Impacts of rapidly urbanizing watershed comprehensive management on per- and polyfluoroalkyl substances pollution: Based on PFAS "diversity" assessment.

The impact of watershed comprehensive management (WCM) on per- and polyfluoroalkyl substances (PFAS) pollution in rapidly urbanizing areas remains unclear. In a typical rapidly urbanizing watershed of Shenzhen, China, we investigated temporal variations in contamination level, primary source and ecological risk of 50 emerging and legacy PFAS, as well as the replacement trends of emerging PFAS before and after WCM during a six-year sampling campaign. We found that large-scale dredging was a non-negligible factor in abnormally increased PFAS concentrations (6.43 %-456.16 %) during WCM through their release from river sediments. To better characterize the diverse and complex PFAS contamination, a novel pollution assessment method, PFAS "diversity", was adopted based on a modified Shannon-Weiner diversity index and Pielou evenness index, reflecting numbers of PFAS detected and how evenly each PFAS contributed to the total PFAS concentrations at specific sampling sites. Importantly, we found that the Pielou evenness index can indicate and quantify abnormal pollution sources (especially point sources) along the river. The results revealed that WCM did not effectively reduce total PFAS concentrations and diversity in the rapidly urbanizing watershed but obviously improved point source pollution. Furthermore, 6:2 polyfluorinated phosphate diesters and hexafluoropropylene oxide dimer acid (GenX) that posed high ecological risks emerged and the number of sampling sites with high risk increased from 16 to 20 after WCM. Finally, we summarize several important issues related to PFAS contamination during WCM and propose specific countermeasures, such as adopting environmental dredging and reducing the proportion of ecological water replenished by wastewater treatment plant effluent for better control of PFAS pollution. Our study highlighted the limited effectiveness of WCM in mitigating PFAS pollution and the importance of emerging contaminant regulation in rapidly urbanizing watersheds during WCM.

Dissection of molecular mechanisms of liver injury induced by microcystin-leucine arginine via single-cell RNA-sequencing.

The occurrence of poisoning incidents caused by cyanobacterial blooms has aroused wide public concern. Microcystin-leucine arginine (MC-LR) is a well-established toxin produced by cyanobacterial blooms, which is widely distributed in eutrophic waters. MC-LR is not only hazardous to the water environment but also exerts multiple toxic effects including liver toxicity in both humans and animals. However, the underlying mechanisms of MC-LR-induced liver toxicity are unclear. Herein, we used advanced single-cell RNA sequencing technology to characterize MC-LR-induced liver injury in mice. We established the first single-cell atlas of mouse livers in response to MC-LR. Our results showed that the differentially expressed genes and pathways in diverse cell types of liver tissues of mice treated with MC-LR are highly heterogeneous. Deep analysis showed that MC-LR induced an increase in a subpopulation of hepatocytes that highly express Gstm3, which potentially contributed to hepatocyte apoptosis in response to MC-LR. Moreover, MC-LR increased the proportion and multiple subtypes of Kupffer cells with M1 phenotypes and highly expressed proinflammatory genes. Furthermore, the MC-LR increased several subtypes of CD8+ T cells with highly expressed multiple cytokines and chemokines. Overall, apart from directly inducing hepatocytes apoptosis, MC-LR activated proinflammatory Kupffer cell and CD8+ T cells, and their interaction may constitute a hostile microenvironment that contributes to liver injury. Our findings not only present novel insight into underlying molecular mechanisms but also provide a valuable resource and foundation for additional discovery of MC-LR-induced liver toxicity.

LNCHC directly binds and regulates YBX1 stability to ameliorate metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non-coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. METHODS: RNA-binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y-Box binding protein 1 (YBX1) were identified by RNA-seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin-like phospholipase domain containing 3 (PNPLA3) in MASLD progression. RESULTS: Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up-regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction-associated steatohepatitis development. CONCLUSIONS: In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment.

[Construction of a mouse model of type 2 diabetes induced by high fat diet alone and evaluation of pathological changes].

The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus (T2DM) mouse model induced by high fat diet (HFD) alone and the effects of HFD on the pathology and function of organs related to glucose and lipid metabolism. C57BL/6 mice were fed with normal diet (NC group) or HFD (HFD group). The time of successful T2DM modeling was evaluated by measuring body weight, fasting blood glucose and glucose tolerance at time points of 0, 4, 8, 12, 16 and 20 weeks. The functional and pathological changes of glucose and lipid metabolism related organs were evaluated by detecting insulin tolerance, plasma lipid levels, vascular function, as well as HE staining of pancreas and liver. The results showed that compared with the NC group, the HFD group had significantly increased body weight after 8 weeks of HFD. After 16 weeks of HFD, the HFD group exhibited impaired fasting glucose tolerance. After 20 weeks of HFD, the HFD group mice reached diabetic state, showing impaired glucose tolerance and insulin resistance, islet volume reduction and vacuolar degeneration; Large number of lipid droplets appeared in liver cells, and the level of AMPK phosphorylation in liver tissue was significantly increased in the HFD groups, compared with the NC group; There was endothelial dependent diastolic dysfunction in the thoracic aorta of the HFD group; Compared with the NC group, the HFD group mice showed a significant increase in urinary protein levels. These results suggest that T2DM mouse model can be successfully established by HFD induction alone for 20 weeks. The model is characterized by insulin resistance, fatty liver, hyperlipidemia, vascular dysfunction, renal dysfunction and pathological changes of islet and liver cells, which are similar to those of T2DM patients. Therefore it can be used as an ideal animal model for T2DM research.

The Effects of Locus Coeruleus Optogenetic Stimulation on Global Spatiotemporal Patterns in Rats.

Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. These results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting.

Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease.

BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

seco-iridoid glycosides and flavonoid glycosides from the Gentiana olivieri Griseb and their anti-inflammatory activities.

Three undescribed seco-iridoid glycosides, one undescribed flavonoid glycoside, and three known glycosides were isolated and identified from Gentiana olivieri Griseb. The structures of these compounds were determined through spectroscopic analysis and ECD calculations. Olivierisecosides NP (1-3) were identified as aromatic conjugated seco-iridoid glucosides, among them olivierisecoside N was representing a particularly rare subtype known as the morroniside seco-iridoids. The compounds 2, 3, 5, and 6 exhibited significant inhibition of COX-2 expression, particularly compound 5 which demonstrated the most pronounced inhibitory activity with IC50 value of 23.33 ± 0.51 µM. This study provides evidence for the potential development and utilization of G. olivieri as a source of anti-inflammatory components.

Evolutionary divergence of CXE gene family in green plants unveils PtoCXEs overexpression reduces fungal colonization in transgenic Populus.

Plant enzymes significantly contribute to the rapidly diversified metabolic repertoire since the colonization of land by plants. Carboxylesterase (CXE) is just one of the ubiquitous, multi-functional, and ancient enzymes, that has particularly diversified during plant evolution. This study provided a status on the CXE landscape within Viridiplantae. A total of 784 CXEs were identified from the genome of 31 plant species representing 9 major lineages of sequenced Viridiplantae, and divided into five clades based on phylogenetic analysis. Clade I CXE genes may be of bacterial origin, and then expanded and diversified during plant evolution. Clade II was first gained in the ancestor of bryophytes after colonization of land by plants, Clade III and Clade IV in ferns which were considered the most advanced seedless vascular plants, while Clade V in seed plants. To date, the functions of CXE genes in woody plants remain unclear. In this study, 51 CXE genes were identified from the genome of Populus trichocarpa and further divided into eight classes. Tandem and segmental duplication events both contributed to the expansion of CXE genes in Populus. Although CXE genes were proven to enhance resistance to pathogens in many herbaceous species, relevant researches on forest trees are still needed. In this study, pathogen incubation assays showed that overexpressing of six Class VI CXEs in Populus tomentosa, to a greater or lesser degree, reduced colonization of detached leaves by fungus Cytospora chrysosperma. A significant difference was also found in functional divergence patterns for genes derived from different gene duplication events. Functional differentiation of duplicated CXE genes in Populus was proved for the first time by in vivo physiological analysis. The identification of the potentially anti-fungal PtoCXE06 gene also laid a theoretical foundation for promoting the genetic improvement of disease-resistance traits in forest trees.

Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist ß-amyloid peptides (Aß) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Cr(VI) removal during cotransport of nano-iron-particles combined with iron sulfides in groundwater: Effects of D. vulgaris and S. putrefaciens.

Iron-based materials such as nanoscale zerovalent iron (nZVI) are effective candidates to in situ remediate hexachromium (Cr(VI))-contaminated groundwater. The anaerobic bacteria could influence the remediation efficiency of Cr(VI) during its cotransport with nZVI in porous media. To address this issue, the present study investigated the adsorption and reduction of Cr(VI) during its cotransport with green tea (GT) modified nZVI (nZVI@GT) and iron sulfides (FeS and FeS2) in the presence of D. vulgaris or S. putrefaciens in water-saturated sand columns. Experimental results showed that the nZVI@GT preferred to heteroaggregate with FeS2 rather than FeS, forming nZVI@GT-FeS2 heteroaggregates. Although the presence of D. vulgaris further induced nZVI@GT-FeS2 heteroaggregates to form larger clusters, it pronouncedly improved the dissolution of FeS and FeS2 for more Cr(VI) reduction associated with lower Cr(VI) flux through sand. In contrast, S. putrefaciens could promote the dispersion of the heteroaggregates of nZVI@GT-FeS2 and the homoaggregates of nZVI@GT or FeS by adsorption on the extracellular polymeric substances, leading to the improved transport of Fe-based materials for a much higher Cr(VI) immobilization in sand media. Overall, our study provides the essential perspectives into a chem-biological remediation technique through the synergistic removal of Cr(VI) by nZVI@GT and FeS in contaminated groundwater. ENVIRONMENTAL IMPLICATION: The green-synthesized nano-zero-valent iron particles (nZVI@GT) using plant extracts (or iron sulfides) have been used for in situ remediation of Cr(VI) contaminated groundwater. Nevertheless, the removal of Cr(VI) (including Cr(VI) adsorption and Cr(III) generation) could be influenced by the anaerobic bacteria governing the transport of engineered nanoparticles in groundwater. This study aims to reveal the inherent mechanisms of D. vulgaris and S. putrefaciens governing the cotransport of nZVI@GT combined with FeS (or FeS2) to further influence the Cr(VI) removal in simulated complex groundwater media. Our findings provides a chemical and biological synergistic remediation strategy for nZVI@GT application in Cr(VI)-contaminated groundwater.

Variation in the Distribution of Large-scale Spatiotemporal Patterns of Activity Across Brain States.

A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

Incremental value of myocardial global longitudinal strain in predicting major adverse cardiac events among patients with hypertrophic cardiomyopathy.

OBJECTIVES: Endocardial global longitudinal strain (endo-GLS) measured with echocardiography (echo) has been demonstrated to be associated with myocardial fibrosis (MF) and is a prognostic predictor in patients with hypertrophic cardiomyopathy (HCM). Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging showed that MF is primarily located in the myocardial layer of the extremely hypertrophic septal or ventricular wall. We hypothesized that GLS of the myocardial layer (myo-GLS) is more strongly correlated with the extent of LGE (%LGE) and is a more powerful prognostic factor than endo-GLS. METHODS: A total of 177 inpatients (54.0 [IQR: 43.0, 64.0] years, female 37.3%) with HCM were retrospectively included from May 2019 to April 2021. Among them, 162 patients underwent echocardiographic examination and contrast-enhanced CMR within 7 days. Myo-GLS and %LGE were blindly assessed in a core laboratory. All the patients were followed after they were discharged. RESULTS: During a mean follow-up of 33.77 [IQR 30.05, 35.40] months, 14 participants (7.91%) experienced major adverse cardiac events (MACE). The MACE (+) group showed lower absolute endo-GLS and myo-GLS than the MACE (-) group. Myo-GLS was more associated with %LGE (r = -.68, P < .001) than endo-GLS (r = -.64, P < .001). Cox multivariable analysis indicated that absolute myo-GLS was independently associated with MACE (adjusted hazard ratio = .75, P < .05). Myo-GLS was better than endo-GLS at detecting MACE (+) patients (-8.64%, AUC .939 vs. - 16.375%, AUC .898, P < .05). CONCLUSIONS: Myo-GLS is a stronger predictor of MACE than endo-GLS in patients with HCM and is highly correlated with %LGE.

PrCRS: a prediction model of severe CRS in CAR-T therapy based on transfer learning.

BACKGROUND: CAR-T cell therapy represents a novel approach for the treatment of hematologic malignancies and solid tumors. However, its implementation is accompanied by the emergence of potentially life-threatening adverse events known as cytokine release syndrome (CRS). Given the escalating number of patients undergoing CAR-T therapy, there is an urgent need to develop predictive models for severe CRS occurrence to prevent it in advance. Currently, all existing models are based on decision trees whose accuracy is far from meeting our expectations, and there is a lack of deep learning models to predict the occurrence of severe CRS more accurately. RESULTS: We propose PrCRS, a deep learning prediction model based on U-net and Transformer. Given the limited data available for CAR-T patients, we employ transfer learning using data from COVID-19 patients. The comprehensive evaluation demonstrates the superiority of the PrCRS model over other state-of-the-art methods for predicting CRS occurrence. We propose six models to forecast the probability of severe CRS for patients with one, two, and three days in advance. Additionally, we present a strategy to convert the model's output into actual probabilities of severe CRS and provide corresponding predictions. CONCLUSIONS: Based on our findings, PrCRS effectively predicts both the likelihood and timing of severe CRS in patients, thereby facilitating expedited and precise patient assessment, thus making a significant contribution to medical research. There is little research on applying deep learning algorithms to predict CRS, and our study fills this gap. This makes our research more novel and significant. Our code is publicly available at https://github.com/wzy38828201/PrCRS . The website of our prediction platform is: http://prediction.unicar-therapy.com/index-en.html .

Towards elevated perfluorooctanoic acid (PFOA) enrichment in water: Sequential liquid-liquid extraction pretreatment for ion chromatography detection.

The widespread detection of perfluorooctanoic acid (PFOA) in the environment has raised significant concerns. The standard PFOA analytical method relies on expensive solid-phase extraction (SPE) and liquid chromatography tandem mass spectrometry (LC-MS/MS) instruments, making routine use prohibitive. We herein proposed a cost-effective yet novel enrichment method for determining PFOA at ng L-1 level. This method entailed a two-step sample preparation process: firstly, PFOA was extracted and enriched using a forward-extraction under acidic conditions, followed by a backward-extraction and enrichment step utilizing alkaline water. The enriched samples were subsequently subjected to a common ion chromatography (IC). Results reveal that maintaining a forward-extraction pH below its pKa value (2.8) is essential, as protonated PFOA proves effective in enhancing the enrichment factor (EF). The challenge lied in driving PFOA from forward-extractant to aqueous backward-extractant due to the decreased hydrophobicity of deprotonated PFOA (log Kow2 = 1.0). In addition, we found that evaporating forward-extractant with alkaline backward-extractant (containing 5% methanol) reduced potential analytical uncertainties associated with PFOA evaporation and sorption. Under optimal conditions, the method achieved a detection limit of 9.2 ng L-1 and an impressive EF value of 719. Comparison with SPE-LC-MS/MS confirmed the proposed method as a promising alternative for PFOA determination. Although initially targeted for PFOA, the novel methodology is likely applicable to preconcentration of other poly-fluoroalkyl substances.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Characterization of a polysaccharide from Amauroderma rugosum and its proangiogenic activities in vitro and in vivo.

Amauroderma rugosum (AR), also known as "Blood Lingzhi" in Chinese, is a basidiomycete belonging to the Ganodermataceae family. Four polysaccharide fractions were systematically isolated and purified from AR. Subsequently, their compositions were examined and analyzed via high-performance gel permeation chromatography (HPGPC), analysis of the monosaccharide composition, Fourier-transform infrared spectroscopy (FT-IR), and 1H nuclear magnetic resonance (NMR). The zebrafish model was then used to screen for proangiogenic activities of polysaccharides by inducing vascular insufficiency with VEGF receptor tyrosine kinase inhibitor II (VRI). The third fraction of AR polysaccharides (PAR-3) demonstrated the most pronounced proangiogenic effects, effectively ameliorating VRI-induced intersegmental vessel deficiency in zebrafish. Concurrently, the mRNA expression levels of vascular endothelial growth factor (VEGF)-A and VEGF receptors were upregulated by PAR-3. Moreover, the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) were also stimulated by PAR-3, consistently demonstrating that PAR-3 possesses favorable proangiogenic properties. The activation of the Akt, ERK1/2, p38 MAPK, and FAK was most likely the underlying mechanism. In conclusion, this study establishes that PAR-3 isolated from Amauroderma rugosum exhibits potential as a bioresource for promoting angiogenesis.

Neutrophil and macrophage crosstalk might be a potential target for liver regeneration.

The regenerative capability of the liver is remarkable, but further research is required to understand the role that neutrophils play in this process. In the present study, we reanalyzed single-cell RNA sequencing data from a mouse partial hepatectomy (PH) model to track the transcriptional changes in hepatocytes and non-parenchymal cells. Notably, we unraveled the regenerative capacity of hepatocytes at diverse temporal points after PH, unveiling the contributions of three distinct zones in the liver regeneration process. In addition, we observed that the depletion of neutrophils reduced the survival and liver volume after PH, confirming the important role of neutrophils in liver regeneration. CellChat analysis revealed an intricate crosstalk between neutrophils and macrophages promoting liver regeneration and, using weighted gene correlation network analysis, we identified the most significant genetic module associated with liver regeneration. Our study found that hepatocytes in the periportal zone of the liver are more active than in other zones, suggesting that the crosstalk between neutrophils and macrophages might be a potential target for liver regeneration treatment.

Correction: Lonicera japonica Thunb. as a promising antibacterial agent for Bacillus cereus ATCC14579 based on network pharmacology, metabolomics, and in vitro experiments.

[This corrects the article DOI: 10.1039/D3RA00802A.].

A nomogram based on contrast-enhanced ultrasound for evaluating the glomerulosclerosis rate in transplanted kidneys.

Background: A high rate of glomerulosclerosis serves as an important signal of poor response to treatment and a high risk of disease progression or adverse prognosis in transplanted kidneys. We hypothesized that contrast-enhanced ultrasound (CEUS) could serve as a novel imaging biomarker in the early prediction of glomerulosclerosis rate by evaluating renal allograft microcirculation. Methods: A retrospective analysis was performed on 143 transplanted kidney recipients with confirmed pathology, including 100 in the training group and 43 in the validation group. All patients underwent conventional ultrasound (CUS) and CEUS examinations. The patients were divided into two groups: those with >50% glomerulosclerosis and those with ≤50% glomerulosclerosis. The nomograms derived from independent predictors identified by multivariate logistic analysis were assessed using receiver operating characteristic (ROC) curve analysis, 1,000 bootstrap resamples, calibration curves, and decision curve analysis (DCA). Results: The patients with >50% glomerulosclerosis and those with ≤50% glomerulosclerosis showed statistically significant differences in CEUS parameters, including in peak intensity (PI) (25 vs. 30; P<0.001), absolute time to peak (ATTP) (10 vs. 9; P=0.004), and time to peak (TTP) (22 vs. 19.5; P=0.026). Multivariate analysis revealed that PI [odds ratio (OR) =0.852; 95% confidence interval (CI): 0.737-0.986], peak systolic velocity (PSV) of the interlobar artery (OR =0.850; 95% CI: 0.758-0.954), cortical echogenicity (OR =38.429; 95% CI: 3.695-399.641), and time since transplantation (OR =1.017; 95% CI: 1.006-1.028) were independent predictors of whether the glomerulosclerosis rate was >50% and were incorporated into the construction of a nomogram. The area under the curve (AUC) of the nomogram in the training and validation groups was 0.914 (95% CI: 0.840-0.960) and 0.909 (95% CI: 0.781-0.975), respectively, with a bootstrap resampling AUC of 0.877. The calibration curve and DCA confirmed the diagnostic performance of the nomogram model. Conclusions: The nomogram, which combined CUS, CEUS, and clinical indicators, exhibited notable predictive efficacy for the glomerulosclerosis rate in transplanted kidneys, thereby demonstrating the potential to improve clinical decision-making.