Clock protein LHY targets SNAT1 and negatively regulates the biosynthesis of melatonin in Hypericum perforatum.

Hypericum perforatum, also known as "natural fluoxetine," is a commonly used herbal remedy for treating depression. It is unclear whether melatonin in plants regulated by the endogenous circadian clock system is like in vertebrates. In this work, we found that the melatonin signal and melatonin biosynthesis gene, serotonin N-acetyltransferase HpSNAT1, oscillates in a 24-hour cycle in H. perforatum. First, we constructed a yeast complementary DNA library of H. perforatum and found a clock protein HpLHY that can directly bind to the HpSNAT1 promoter. Second, it was confirmed that HpLHY inhibits the expression of HpSNAT1 by targeting the Evening Element. Last, it indicated that HpLHY-overexpressing plants had reduced levels of melatonin in 12-hour light/12-hour dark cycle photoperiod, while loss-of-function mutants exhibited high levels, but this rhythm seems to disappear as well. The results revealed the regulatory role of LHY in melatonin biosynthesis, which may make an important contribution to the field of melatonin synthesis regulation.

Diversity and Activity of Soil N2O-Reducing Bacteria Shaped by Urbanization.

Nitrous oxide (N2O) is a potent greenhouse gas with various production pathways. N2O reductase (N2OR) is the primary N2O sink, but the distribution of its gene clades, typically nosZI and atypically nosZII, along urbanization gradients remains poorly understood. Here we sampled soils from forests, parks, and farmland across eight provinces in eastern China, using high-throughput sequencing to distinguish between two N2O-reducing bacteria clades. A deterministic process mainly determined assemblies of the nosZI communities. Homogeneous selection drove nosZI deterministic processes, and both homogeneous and heterogeneous selection influenced nosZII. This suggests nosZII is more sensitive to environmental changes than nosZI, with significant changes in community structure over time or space. Ecosystems with stronger anthropogenic disturbance, such as urban areas, provide diverse ecological niches for N2O-reducing bacteria (especially nosZII) to adapt to environmental fluctuations. Structural equation modeling (SEM) and correlation analyses revealed that pH significantly influences the community composition of both N2O-reducing bacteria clades. This study underscores urbanization's impact on N2O-reducing bacteria in urban soils, highlighting the importance of nosZII and survival strategies. It offers novel insights into the role of atypical denitrifiers among N2O-reducing bacteria, underscoring their potential ecological importance in mitigating N2O emissions from urban soils.

Engineered Extracellular Vesicle-Based Nanoformulations That Coordinate Neuroinflammation and Immune Homeostasis, Enhancing Parkinson's Disease Therapy.

Although conventional intervention to microglia can mitigate neuroinflammation in the short term, immune disorders by peripheral inflammatory cells can infiltrate continuously, resulting in an overactivated immune microenvironment of Parkinson's disease (PD). Here, we design engineered extracellular vesicle-based nanoformulations (EVNs) to address multiple factors for the management of PD. Specifically, EVN is developed by coating CCR2-enriched mesenchymal stem cell-derived extracellular vesicles (MSCCCR2 EVs) onto a dihydrotanshinone I-loaded nanocarrier (MSeN-DT). The MSCCCR2 EVs (the shell of EVN) can actively show homing to specific chemokines CCL2 in the substantia nigra, which enables them to block the infiltration of peripheral inflammatory cells. Interestingly, MSeN-DT (the core of EVN) can promote the Nrf2-GPX4 pathway for the suppression of the source of inflammation by inhibiting ferroptosis in microglia. In the PD model mice, a satisfactory therapeutic effect is achieved, with inhibition of peripheral inflammatory cell infiltration, precise regulation of inflammatory microglia in the substantia nigra, as well as promotion of behavioral improvement and repairing damaged neurons. In this way, the combinatorial code of alleviation of inflammation and modulation of immune homeostasis can reshape the immune microenvironment in PD, which bridges internal anti-inflammatory and external immunity. This finding reveals a comprehensive therapeutic paradigm for PD that breaks the vicious cycle of immune overactivation.

Colonization ability and uniformity of resources and environmental factors determine biological homogenization of soil protists in human land-use systems.

Humans have substantially transformed the global land surface, resulting in the decline in variation in biotic communities across scales, a phenomenon known as "biological homogenization." However, different biota are affected by biological homogenization to varying degrees, but this variation and the underlying mechanisms remain little studied, particularly in soil systems. To address this topic, we used metabarcoding to investigate the biogeography of soil protists and their prey/hosts (prokaryotes, fungi, and meso- and macrofauna) in three human land-use ecosystem types (farmlands, residential areas, and parks) and natural forest ecosystems across subtropical and temperate regions in China. Our results showed that the degree of community homogenization largely differed between taxa and functional groups of soil protists, and was strongly and positively linked to their colonization ability of human land-use systems. Removal analysis showed that the introduction of widespread, generalist taxa (OTUs, operational taxonomic units) rather than the loss of narrow-ranged, specialist OTUs was the major cause of biological homogenization. This increase in generalist OTUs seemingly alleviated the negative impact of land use on specialist taxa, but carried the risk of losing functional diversity. Finally, homogenization of prey/host biota and environmental conditions were also important drivers of biological homogenization in human land-use systems, with their importance being more pronounced in phagotrophic than parasitic and phototrophic protists. Overall, our study showed that the variation in biological homogenization strongly depends on the colonization ability of taxa in human land-use systems, but is also affected by the homogenization of resources and environmental conditions. Importantly, biological homogenization is not the major cause of the decline in the diversity of soil protists, and conservation and study efforts should target at taxa highly sensitive to local extinction, such as parasites.

Application of neutrophil-lymphocyte ratio and red blood cell distribution width in diabetes mellitus complicated with heart failure.

BACKGROUND: Accumulating clinical evidence has shown that diabetes mellitus (DM) is a serious risk factor for cardiovascular disorders and an important factor for adverse cardiovascular events. AIM: To explore the value of the combined determination of the neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in the early diagnosis and prognosis evaluation of DM complicated with heart failure (HF). METHODS: We retrospectively analyzed clinical data on 65 patients with type 2 DM (T2DM) complicated with HF (research group, Res) and 60 concurrent patients with uncomplicated T2DM (control group, Con) diagnosed at Zhejiang Provincial People's Hospital between January 2019 and December 2021. The NLR and RDW values were determined and comparatively analyzed, and their levels in T2DM + HF patients with different cardiac function grades were recorded. The receiver operating characteristic (ROC) curves were plotted to determine the NLR and RDW values (alone and in combination) for the early diagnosis of HF. The correlation between NLR and RDW with the presence or absence of cardiac events was also investigated. RESULTS: Higher NLR and RDW levels were identified in the Res vs the Con groups (P < 0.05). The NLR and RDW increased gradually and synchronously with the deterioration of cardiac function in the Res group, with marked differences in their levels among patients with grade II, III, and IV HF (P < 0.05). ROC curve analysis revealed that NLR combined with RDW detection had an area under the curve of 0.915, a sensitivity of 76.9%, and a specificity of 100% for the early diagnosis of HF. Furthermore, HF patients with cardiac events showed higher NLR and RDW values compared with HF patients without cardiac events. CONCLUSION: NLR and RDW were useful laboratory indicators for the early diagnosis of DM complicated with HF, and their joint detection was beneficial for improving diagnostic efficiency. Additionally, NLR and RDW values were directly proportional to patient outcomes.

Room temperature high-efficiency welding of an ultra-long silver nanowire network for flexible transparent electrodes.

In the preparation of flexible electronic devices, obtaining a transparent conductive electrode with high electrical conductivity, high transparency, and mechanical flexibility is a significant challenge. This study developed a simple method for preparing ultra-long silver nanowires (ul-AgNWs), obtaining high-purity ul-AgNWs with an average length of 317.66 ± 98.60 µm, an average diameter of 78.06 ± 13.87 nm, and an aspect ratio exceeding 4000. Integrating these ul-AgNWs with a polyethylene terephthalate (PET) film, a flexible transparent electrode (FTE) with Rs = 561 Ω and T = 97% was obtained. The ul-AgNWs were welded by driving the welding liquid to the intersection points through surface tension, resulting in a decrease of Rs to 61 Ω, T = 98.2%, and achieving a FTE with excellent mechanical properties. Furthermore, this FTE was applied in the preparation of OLED devices, showing a turn-on voltage of 2.7 V, and the maximum current efficiency and power efficiency reached 58.6 mA cm-2 and 64.7 lm W-1, respectively, demonstrating its significant potential in flexible optoelectronic devices.

Mendelian randomization study of inflammatory bowel disease and type 1 diabetes.

PURPOSE: Our purpose was to investigate and test the causal relationship between type 1 diabetes (T1D) and inflammatory bowel disease (IBD) and its major phenotypes, including ulcerative colitis (UC) and Crohn's disease (CD), in two large datasets. METHODS: We obtained IBD samples from the largest publicly available genome-wide association study (GWAS), as well as the FinnGen database and the publicly accessible IEU GWAS database of T1D. We employed a two-sample Mendelian randomization approach to assess bidirectional causality using the inverse variance weighting (IVW) method as the primary outcome. RESULTS: Genetic predisposition to T1D was associated with reduced risk of IBD (IVW: odds ratio (OR), 0.867; 95% confidence interval (CI), [0.852, 0.883]; P < 0.001), UC (OR = 0.879 [0.823, 0.939], P < 0.001), and CD (OR = 0.925 [0.872, 0.981], P = 0.009). The republication results found IBD genetically possessed negative association with T1D (OR = 0.781 [0.684, 0.891], P < 0.001). Additionally, a meta-analysis of results was conducted to prove the strong evidence between T1D and CD (OR = 0.95 [0.91, 0.98]; p = 0.01). CONCLUSIONS: This study first demonstrated a causal effect of TID on the reduced risk of CD in the mendelian randomization study.

Distance-decay equations of antibiotic resistance genes across freshwater reservoirs.

Distance-decay (DD) equations can discern the biogeographical pattern of organisms and genes in a better way with advanced statistical methods. Here, we developed a data Compilation, Arrangement, and Statistics framework to advance quantile regression (QR) into the generation of DD equations for antibiotic resistance genes (ARGs) across various spatial scales using freshwater reservoirs as an illustration. We found that QR is superior at explaining dissemination potential of ARGs to the traditionally used least squares regression (LSR). This is because our model is based on the 'law of limiting factors', which reduces influence of unmeasured factors that reduce the efficacy of the LSR method. DD equations generated from the 99th QR model for ARGs were 'Sall = 90.03e-0.01Dall' in water and 'Sall = 92.31e-0.011Dall' in sediment. The 99th QR model was less impacted by uneven sample sizes, resulting in a better quantification of ARGs dissemination. Within an individual reservoir, the 99th QR model demonstrated that there is no dispersal limitation of ARGs at this smaller spatial scale. The QR method not only allows for construction of robust DD equations that better display dissemination of organisms and genes across ecosystems, but also provides new insights into the biogeography exhibited by key parameters, as well as the interactions between organisms and environment.

Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis.

Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.

Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.

Study of the Rolling Effect on MoS2-Carbon Fiber Density and Its Consequences for the Functionality of Li-Ion Batteries.

In this study, an electrode slurry composed of molybdenum disulfide (MoS2) and vapor-grown carbon fiber (VGCF) prepared through a solid-phase synthesis method was blade-coated onto copper foil to form a thick film as the anode for lithium-ion batteries. In previously reported work, MoS2-based lithium-ion batteries have experienced gradual deformation, fracture, and pulverization of electrode materials during the charge and discharge cycling process. This leads to an unstable electrode structure and rapid decline in battery capacity. Furthermore, MoS2 nanosheets tend to aggregate over charge and discharge cycles, which diminishes the surface activity of the material and results in poor electrochemical performance. In this study, we altered the density of the MoS2-carbon fiber/Cu foil anode electrode by rolling. Three different densities of electrode sheets were obtained through varying rolling repetitions. Our study shows the best electrochemical performance was achieved at a material density of 2.2 g/cm3, maintaining a capacity of 427 mAh/g even after 80 cycles.

Comprehensive analysis of metal(loid)s and associated metal(loid) resistance genes in atmospheric particulate matter.

Despite global concerns about metal(loid)s in atmospheric particulate matter (PM), the presence of metal(loid) resistance genes (MRGs) in PM remains unknown. Therefore, we conducted a comprehensive investigation of the metal(loid)s and associated MRGs in PMs in two seasons (summer and winter) in Xiamen, China. According to the geoaccumulation index (Igeo), most metal(loid)s, except for V and Mn, exhibited enrichment in PM, suggesting potential anthropogenic sources. By employing Positive Matrix Factorization (PMF) model, utilizing a dataset encompassing both total and bioaccessible metal(loid)s, along with backward trajectory simulations, traffic emissions were determined to be the primary potential contributor of metal(loid)s in summer, whereas coal combustion was observed to have a dominant contribution in winter. The major contributor to the carcinogenic risk of metal(loid)s in both summer and winter was predominantly attributed to coal combustion, which serves as the main source of bioaccessible Cr. Bacterial communities within PMs showed lower diversity and network complexity in summer than in winter, with Pseudomonadales being the dominant order. Abundant MRGs, including the As(III) S-adenosylmethionine methyltransferase gene (arsM), Cu(I)-translocating P-type ATPase gene (copA), Zn(II)/Cd(II)/Pb(II)-translocating P-type ATPase gene (zntA), and Zn(II)-translocating P-type ATPase gene (ziaA), were detected within the PMs. Seasonal variations were observed for the metal(loid) concentration, bacterial community structure, and MRG abundance. The bacterial community composition and MRG abundance within PMs were primarily influenced by temperature, rather than metal(loid)s. This research offers novel perspectives on the occurrence of metal(loid)s and MRGs in PMs, thereby contributing to the control of air pollution.

Long Non-coding RNA Neat1, NLRP3 Inflammasome, and Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and is associated with high mortality. Inflammation plays a key role in the pathophysiology of AKI. Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of the inflammatory and immune response, but its role in AKI remains unclear. METHODS: We explored the role of lncRNA Neat1 in (1) a cross-sectional and a longitudinal cohort of AKI in human; (2) three murine models of septic and aseptic AKI and (3) cultured C1.1 mouse kidney tubular cells. RESULTS: In human, hospitalized patients with AKI (n=66) demonstrated significantly increased lncRNA Neat1 levels in urinary sediment cells and buffy coat versus control participants (n=152) from a primary care clinic; and among 6 kidney transplant recipients, Neat1 levels were highest immediately after transplant surgery followed by a prompt decline to normal levels in parallel with recovery of kidney function. In mice with AKI induced by sepsis (via LPS injection or cecal ligation and puncture) and renal ischemia-reperfusion, kidney tubular Neat1 was increased versus sham-operated mice. Knockdown of Neat1 in the kidney using short hairpin RNA preserved kidney function, suppressed overexpression of the AKI biomarker NGAL, leukocyte infiltration and both intrarenal and systemic inflammatory cytokines IL-6, CCL-2 and IL-1ß. In LPS-treated C1.1 cells, Neat1 was overexpressed via TLR4/NF-κB signaling, and translocated from the cell nucleus into the cytoplasm where it promoted activation of NLRP3 inflammasomes via binding with the scaffold protein Rack1. Silencing Neat1 ameliorated LPS-induced cell inflammation, whereas its overexpression upregulated IL-6 and CCL-2 expression even without LPS stimulation. CONCLUSIONS: Our findings demonstrate a pathogenic role of Neat1 induction in human and mice during AKI with alleviation of kidney injury in 3 experimental models of septic and aseptic AKI after knockdown of Neat1. LPS/TLR4-induced Neat1 overexpression in tubular epithelial cells increases the inflammatory response by binding with the scaffold protein, Rack1, to activate NLRP3 inflammasomes.

Comparison of efficacy and safety of equivalent doses of remimazolam versus propofol for gastroscopy anesthesia in elderly patients.

Remimazolam, a novel intravenous anesthetic, has been proven to be safe and efficacious in the gastroscopy setting among the elderly. However, reports comparing the effectiveness and safety of using equivalent doses of remimazolam with propofol have not been seen. The aim of this study was to compare the sedation efficacy and safety of the 95% effective doses (ED95) of remimazolam versus propofol combined with sufentanil in the gastroscopy setting among the elderly. In the first step of this two-step study, a modified up-and-down method was used to calculate the ED95 of remimazolam and propofol when combined with 0.1 µg/kg sufentanil in inhibiting body movement of elderly patients undergoing gastroscopy. In the second step, ED95 of both agents calculated in the first step were administered, endpoints of efficacy, safety, and incidence of adverse events were compared. A total of 46 individuals completed the first step. The ED95 of remimazolam was 0.163 mg/kg (95% CI 0.160-0.170 mg/kg), and that of propofol was 1.042 mg/kg (95% CI 1.007-1.112 mg/kg). In the second step, 240 patients completed the trial. The anesthetic effective rates of the remimazolam group and the propofol group were 78% and 83%, respectively, with no statistical difference (P = 0.312). Patients in the remimazolam group had more stable circulatory functions (P < 0.0001) and a lower incidence of pain on injection (3.3% vs. 19.5%, P < 0.0001). The incidence of hypotension was low in the remimazolam versus propofol group (15.6% vs. 39.0%, P < 0.0001). Overall adverse event was low in the remimazolam versus propofol group (21.3% vs. 62.7%, P < 0.0001).In this study, we found that when anesthesia was administered to elderly gastroscopy patients based on 95% effective doses of remimazolam and propofol, remimazolam was as effective as propofol, but was safer with a lower incidence of adverse events.Study registration: Chinese Clinical Trial Registry, ChiCTR2000034234. Registered 29/06/2020, https://www.chictr.org.cn .

Assembly and succession of the phyllosphere microbiome and nutrient-cycling genes during plant community development in a glacier foreland.

The phyllosphere, particularly the leaf surface of plants, harbors a diverse range of microbiomes that play a vital role in the functioning of terrestrial ecosystems. However, our understanding of microbial successions and their impact on functional genes during plant community development is limited. In this study, considering core and satellite microbial taxa, we characterized the phyllosphere microbiome and functional genes in various microhabitats (i.e., leaf litter, moss and plant leaves) across the succession of a plant community in a low-altitude glacier foreland. Our findings indicate that phyllosphere microbiomes and associated ecosystem stability increase during the succession of the plant community. The abundance of core taxa increased with plant community succession and was primarily governed by deterministic processes. In contrast, satellite taxa abundance decreased during plant community succession and was mainly governed by stochastic processes. The abundance of microbial functional genes (such as C, N, and P hydrolysis and fixation) in plant leaves generally increased during the plant community succession. However, in leaf litter and moss leaves, only a subset of functional genes (e.g., C fixation and degradation, and P mineralization) showed a tendency to increase with plant community succession. Ultimately, the community of both core and satellite taxa collaboratively influenced the characteristics of phyllosphere nutrient-cycling genes, leading to the diverse profiles and fluctuating abundance of various functional genes during plant community succession. These findings offer valuable insights into the phyllosphere microbiome and plant-microbe interactions during plant community development, advancing our understanding of the succession and functional significance of the phyllosphere microbial community.

Association between dietary inflammation index and inflammatory bowel disease in adults: Results from National Health and Nutrition Examination Survey 2009-2010.

Previous study has demonstrated that the Dietary Inflammation Index (DII) played a role in the risk of inflammatory bowel disease (IBD), however, the prevalence and risk factors for IBD are distinct across locations and groups, and therefore, the findings are debatable and warrant further investigation. A total of 4363 participants were calculated in the National Health and Nutrition Examination Survey (NHANES) 2009 to 2010, of whom 1.21% self-reported a history of IBD. DII values were performed as a good predictor of dietary inflammation based on data from two 24-h dietary reviews in the NHANES database. Comparing the multifarious effects along with variations of the whole population by grouping populations according to DII quartiles, dietary inflammation levels increased progressively from DII quartile 1(Q1) to quartile 4(Q4). The association between DII and IBD was tested with multi-variable logistic regression models, subgroup analyses and weighted generalized additive models. Participants in the Q4 group showed the highest levels of C-reactive protein and reduced haemoglobin and albumin levels. Logistic regression confirmed the odds ratios (95% confidence intervals) of IBD for DII were 0.99 (0.86, 1.15), 0.97 (0.84, 1.13) and 0.80 (0.66, 0.98) in models 1, 2 and 3, respectively. The negative correlation between DII and IBD among United States adults from the NHANES database became increasingly apparent as covariates were adjusted. Subgroup analyses and smoothed curve fitting confirmed the inverse results. The study revealed that DII was correlated with the overall physical well-being of participants. However, there was no significant association between DII and IBD.

Effect of Cinnamaldehyde on Systemic Candida albicans Infection in Mice.

OBJECTIVE: To investigate the therapeutic efficacy of cinnamaldehyde (CA) on systemic Candida albicans infection in mice and to provide supportive data for the development of novel antifungal drugs. METHODS: Ninety BALB/c mice were randomly divided into 3 groups according to a random number table: CA treatment group, fluconazole (positive control) group, and Tween saline (negative control) group, with 30 mice in each group. Initially, all groups of mice received consecutive intraperitoneal injections of cyclophosphamide at 200 mg/kg for 2 days, followed by intraperitoneal injection of 0.25 mL C. albicans fungal suspension (concentration of 1.0 × 107 CFU/mL) on the 4th day, to establish an immunosuppressed systemic Candida albicans infection animal model. Subsequently, the mice were orally administered CA, fluconazole and Tween saline, at 240, 240 mg/kg and 0.25 mL/kg respectively for 14 days. After a 48-h discontinuation of treatment, the liver, small intestine, and kidney tissues of mice were collected for fungal direct microscopic examination, culture, and histopathological examination. Additionally, renal tissues from each group of mice were collected for (1,3)- ß -D-glucan detection. The survival status of mice in all groups was monitored for 14 days of drug administration. RESULTS: The CA group exhibited a fungal clearance rate of C. albicans above 86.7% (26/30), significantly higher than the fluconazole group (60.0%, 18/30, P<0.01) and the Tween saline group (30.0%, 9/30, P<0.01). Furthermore, histopathological examination in the CA group revealed the disappearance of inflammatory cells and near-normal restoration of tissue structure. The (1,3)-ß-D-glucan detection value in the CA group (860.55 ± 126.73 pg/mL) was significantly lower than that in the fluconazole group (1985.13 ± 203.56 pg/mL, P<0.01) and the Tween saline group (5910.20 ± 320.56 pg/mL, P<0.01). The mouse survival rate reached 90.0% (27/30), higher than the fluconazole group (60.0%, 18/30) and the Tween saline group (30.0%, 9/30), with a significant difference between the two groups (both P<0.01). CONCLUSIONS: CA treatment exhibited significant therapeutic efficacy in mice with systemic C. albicans infection. Therefore, CA holds potential as a novel antifungal agent for targeted treatment of C. albicans infection.

A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated protein kinase C regulation.

Regulated hydrolysis of the phosphoinositide phosphatidylinositol(4,5)-bis-phosphate to diacylglycerol and inositol-1,4,5-P3 defines a major eukaryotic pathway for translation of extracellular cues to intracellular signaling circuits. Members of the lipid-activated protein kinase C isoenzyme family (PKCs) play central roles in this signaling circuit. One of the regulatory mechanisms employed to downregulate stimulated PKC activity is via a proteasome-dependent degradation pathway that is potentiated by peptidyl-prolyl isomerase Pin1. Here, we show that contrary to prevailing models, Pin1 does not regulate conventional PKC isoforms α and ßII via a canonical cis-trans isomerization of the peptidyl-prolyl bond. Rather, Pin1 acts as a PKC binding partner that controls PKC activity via sequestration of the C-terminal tail of the kinase. The high-resolution structure of full-length Pin1 complexed to the C-terminal tail of PKCßII reveals that a novel bivalent interaction mode underlies the non-catalytic mode of Pin1 action. Specifically, Pin1 adopts a conformation in which it uses the WW and PPIase domains to engage two conserved phosphorylated PKC motifs, the turn motif and hydrophobic motif, respectively. Hydrophobic motif is a non-canonical Pin1-interacting element. The structural information combined with the results of extensive binding studies and experiments in cultured cells suggest that non-catalytic mechanisms represent unappreciated modes of Pin1-mediated regulation of AGC kinases and other key enzymes/substrates.

CircRNA: a rising therapeutic strategy for lung injury induced by pulmonary toxicants.

Lung injury has been a serious medical problem that requires new therapeutic approaches and biomarkers. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) that exist widely in eukaryotes. CircRNAs are single-stranded RNAs that form covalently closed loops. CircRNAs are significant gene regulators that have a role in the development, progression, and therapy of lung injury by controlling transcription, translating into protein, and sponging microRNAs (miRNAs) and proteins. Although the study of circRNAs in lung injury caused by pulmonary toxicants is just beginning, several studies have revealed their expression patterns. The function that circRNAs perform in relation to pulmonary toxicants (severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2), drug abuse, PM2.5, and cigarette smoke) is the main topic of this review. A variety of circRNAs can serve as potential biomarkers of lung injury. In this review, the biogenesis, properties, and biological functions of circRNAs were concluded, and the relationship between circRNAs and pulmonary toxicants was discussed. It is expected that the new ideas and potential treatment targets that circRNAs provide would be beneficial to research into the molecular mechanisms behind lung injury.