC dynamics. Here, we performed a four-month pot experiment using rice seedlings with a biochar amendment under waterlogged conditions. Then, soil aggregate sizes were examined to explore the factors influencing the SOC patterns and the underlying mechanisms. We found that biochar altered soil enzyme activities, especially in macroaggregates. Fe oxides and necromass exhibited significant negative relationships with SOC. Bacterial communities were notably associated with viral communities. Here, the keystone ecological cluster (module 1) and keystone taxa in the bacteria-virus network showed significant negative correlations with SOC. However, Fe oxides exhibited substantial positive relationships with module 1. In contrast to the prevailing view, the SOC increase was not primarily driven by Fe oxides but strongly influenced by bacteria-virus interactions and keystone taxa. These findings indicate that biochar governs microbial-mediated SOC accumulation in paddy soil and ascertains the role of viruses in regulating the bacterial community, thus predicting SOC stock.

Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Multi-signal aptasensor for thrombin detection based on catalytically active gold nanoparticles and fluorescent silicon quantum dots.

A multi-signal aptasensor for thrombin determination is proposed based on catalytically active gold nanoparticles (AuNPs) and fluorescent silicon quantum dots (SiQDs). Yellow 4-Nitrophenol (4-NP) could be converted to colorless 4-Aminophenol (4-AP) by catalytically active aptamer-modified AuNPs (S1-AuNPs). The SiQDs emitted strong blue fluorescence at 455 nm at the excitation wavelength of 367 nm. When thrombin was absent, S1-AuNPs could catalytically reduce yellow 4-NP to colorless 4-AP. When thrombin was added, the aptamer could be transformed into a G-quadruplex structure, which masked the surface-active catalytic sites of AuNPs and restrained the reduction of 4-NP. Thus, the fluorescence of SiQDs was greatly quenched by 4-NP through the inner filter effect (IFE), and the solution color remained yellow. As the concentration of thrombin increased, the catalytic activity of S1-AuNPs decreased. The concentration of 4-NP that was converted to 4-AP declined and the unconverted 4-NP increased. In this process, the absorption peak of 4-NP at 400 nm increased while the fluorescence emission of SiQDs at 455 nm decreased. The linear ranges of the fluorometric and colorimetric aptasensor were 0.5-30 nM and 0.3-30 nM, respectively. The limits of detection (LOD) for the two modes were 0.15 nM and 0.13 nM. Furthermore, a portable sensing platform was constructed by combining the smartphone-based device with the software ImageJ for the determination of thrombin. With the advantages of cost-effectiveness, simplicity of operation and broad applicability, this aptasensor provided a new perspective for on-site determination of thrombin in the clinical field.