Herb induced liver injury by Xianling Gubao Tablets: A case assessed for causality using updated RUCAM and integrated evidence chain.

Objective: A typical case of Xianling Gubao (XLGB) Tablets-induced liver injury was systematically studied in the clinic and the laboratory. Methods: A patient with herb-induced liver injury (HILI) and a history of taking XLGB Tablets before disease onset was engaged as the study subject, and the case was diagnosed according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the integrated evidence chain (iEC) method recommended by the Guidelines for Diagnosis and Treatment of Herb-induced Liver Injury (HILI Guidelines). Results: Clinical history, biochemical indexes and imaging tests were used to exclude the influence of fundamental diseases and confusing liver diseases such as viral, alcoholic and autoimmune liver diseases on the diagnosis. Based on an investigation of the patient's medication history, she was suspected to have HILI caused by XLGB Tablets, as the patient was only taking an oral preparation of XLGB Tablets, and the influence of other drugs on the diagnosis was excluded. This patient with alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and a calculated R of 6 was diagnosed with possible acute drug-induced hepatocellular injury. The relationship was considered "highly probable" (score of 9) using the updated RUCAM of 2016. Moreover, the fingerprint similarity between the preparation taken by the patient and a commercially available preparation was 0.99, suggesting that the patient was consuming XLGB Tablets rather than another drug. LC-MS technology and the Agilent Fake TCM-Drugs database were used to investigate the drug, and no chemical additions were found. Examination of the drug for pesticide residues, heavy metals, aflatoxins and other exogenous substances indicated compliance with the content limits of the Chinese Pharmacopoeia. Conclusion: In summary, the final diagnosis of XLGB-induced liver injury reached the clinical diagnosis of HILI and was acute severe hepatocellular injury type by the updated RUCAM and iEC. Therefore, this study provides scientific evidence regarding the causality evaluation of compound preparations of traditional Chinese medicines-induced liver injury.

Polyfluoroalkyl Tag Decoration Enables Significantly Enhanced Tumor Penetration Ability of a PTK7 Targeting Aptamer.

Aptamers are widely used molecular recognition tools in targeted therapy, but their ability to effectively penetrate deep into solid tumors remains a significant challenge, leading to suboptimal treatment efficacy. Here, we developed a polyfluoroalkyl (PFA) decoration strategy to enhance aptamer recognition, cell internalization, and solid tumor penetration. Our results indicate that PFA with around 11 fluorine atoms significantly improves aptamer internalization both in vitro and in vivo settings. However, we also observed that the use of PFA tags containing 19 and 23 fluorine atoms on aptamers resulted in nonspecific cell anchoring in control cell lines, affecting the specificity of aptamers. Overall, we found that using a chemical modification strategy could enhance the deep tumor penetration ability of aptamers and validate their effectiveness in vivo. This approach has significant practical applications in targeted drug delivery for cancer treatment.

Dissection of the spatial dynamics of biosynthesis, transport, and turnover of major amino acids in tea plants (Camellia sinensis).

High levels of free amino acids (AAs) in tea leaves are crucial for tea flavor and health function; however, the dynamic AA biosynthesis, transport, and turnover in tea plants remain elusive. Here we dissected whole tea plants for these dynamics by assessing AA profiles and transcriptomes of metabolic pathway genes in tea roots, stems, and leaves and revealing their distinctive features with regard to AA synthesis, transport, and degradation/recycling. Nitrogen assimilation dominated in the roots wherein glutamine (Gln), theanine, and arginine (Arg) were actively synthesized. Arg was transported into trunk roots and stems, together with Glu, Gln, and theanine as the major AAs in the xylem sap for long-distance root-to-leaf transport. Transcriptome analysis revealed that genes involved in Arg synthesis were highly expressed in roots, but those for Arg transport and degradation were highly expressed in stems and young leaves, respectively. CsGSIa transcripts were found in root meristem cells, root, stem and leaf vascular tissues, and leaf mesophyll where it appeared to participate in AA synthesis, transport, and recycling. Overexpression of CsGSIa in tea transgenic hairy roots and knockdown of CsGSIa in transgenic hairy roots and tea leaves produced higher and lower Gln and theanine than wild-type roots and leaves, respectively. This study provides comprehensive and new insights into AA metabolism and transport in the whole tea plant.

Development of real-time recombinase polymerase amplification (RPA) and RPA combined with lateral flow dipstick (LFD) assays for the rapid and sensitive detection of cyprinid herpesvirus 3.

In this issue, we established rapid, cost-effective, and simple detection methods including recombines polymerase amplification with lateral flow dipstick (RPA-LFD) and real-time RPA for cyprinid herpesvirus 3(CyHV-3), and evaluated their sensitivity, specificity, and applicability, the real-time RPA method could achieve sensitive diagnosis of CyHV-3 within 1.3 copies per reaction, respectively. The real-time RPA method is 10-fold more sensitive than RPA-LFD method. The exact number of CyHV-3 can be calculated in each sample by real-time RPA. The sera from koi also can be tested in these methods. In addition, no cross-reaction was observed with other related pathogens, including carp oedema virus (CEV), spring viraemia of carp virus (SVCV), cyprinid herpesvirus 1(CyHV-1), cyprinid herpesvirus 2(CyHV-2), type I grass carp reovirus (GCRV-I), type II GCRV (GCRV-II), type III GCRV (GCRV-III), and Aeromonas hydrophila.

Structural network disruption of corticothalamic pathways in cerebral small vessel disease.

Generalized fractional anisotropy (GFA) can eliminate the crossing fiber effect, which may be more reflective of brain tissue changes in patients with cerebral small vessel disease (CSVD). This study aimed to explore the alterations of structural networks based on GFA and its relationship with cognitive performance in CSVD patients. We recruited 50 CSVD patients which were divided into two groups: cognitive impairment (CSVD-CI) and normal cognition (CSVD-NC), and 22 healthy controls (HCs). All participants underwent the Montreal Cognitive Assessment (MoCA) and MRI examinations. The structural topological properties were compared among the three groups. The correlation between these structural alterations and MoCA was analyzed. Compared with HCs, significantly decreased nodal efficiency and connectivity were detected in the corticothalamic pathways in both patient groups, of which some were significantly decreased in CSVD-CIs compared with CSVD-NCs. Moreover, both patient groups exhibited global network disruption including decreased global efficiency and increased characteristic path length compared with HCs. Furthermore, the nodal efficiency in the right pallidum positively correlated with MoCA in CSVD-NCs controlling for nuisance variables (r = 0.471, p = 0.031). The alterations in corticothalamic pathways indicated that the brain structural network underwent extensive disruption, providing evidence for the consideration of CSVD as a global brain disease.

Pure-high-even-order dispersion bound solitons complexes in ultra-fast fiber lasers.

Temporal solitons have been the focus of much research due to their fascinating physical properties. These solitons can form bound states, which are fundamentally crucial modes in fiber laser and present striking analogies with their matter molecules counterparts, which means they have potential applications in large-capacity transmission and all-optical information storage. Although traditionally, second-order dispersion has been the dominant dispersion for conventional solitons, recent experimental and theoretical research has shown that pure-high-even-order dispersion (PHEOD) solitons with energy-width scaling can arise from the interaction of arbitrary negative-even-order dispersion and Kerr nonlinearity. Despite these advancements, research on the bound states of PHEOD solitons is currently non-existent. In this study, we obtained PHEOD bound solitons in a fiber laser using an intra-cavity spectral pulse shaper for high-order dispersion management. Specifically, we experimentally demonstrate the existence of PHEOD solitons and PHEOD bound solitons with pure-quartic, -sextic, -octic, and -decic dispersion. Numerical simulations corroborate these experimental observations. Furthermore, vibrating phase PHEOD bound soliton pairs, sliding phase PHEOD bound soliton pairs, and hybrid phase PHEOD bound tri-soliton are discovered and characterized. These results broaden the fundamental understanding of solitons and show the universality of multi-soliton patterns.

Research hotspots and trends of complementary and alternative therapy for neuropathic pain: A bibliometric analysis.

BACKGROUND: Neuropathic pain (NP) is a common type of pain in clinic. Due to the limited effect of drug treatment, many patients with NP are still troubled by this disease. In recent years, complementary and alternative therapy (CAT) has shown good efficacy in the treatment of NP. As the interest in CAT for NP continues to grow, we conducted a bibliometric study of publications on CAT treatment for NP. The aim of this study is to analyze the development overview, research hotspots and future trends in the field of CAT and NP through bibliometric methodology, so as to provide a reference for subsequent researchers. METHODS: Publications on CAT in the treatment of NP from 2002 to 2022 were retrieved from the Web of Science Core Collection. Relevant countries, institutions, authors, journals, keywords, and references were analyzed bibliometrically using Microsoft Excel 2021, bibliometric platform, VOSviewer, and CiteSpace. RESULTS: A total of 898 articles from 46 countries were published in 324 journals, and they were contributed by 4455 authors from 1102 institutions. The most influential country and institution are China (n = 445) and Kyung Hee University (n = 63), respectively. Fang JQ (n = 27) and Evidence-Based Complementary and Alternative Medicine (n = 63) are the author and journal with the most publications in this field. The clinical efficacy, molecular biological mechanisms and safety of CAT for NP are currently hot directions. Low back pain, postherpetic neuralgia, acupuncture, and herbal are the hot topics in CAT and NP in recent years. CONCLUSION: This study reveals the current status and hotspots of CAT for NP. The study also indicates that the effectiveness and effect mechanism of acupuncture or herbs for treating emotional problems caused by low back pain or postherpetic neuralgia may be a trend for future research.

Exploring the Cooperation of the Redox Non-innocent Ligand and Di-Cobalt Center for the Water Oxidation Reaction Catalyzed by a Binuclear Complex.

Water oxidation is a crucial reaction in the artificial photosynthesis system. In the present work, density functional calculations were employed to decipher the mechanism of water oxidation catalyzed by a binuclear cobalt complex, which was disclosed to be a homogeneous water oxidation catalyst in pH=7 phosphate buffer. The calculations showed that the catalytic cycle starts from the CoIII,III-OH2 species. Then, a proton-coupled electron transfer followed by a one-electron transfer process leads to the generation of the formal CoIV,IV-OH intermediate. The subsequent PCET produces the active species, namely the formal CoIV,V=O intermediate (4). The oxidation processes mainly occur on the ligand moiety, including the coordinated water moiety, implying a redox non-innocent behavior. Two cobalt centers keep their oxidation states and provide one catalytic center for water activation during the oxidation process. 4 triggers the O-O bond formation via the water nucleophilic attack pathway, in which the phosphate buffer ion functions as the proton acceptor. The O-O bond formation is the rate-limiting step with a calculated total barrier of 17.7 kcal/mol. The last electron oxidation process coupled with an intramolecular electron transfer results in the generation of O2.

Trends in the Notification Rates and Treatment Outcome of Tuberculosis in Shandong Province, China, 2005-2021.

Purpose: To analyze the time trends in the notification rates of registered tuberculosis (TB) and bacteriologically confirmed TB in Shandong Province. And analyze the changes in TB treatment outcomes during 2005-2021. Patients and Methods: The information of TB patients registered in the Shandong Information Center for Disease Control and Prevention (CDC) was collected during 2005-2021. We calculated the notification rates of registered TB and bacteriologically confirmed TB. Moreover, we calculated the year-to-year change rate of TB in treatment outcomes before and after COVID-19. The time trends were analyzed using the joinpoint regression method and illustrated as the annual percentage change (APC) of notification rates. Results: A total of 236,898 cases of TB were diagnosed during 2005-2021, of which 51.11% were bacteriologically confirmed cases. Since 2008, the notification rates of registered TB have declined. The notification rates of bacteriologically confirmed TB had been declining during 2005-2016, then remained stable after 2016. In subgroup, the notification rates of both registered TB and bacteriologically confirmed TB were higher among men, rural residents, and people aged ≥ 60 years. Compared with clinically confirmed TB, bacteriologically confirmed TB has shown higher rates of poor outcomes since 2008 and higher case fatality rate since 2005. The rate of poor outcomes remained stable during 2008-2019. However, after the COVID-19 outbreak, the rate of poor outcomes and case fatality rate of TB has risen significantly. Conclusion: After unremitting efforts to fight against TB, the notification rates of registered TB and bacteriologically confirmed TB declined in Shandong Province. The rate of poor outcomes remained stable during 2008-2019, then rise significantly after the COVID-19 outbreak. In the context of the long-term existence of COVID-19, further efforts should be made in TB diagnosis and treatment among high-risk population, especially with regard to males, rural residents and older adults.

Lactate and lactylation: Behind the development of tumors.

There is growing evidence that lactate can have a wide range of biological impacts in addition to being a waste product of metabolism. Because of the Warburg effect, tumors generate lots of lactate, which create a tumor microenvironment (TME) with low nutrition, hypoxia, and low pH. As a result, the immunosuppressive network is established to gain immune escape potential and regulate tumor growth. Consequently, the tumor lactate pathway is emerging as a possible therapeutic target for tumor. Importantly, Zhao et al. first discovered histone lysine lactylation (Kla) in 2019, which links gene regulation to cell metabolism through dysmetabolic activity and epigenetic modifications, influencing TME and tumor development. Therefore, the aim of this paper is to explore the effects of lactate and lactylation on the TME and tumors, and provide theoretical basis for further research on potential therapeutic targets and biomarkers, with the view to providing new ideas and methods for tumor treatment and prognosis evaluation.

Significant improvements in the olfactory sensitivity of bipolar I disorder patients during euthymia versus manic episodes: a longitudinal study.

Introduction: Research has indicated that individuals diagnosed with bipolar disorder (BD) might experience alterations in their olfaction or levels of serum tumor necrosis factor-α (TNF-α), but no studies have investigated olfactory function and serum TNF-α in BD patients simultaneously. Moreover, there is a lack of existing research that compares the longitudinal olfactory function between individuals with manic and euthymic BD I. Methods: Patients with manic BD I (BDM, n=44) and healthy controls (HCs, n=32) were evaluated symptoms (measured via the Young Manic Rating Scale, YRMS), social function (measured via the Global Assessment Function, GAF), serum TNF-α, and olfactory function (via the Sniffin' Sticks test) including olfactory sensitivity (OS) and olfactory identification (OI). The BDM patients were followed up to the remission period and re-evaluated again. We compared OS, OI and serum TNF-α in manic and euthymic patients with BD I and HCs. We examined the correlation between olfactory function and symptoms, social function, and serum TNF-α in patients with BD I. Results: The BDM patients exhibited significantly lower OS and OI compared to the HCs (Z = -2.235, P = 0.025; t = -6.005, P < 0.001), while a positive correlation was observed between OS and GAF score (r = 0.313, P = 0.039). The OS in the BD I remission group (n=25) exhibited significantly superior performance compared to the BDM group (t = -4.056, P < 0.001), and the same as that in the HCs (P = 0.503). The change in OS showed a positive correlation with the decrease in YMRS score (r = 0.445, P = 0.026), and a negative correlation with the course of disease (r = -0.594, P = 0.002). The TNF-α in BD I patients was significantly lower compared to HCs (P < 0.001), and not significantly correlated with olfactory function (all P > 0.05). Conclusion: The findings suggest that OS and OI are impaired in BDM patients, and the impaired OS in those patients can be recovered in the remission stage. OI may serve as a potential characteristic marker of BD. OS might be useful as an index for BDM treatment efficacy and prognosis.

Mutation of neurotrophic tyrosine receptor kinase can promote pan-cancer immunity and the efficacy of immunotherapy.

The Neurotrophic tyrosine receptor kinase (NTRK) family plays important roles in tumor progression and is involved in tumor immunogenicity. Here, we conducted a comprehensive bioinformatic and clinical analysis to investigate the characteristics of NTRK mutations and their association with the outcomes in pan-cancer immunotherapy. In 3888 patients across 12 cancer types, patients with NTRK-mutant tumors showed more benefit from immunotherapy in terms of objective response rate (ORR; 41.7% vs. 27.5%; P < 0.001), progress-free survival (PFS; HR = 0.80; 95% CI, 0.68-0.96; P = 0.01), and overall survival (OS; HR = 0.71; 95% CI, 0.61-0.82; P < 0.001). We further constructed and validated a nomogram to estimate survival probabilities after the initiation of immunotherapy. Multi-omics analysis on intrinsic and extrinsic immune landscapes indicated that NTRK mutation was associated with enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses. In summary, NTRK mutation may promote cancer immunity and indicate favorable outcomes in immunotherapy. Our results have implications for treatment decision-making and developing immunotherapy for personalized care.

Diagnosis model of early Pneumocystis jirovecii pneumonia based on convolutional neural network: a comparison with traditional PCR diagnostic method.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an interstitial pneumonia caused by pneumocystis jirovecii (PJ). The diagnosis of PJP primarily relies on the detection of the pathogen from lower respiratory tract specimens. However, it faces challenges such as difficulty in obtaining specimens and low detection rates. In the clinical diagnosis process, it is necessary to combine clinical symptoms, serological test results, chest Computed tomography (CT) images, molecular biology techniques, and metagenomics next-generation sequencing (mNGS) for comprehensive analysis. PURPOSE: This study aims to overcome the limitations of traditional PJP diagnosis methods and develop a non-invasive, efficient, and accurate diagnostic approach for PJP. By using this method, patients can receive early diagnosis and treatment, effectively improving their prognosis. METHODS: We constructed an intelligent diagnostic model for PJP based on the different Convolutional Neural Networks. Firstly, we used the Convolutional Neural Network to extract CT image features from patients. Then, we fused the CT image features with clinical information features using a feature fusion function. Finally, the fused features were input into the classification network to obtain the patient's diagnosis result. RESULTS: In this study, for the diagnosis of PJP, the accuracy of the traditional PCR diagnostic method is 77.58%, while the mean accuracy of the optimal diagnostic model based on convolutional neural networks is 88.90%. CONCLUSION: The accuracy of the diagnostic method proposed in this paper is 11.32% higher than that of the traditional PCR diagnostic method. The method proposed in this paper is an efficient, accurate, and non-invasive early diagnosis approach for PJP.

Identification and analysis of MSC-Exo-derived LncRNAs related to the regulation of EMT in hypospadias.

OBJECTIVE: This study aims to screen the differentially expressed long non-coding RNAs (DELncRNAs) related to the regulation of epithelial-mesenchymal transition (EMT) in hypospadias in mesenchymal stem cell-derived exosomes (MSC-Exons) and explore the potential mechanism of these lncRNAs for the EMT in hypospadias. METHODS: In this study, the microarray data related to MSC-Exos and hypospadias were downloaded from Gene Expression Omnibus (GEO). Besides, the lncRNAs highly expressed in MSC-Exos and the differentially expressed mRNAs and lncRNAs in children with hypospadias were screened, respectively. In addition, the lncRNAs enriched in MSC-Exos and differentially expressed lncRNAs in hypospadias were intersected to obtain the final DElncRNAs. Moreover, the co-expression interaction pairs of differentially expressed lncRNAs and mRNAs were analyzed to construct a Competing Endogenous RNA (ceRNA) network. Finally, the candidate lncRNAs in exosomes were subjected to in vitro cell function verification. RESULTS: In this study, a total of 4 lncRNAs were obtained from the microarray data analysis. Further, a ceRNA regulatory network of MSC-Exo-derived lncRNAs related to the regulation of EMT in hypospadias was constructed, including 4 lncRNAs, 2 mRNAs, and 6 miRNAs. The cell function verification results indicated that the exosomes secreted by MSCs may transport HLA complex group 18 (HCG18) into target cells, which promoted the proliferation, migration, and EMT of these cells. CONCLUSION: MSC-Exo-derived lncRNA HCG18 can enter target cells, and it may be involved in the regulation of EMT in hypospadias through the ceRNA network.

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study.

Due to the unique effect of fluorine atoms, the efficient construction of high-value alkyl fluorides has attracted significant interest in modern drug development. However, enantioselective catalytic strategies for the efficient assembly of highly functionalized chiral C(sp3)-F scaffolds from simple starting materials have been underutilized. Herein, we demonstrate a nickel-catalyzed radical transfer strategy for the efficient, modular, asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with primary, secondary, and tertiary alkyl halides under mild conditions. The transformation provides facile access to various structurally complex secondary and tertiary α-fluoro amide products from readily available starting materials with excellent substrate compatibility and distinct selectivity. Furthermore, the utility of this method is demonstrated by late-stage modifications and product derivatizations. Detailed mechanistic studies and DFT calculations have been conducted, showing that the rate-determining step for asymmetric hydrogenation reaction is NiH-HAT toward alkenyl fluorides and the stereo-determining step is alcohol coordination to Ni-enolates followed by a barrierless protonation. The mechanism for the asymmetric hydroalkylation reaction is also delivered in this investigation.

Histopathological staging of atrophic lesions of gastric mucosa.

Objective: To study the histopathological staging of atrophic lesions of the gastric mucosa. Methods: Histology and immunohistochemistry were used to closely examine 2144 specimens of atrophic gastric mucosa that were taken from endoscopic biopsies. Results: When the gastric mucosa epithelium is affected by infection, chemical stimulation, immune factors, genetic factors, and other factors, it may cause an atrophy of gastric mucosa epithelium and a decrease in the number of glands, intestinal metaplasia, hyperplasia of smooth muscle fibers, and atrophy of stem cells in the proliferative zone. In this study, we characterized the above lesions as atrophic lesions of the gastric mucosa. Based on the morphological and histological characteristics of the lesion, as well as the law of cell proliferation and transformation during its occurrence and development, we propose five stages. We also noted the onset age, gender correlation, and histopathological characteristics of each stage of gastric mucosal atrophies. Conclusion: Understanding the pathological staging of gastric mucosal atrophy is essential for treating patients correctly and keeping track of changes in malignant cells. It is also very important in preventing the initiation of gastric cancer or from getting worse.

Identification of an anaplastic subtype of prostate cancer amenable to therapies targeting SP1 or translation elongation.

Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.

An integrated ceRNA network identifies miR-375 as an upregulated miRNA playing a tumor suppressive role in aggressive prostate cancer.

Prostate cancer (PCa) remains a significant cause of morbidity and mortality among men worldwide. A number of genes have been implicated in prostate tumorigenesis, but the mechanisms underlying their dysregulation are still incompletely understood. Evidence has established the competing endogenous RNA (ceRNA) theory as a novel regulatory mechanism for post-transcriptional alterations. Yet, a comprehensive characterization of ceRNA network in PCa lacks. Here we utilize stringent in-silico methods to construct a large ceRNA network across different PCa stages, and provide experimental demonstration for the competing regulation among protumorigenic SEC23A, PHTF2, and their corresponding ceRNA pairs. Using machine learning, we establish a ceRNA-based signature (ceRNA_sig) predictive of androgen receptor (AR) activity, tumor aggressiveness, and patient outcomes. Importantly, we identify miR-375 as a key node in PCa ceRNA network, which is upregulated in PCa relative to normal tissues. Forced expression of miR-375 significantly inhibits, while its inhibition promotes, aggressive behaviors of both AR+ and AR- PCa cells in vitro and in vivo. Mechanistically, we show that miR-375 predominantly targets genes possessing oncogenic roles (e.g., proliferation, DNA repair, and metastasis), and thus release targets with tumor suppressive functions. This action model well clarifies why an upregulated miRNA plays a tumor suppressive role in PCa. Together, our study provides new insights into understanding of transcriptomic aberrations during PCa evolution, and nominates miR-375 as a potential therapeutic target for combating aggressive PCa.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

Establishment and characterization of a kidney cell line from hybrid snakehead (male Channa argus × female Channa maculata) and its susceptibility to hybrid snakehead rhabdovirus (HSHRV).

Hybrid snakehead (male Channa argus × female Channa maculata) is an emerging fish breed with increasing production levels. However, infection with hybrid snakehead rhabdovirus (HSHRV) critically affects hybrid snakehead farming. In this study, a fish cell line called CAMK, derived from the kidneys of hybrid snakehead, was established and characterized. CAMK cells exhibited the maximum growth rate at 28 °C in Leibovitz's-15 medium supplemented with 10% fetal bovine serum(FBS). Karyotyping revealed diploid chromosomes in 54% of the cells at the 50th passage (2n = 66), and 16S rRNA sequencing validated that CAMK cells originated fromhybrid snakehead, and the detection of kidney-specific antibodies suggested that it originated from kidney. .The culture was free from mycoplasma contamination, and the green fluorescent protein gene was effectively transfected into CAMK cells, indicating their potential use for in vitro gene expression investigations. Furthermore, qRT-PCR and immunofluorescence analysis revealed that HSHRV could replicate in CAMK cells, indicating that the cells were susceptible to the virus. Transmission electron microscopy revealed that the viral particles had bullet-like morphology. The replication efficiency of HSHRV was 107.33 TCID50/mL. Altogether, we successfully established and characterized a kidney cell line susceptible to the virus. These findings provide a valuable reference for further genetic and virological studies.