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The large yellow croaker (Larimichthys crocea) displays pronounced behavioral changes in response to low oxygen environments, including restlessness, constant floating, and increases in respiratory rate and tail beat frequency. However, the underlying molecular mechanisms governing these behavioral and physiological alterations remain unclear. To address this knowledge gap, the present study employed transcriptome analysis to investigate the molecular responses in the large yellow croaker muscle tissue after the fish were exposed to hypoxic treatment. A total of 4553, 1797, 3222, 3148, and 4815 differentially expressed genes (DEGs) were identified at 1 h, 6 h, 9 h, 24 h, and 72 h after hypoxia treatment, respectively. Subsequent analysis utilizing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichments unveiled a notable up-regulation of genes related to muscular movement-related pathways, specifically the calcium pathway. This up-regulation coincided with an observed increase in the intracellular Ca2+ concentration and Ca2+ transport enzyme activity, suggesting that hypoxia-induced muscle contraction and relaxation occurred by elevating the intracellular Ca2+ concentration within the muscle tissue. Key DEGs associated with the glycolysis and the TCA cycle pathways were also found to be significantly increased in expression, indicating an activation of energy generation pathways in the muscle of hypoxic large yellow croakers. Conversely, genes related to protein synthesis and cell growth were significantly down-regulated, suggesting an inhibition of energy-consuming processes. Additionally, hypoxia was observed to impact various physiological processes such as oxygen transport, vascular control, and apoptosis. These processes may have been mediated by the up-regulation of HIF-1α and its target genes. Consequently, these results offer novel insights into comprehending the molecular basis of the changes in behavior and physiology of large yellow croaker in response to the stress induced by low oxygen levels.

Parkinson’s disease (PD) is a neurodegenerative disorder that significantly impacts patients’ quality of life. Recent evidence has highlighted a complex relationship between the gut microbiota (GM) and PD. Understanding this relationship is crucial for potentially targeting GM in PD treatment and expanding therapeutic options. This study aimed to comprehensively analyze the global landscape, trends, and research focus on GM and PD using bibliometric analysis. Utilizing publications from the Web of Science Core Collection (WsSCC), bibliometric tools such as the R package ‘Bibliometrix,’ VOS viewer, and CiteSpace software were employed to assess parameters like yearly publications, countries/regions, institutions, and authors. Research trends and hotspots were identified through keyword analysis. The results revealed 1,161 articles published between 2013-2023, with China leading in publications (n=352, 30.31% of total), while the United States had a higher influence (H-index=58). The University of California System was the top institution in terms of publications (n=35), with the National Natural Science Foundation of China funding the most projects (n=172). Keshavarzian A and Sampson TR were the authors with the highest publication and co-citation counts, respectively. The International Journal of Molecular Sciences had the most articles published (n=48). Keyword analysis identified parkinson’s disease, gut microbiota, short-chain fatty acids, inflammation, and probiotics as main research topics. Biomarkers, ketogenic diet, and NF-κB were recent research hotspots and trends (2021-2023). The current study conducts an objective and comprehensive analysis of these publications, identifying trends and hotspots in the field of research. The findings offer valuable insights to scholars globally and in-vestigate potential therapeutic strategies for Parkinson’s Disease.

Background: China has experienced a COVID-19 wave caused by Omicron XBB variant starting in April 2023. Our aim is to conduct a retrospective analysis exploring the dynamics of the outbreak under counterfactual scenarios that combine the use of vaccines, antiviral drugs, and nonpharmaceutical interventions. Methods: We developed a mathematical model of XBB transmission in China, which has been calibrated using SARS-CoV-2 positive rates per week. Intrinsic age-specific infection-hospitalization risk, infection-ICU risk, and infection-fatality risk were used to estimate disease burdens, characterized as number of hospital admissions, ICU admissions, and deaths. Results: We estimated that in absence of behavioral change, the XBB outbreak in spring 2023 would have resulted in 0.86 billion infections (∼61% of the total population). Our counterfactual analysis shows that the synergetic effect of vaccination (70% vaccination coverage), antiviral treatment (20% receiving antiviral treatment), and moderate nonpharmaceutical interventions (20% isolation and L1 PHSMs) could reduce the number of deaths to levels close to seasonal influenza (1.17 vs. 0.65 per 10,000 individuals and 5.85 vs. 3.85 per 10,000 individuals aged 60+, respectively). The maximum peak prevalence of hospital and ICU admissions are estimated to be lower than the corresponding capacities (8.6 vs. 10.4 per 10,000 individuals and 1.2 vs. 2.1 per 10,000 individuals, respectively). Conclusion: Our findings suggest that the capacity of the Chinese healthcare system was adequate to face the Omicron XBB wave in spring 2023 but, at the same time, supports the importance of administering highly effective vaccine with long-lasting immune response, and the use of antiviral treatments.

Abstract Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.

Suppressors of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Within the SOCS family, SOCS3 is one of the most potent inhibitors of cytokine signaling. However, there is limited knowledge regarding the function of SOCS3 on regulating type I interferon (IFN) signaling in fish. In this study, the complete open reading frame (ORF) of SOCS3 from the large yellow croaker (Larimichthys crocea, LcSOCS3) was cloned and characterized. The ORF of LcSOCS3 was 618 nucleotides in length and encoded a protein containing 205 amino acids. LcSOCS3 had the typical domain architecture of the SOCS family, including an SRC homology 2 (SH2) domain, a SOCS box, an additional kinase inhibition region (KIR), and an extended SH2 subdomain (ESS). Phylogenetic analysis revealed that LcSOCS3 was clustered with other fish SOCS3s and most closely related to the SOCS3 of Collichthy lucidus. LcSOCS3 mRNA was detected in all organs or tissues examined, and its expression was significantly increased in both head kidney and spleen tissues, and primary head kidney leukocytes after poly(I:C) stimulation. Overexpression of LcSOCS3 significantly promoted Spring viremia of carp virus (SVCV) replication, resulting in a more severe cytopathic effect, increased viral titer, enhanced copy number of the SVCV-G gene, and decreased expression levels of IFN1, IRF7, ISG15, Viperin, PKR, and Mx in epithelioma papulosum cyprinid (EPC) cells. Silencing of LcSOCS3 correspondingly up-regulated the expression of IFNi, IFNh, PKR, Viperin, and Mx in large yellow croaker head kidney (LYCK) cells. Additionally, LcSOCS3 was shown to interact with Signal Transducer and Activator of Transcription 1 (STAT1) which may inhibit STAT1 translocating into the nucleus. This speculation was supported by the increased phosphorylation level of STAT1 in head kidney leukocytes after LcSOCS3 silencing. These results indicated that LcSOCS3 functioned as a potential negative regulator of type I IFN signaling in large yellow croaker through its interaction with STAT1.

In recent years, the abalone aquaculture industry has been threatened by the bacterial pathogens. The immune responses mechanisms underlying the phagocytosis of haemocytes remain unclear in Haliotis discus hannai. It is necessary to investigate the immune mechanism in response to these bacterial pathogens challenges. In this study, the phagocytic activities of haemocytes in H. discus hannai were examined by flow cytometry combined with electron microscopy and transcriptomic analyses. The results of Vibrio parahaemolyticus, Vibrio alginolyticus and Staphylococcus aureu challenge using electron microscopy showed a process during phagosome formation in haemocytes. The phagocytic rate (PP) of S. aureus was higher than the other five foreign particles, which was about 63%. The PP of Vibrio harveyi was about 43%, the PP peak of V. alginolyticus in haemocyte was 63.7% at 1.5 h. After V. parahaemolyticus and V. alginolyticus challenge, acid phosphatase, alkaline phosphatase, total superoxide dismutase, lysozyme, total antioxidant capacity, catalase, nitric oxide synthase and glutathione peroxidase activities in haemocytes were measured at different times, differentially expressed genes (DEGs) were identified by quantitative transcriptomic analysis. The identified DEGs after V. parahaemolyticus challenge included haemagglutinin/amebocyte aggregation factor-like, supervillin-like isoform X4, calmodulin-like and kyphoscoliosis peptidase-like; the identified DEGs after V. alginolyticus challenge included interleukin-6 receptor subunit beta-like, protein turtle homolog B-like, rho GTPase-activating protein 6-like isoform X2, leukocyte surface antigen CD53-like, calponin-1-like, calmodulin-like, troponin C, troponin I-like isoform X4, troponin T-like isoform X18, tumor necrosis factor ligand superfamily member 10-like, rho-related protein racA-like and haemagglutinin/amebocyte aggregation factor-like. Some immune-related KEGG pathways were significantly up-regulated or down-regulated after challenge, including thyroid hormone synthesis, Th17 cell differentiation signalling pathway, focal adhesion, melanogenesis, leukocyte transendothelial migration, inflammatory mediator regulation of TRP channels, ras signalling pathway, rap1 signalling pathway. This study is the first step towards understanding the H. discus hannai immune system by adapting several tools to gastropods and providing a first detailed morpho-functional study of their haemocytes.

Pseudomonas plecoglossicida is a major pathogen that causes visceral white nodules disease (VWND), a highly devastating disease, in cultured large yellow croaker (Larimichthys crocea), leading to severe economic losses. Peptide chain release factor methyltransferase hemK in bacteria plays a role in pathogenicity, but its exact function in P. plecoglossicida remains unclear. In this study, a P. plecoglossicida mutant strain (ΔhemK) was constructed by deleting hemK, and the roles of hemK in regulating P. plecoglossicida virulence were thereafter investigated. Compared to the wildtype strain, cell motility and biofilm formation of ΔhemK were weaken, and extracellular protein profile was altered. In vitro study showed that the hemK deletion significantly decreased the survival rate of P. plecoglossicida in large yellow croaker macrophage cell line (LYC-FM) by impairing oxidative stress tolerance. Furthermore, large yellow croakers infected with ΔhemK showed a significant reduction in mortality rate, bacterial load, and noticeable nodules within the spleen, when compared to the wild-type strain. These findings indicated that hemK plays an essential role in the pathogenicity of P. plecoglossicida, thus providing a valuable insight into the pathogenic mechanisms of P. plecoglossicida and offering a potential target for its attenuated-vaccine development.

Abstract Clostridioides difficile (C. difficile) is the predominant causative agent of nosocomial diarrhea worldwide. Infection with C. difficile occurs due to the secretion of large glycosylating toxin proteins, which can lead to toxic megacolon or mortality in susceptible hosts. A critical aspect of C. difficile's biology is its ability to persist asymptomatically within the human host. Individuals harboring asymptomatic colonization or experiencing a single episode of C. difficile infection (CDI) without recurrence exhibit heightened immune responses compared to symptomatic counterparts. The significance of these immune responses cannot be overstated, as they play critical roles in the development, progression, prognosis, and outcomes of CDI. Nonetheless, our current comprehension of the immune responses implicated in CDI remains limited. Therefore, further investigation is imperative to elucidate their underlying mechanisms. This review explores recent advancements in comprehending CDI pathogenesis and how the host immune system response influences disease progression and severity, aiming to enhance our capacity to develop immunotherapy‐based treatments for CDI.

Clostridioides difficile, the etiological agent of C. difficile infection (CDI), elicits a spectrum of diarrheal symptoms with varying severity and the potential to result in severe complications such as colonic perforation, pseudomembranous colitis, and toxic megacolon. The perturbation of gut microbiome, often triggered by antibiotic usage, represents the primary factor augmenting the risk of CDI. This underscores the significance of interactions between C. difficile and the microbiome in determining pathogen adaptability. In recent years, researchers have increasingly recognized the pivotal role played by intestinal microbiota in host health and its therapeutic potential as a target for medical interventions. While extensive evidence has been established regarding the involvement of gut bacteria in CDI, our understanding of symbiotic interactions between hosts and fungi within intestinal microbiota remains limited. Herein, we aim to comprehensively elucidate both composition and key characteristics of gut fungal communities that significantly contribute to CDI, thereby enhancing our comprehension from pharmacological and biomarker perspectives while exploring their prospective therapeutic applications for CDI.

BackgroundEvaluating the correlation between serum potassium and Parkinson’s disease (PD) in US adults.MethodsA cross-sectional study was conducted on 20,495 adults aged 40 years or older using NHANES data from 2005 to 2020. The study utilized one-way logistic regression and multifactorial logistic regression to examine the correlation between serum potassium levels and PD. Additionally, a smoothed curve fitting approach was employed to assess the concentration-response relationship between serum potassium and PD. Stratified analyses were carried out to investigate potential interactions between serum potassium levels and PD with variables such as age, sex, race, marital status, education, BMI, smoking and medical conditions like coronary, stroke, diabetes, hypertension, and hypercholesterolemia.ResultsIn this study, a total of 20,495 participants, comprising 403 PD and 20,092 non-PD individuals, were included. After adjusted for covariates, multivariable logistic regression revealed that high serum potassium level was an independent risk factor for PD (OR:1.86, 95% CI:1.45 ~ 2.39, p 0.05).ConclusionSerum potassium levels are elevated in patients with Parkinson's disease compared to non-PD patients. Additional prospective studies are required to explore the significance of serum potassium levels in individuals with Parkinson's disease.

Abstract Background Epigenetic alterations contribute greatly to the development and progression of colorectal cancer, and effect of aberrant miR-622 expression is still controversial. This study aimed to discover miR-622 regulation in CRC proliferation. Methods miR-622 expression and prognosis were analyzed in clinical CRC samples from Nanfang Hospital. miR-622 regulation on cell cycle and tumor proliferation was discovered, and FOLR2 was screened as functional target of miR-622 using bioinformatics analysis, which was validated via dual luciferase assay and gain-of-function and loss-of-function experiments both in vitro and in vivo. Results miR-622 overexpression in CRC indicated unfavorable prognosis and it regulated cell cycle to promote tumor growth both in vitro and in vivo. FOLR2 is a specific, functional target of miR-622, which negatively correlates with signature genes in cell cycle process to promote CRC proliferation. Conclusions miR-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation, proposing a novel mechanism and treatment target in CRC epigenetic regulation of miR-622.

Abstract Purpose This investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy. Methods This case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study’s primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles. Results The study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P

Abstract In recent years, immunotherapy has emerged as a promising strategy for treating solid tumors, although its efficacy remains limited to a subset of patients. Transforming non-responsive “cold” tumor types into immuno-responsive “hot” ones is critical to enhance the efficacy of immune-based cancer treatments. Pyroptosis, a programmed cell death mechanism, not only effectively eliminates tumor cells but also triggers a potent inflammatory response to initiate anti-tumor immune activities. This sheds light on the potential of pyroptosis to sensitize tumors to immune therapy. Hence, it is urgent to explore and develop novel treatments (e.g., nanomedicines) which are capable of inducing pyroptosis. In this study, we constructed tumor-targeting nanoparticles (CS-HAP@ATO NPs) by loading atorvastatin (ATO) onto chondroitin sulfate (CS) modified hydroxyapatite (HAP) nanoparticles (CS-HAP). CS was strategically employed to target tumor cells, while HAP exhibited the capacity to release calcium ions (Ca2+) in response to the tumor microenvironment. Moreover, ATO disrupted the mitochondrial function, leading to intracellular energy depletion and consequential changes in mitochondrial membrane permeability, followed by the influx of Ca2+ into the cytoplasm and mitochondria. CS and HAP synergetically augmented mitochondrial calcium overload, inciting the production of substantial amount of reactive oxygen species (ROS) and the subsequent liberation of oxidized mitochondrial DNA (OX-mitoDNA). This intricate activation process promoted the assembly of inflammasomes, most notably the NLRP3 inflammasome, followed by triggering caspase-1 activation. The activated caspase-1 was able to induce gasderminD (GSDMD) protein cleavage and present the GSDM-N domain, which interacted with phospholipids in the cell membrane. Then, the cell membrane permeability was raised, cellular swelling was observed, and abundant cell contents and inflammatory mediators were released. Ultimately, this orchestrated sequence of events served to enhance the anti-tumor immunoresponse within the organism.

Background: Patients with Triple-negative breast cancer (TNBC) face a poor prognosis and limited therapeutic options. Current data on eribulin usage to treat TNBC is scarce. Therefore, we sought to compare the feasibility and tolerability of eribulin-based regimens with other chemotherapy regimens in patients with TNBC.Method: This retrospective study was conducted at Fujian Medical University Cancer Hospital and included 159 patients with TNBC enrolled between October 2011 and January 2023. Patients underwent treatment with eribulin-based and other chemotherapy regimens. The study’s primary endpoints were progression-free survival (PFS) and overall survival (OS), while its secondary endpoint was objective response rate (ORR), disease control rate (DCR), and safety. Tumour response was assessed using RECIST V.1.1 criteria.Results: Of the 159 participants in the study, 42 individuals (26.4%) received treatment with eribulin, whereas 117 participants (73.6%) were administered alternative chemotherapy regimens, which included nab-paclitaxel-based therapy (n = 45) and platinum-based therapy (n = 51). The follow-up period for all patients ended on 31 December 2022, and the median follow-up time was 18.3 months (range:0.7–27.5). Following propensity score matching (PSM), eribulin-based treatment resulted in longer median progression-free survival compared to platinum-based (hazard ratio (HR) = 0.41, p = 0.006), nab-paclitaxel-based (hazard ratio = 0.36, p = 0.001) and other chemotherapy (HR = 0.39, p < 0.001). Also, eribulin induced a remarkable prolongation of the median overall survival duration in all three comparative groups. The group receiving eribulin treatment showed significantly reduced incidences of any grade of anaemia, peripheral neuropathy, nausea and vomiting, and hair loss compared to other chemotherapy groups.Conclusion: For the salvage treatment of advanced TNBC, treatment with eribulin produced longer median PFS and OS than other chemotherapy regimens, with a well-tolerated safety profile. Therefore, further investigation of eribulin-based treatment in larger randomized trials for patients with advanced TNBC is warranted.

In mammals, the transcription factor Pax5 is a key regulator of B cell development and maturation and specifically expressed in naive/mature B cells but repressed upon B cell activation. Despite the long-standing proposal that Pax5 repression is essential for proper B cell activation, the underlying mechanisms remain largely elusive. In this study, we used a teleost model to elucidate the mechanisms governing Pax5 repression during B cell activation. Treatment with lipopolysaccharide (LPS) and chitosan oligosaccharide (COS) significantly enhanced the antibody secreting ability and phagocytic capacity of IgM+ B cells in large yellow croaker (Larimichthys crocea), coinciding with upregulated expression of activation-related genes, such as Bcl6, Blimp1, and sIgM, and downregulated expression of Pax5. Intriguingly, two CpG islands were identified within the promoter region of Pax5. Both CpG islands exhibited hypomethylation in naive/mature B cells, while CpG island1 was specifically transited into hypermethylation upon B cell activation. Furthermore, treatment with DNA methylation inhibitor 5-aza-2’-deoxycytidine (AZA) prevented the hypermethylation of CpG island1, and concomitantly impaired the downregulation of Pax5 and activation of B cells. Finally, through in vitro methylation experiments, we demonstrated that DNA methylation exerts an inhibitory effect on promoter activities of Pax5. Taken together, our findings unveil a novel mechanism underlying Pax5 repression during B cell activation, thus promoting the understanding of B cell activation process.

Objective: To explore the clinical value of two kinds of AI detection software in ≥5 mm pulmonary nodules. Methods: A total of 92 patients with pulmonary nodules (483 nodules) were selected from the affiliated Hospital of Yan'an University between June and October 2021. The nodules detected by AI software were evaluated and the number and type of nodules were recorded by two senior radiologists. Two senior imaging doctors then evaluated the manual film reading, which was used as the gold standard for nodule recognition. Subsequently, the detection rate and false positive and negative rates of the two software were calculated, and the nodule detection value of the two AI software was evaluated. Additionally, the chi-square and Fisher precision tests were used to compare the differences between the different software and the gold standard. Finally, the diagnostic value of the combination of the two kinds of AI software for pulmonary nodules was calculated. Results: The detection rates of software A and software B nodules were 92.1% and 87.0%, respectively. Moreover, the coincidence degree between software A and manual reading was general (Kappa=0.213), while that between software B and manual reading was weak (Kappa=0.150). There was also a significant difference in the detection of solid nodules and calcified nodules between software A and manual reading, as well as between software B and pure ground glass nodules. The detection rate of nodules with the combined two kinds of AI software was 97.1%. However, compared with manual reading, there was no significant difference in the detection of nodule types. The combination of the two AI software had a good agreement with manual reading (Kappa=0.439). Conclusion: The combination of two kinds of AI software improved the ability of nodule detection and classification analysis. Furthermore, the method of joint diagnosis is recommended for clinical use and it provides evidence for further improving the homogenization management of AI data sets.

Preclinical studies have proven that nanosecond pulsed electric field (nsPEF) ablation can be a safe and effective treatment for humans with unresectable liver cancer that are ineligible for thermal ablation. The concomitant activation of antitumor immunity by nsPEF can also potentially prevent tumor recurrence. However, whether nsPEF exhibits similar efficacy in a clinical setting remains to be investigated. A prospective clinical trial (clinicaltrials.gov identifier: NCT04039747) was conducted to evaluate the safety and efficacy of ultrasound (US)‐guided nsPEF ablation in 15 patients with unresectable liver cancer that were ineligible for thermal ablation. We found that nsPEF ablation was safe and produced a 12‐month recurrence‐free survival (RFS) and local RFS of 60% (9/15) and 86.7% (13/15), respectively, in the enrolled patients. Integrative proteomic and metabolomic analysis showed that sphingolipid metabolism was the most significantly enriched pathway in patient sera after nsPEF without recurrence within 8 months. A similar upregulation of sphingolipid metabolism was observed in the intratumoral mononuclear phagocytes (MNPs), rather than other immune and nonimmune cells, of an nsPEF‐treated mouse model. We then demonstrated that lymphocyte antigen 6 complex, locus C2‐positive (Ly6c2+) monocytes first differentiated into Ly6c2+ monocyte‐derived macrophages with an increase in sphingolipid metabolic activity, and subsequently into Ly6c2+ dendritic cells (DCs). Ly6c2+ DCs communicated with CD8+ T cells and increased the proportions of IFN‐γ+ CD8+ memory T cells after nsPEF, and this finding was subsequently confirmed by depletion of liver Ly6c2+ MNPs. In conclusion, nsPEF was a safe and effective treatment for liver cancer. The alteration of sphingolipid metabolism induced by nsPEF was associated with the differentiation of Ly6c2+ MNPs, and subsequently induced the formation of memory CD8+ T cells with potent antitumor effect.

BackgroundHypertensive nephropathy (HN) is one of the main causes of end-stage renal disease (ESRD), leading to serious morbidity and mortality in hypertensive patients. However, existing treatment for hypertensive nephropathy are still very limited. It has been demonstrated that aerobic exercise has beneficial effects on the treatment of hypertension. However, the underlying mechanisms of exercise in HN remain unclear.MethodsThe spontaneously hypertensive rats (SHR) were trained for 8 weeks on a treadmill with different exercise prescriptions. We detected the effects of moderate intensity continuous training (MICT) and high intensity interval training (HIIT) on inflammatory response, renal function, and renal fibrosis in SHR. We further investigated the relationship between TLR4 and the NLRC4 inflammasome in vitro HN model.ResultsMICT improved renal fibrosis and renal injury, attenuating the inflammatory response by inhibiting TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. However, these changes were not observed in the HIIT group. Additionally, repression of TLR4/NF-κB pathway by TAK-242 inhibited activation of NLRC4 inflammasome and alleviated the fibrosis in Ang II-induced HK-2 cells.ConclusionMICT ameliorated renal damage, inflammatory response, and renal fibrosis via repressing TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. This study might provide new references for exercise prescriptions of hypertension.

Non-motor symptoms are prevalent among individuals with Parkinson’s disease (PD) and seriously affect patient quality of life, even more so than motor symptoms. In the past decade, an increasing number of studies have investigated non-motor symptoms in PD. The present study aimed to comprehensively analyze the global literature, trends, and hotspots of research investigating non-motor symptoms in PD through bibliometric methods. Studies addressing non-motor symptoms in the Web of Science Core Collection (WoSCC), published between January 2013 and December 2022, were retrieved. Bibliometric methods, including the R package “Bibliometrix,” VOS viewer, and CiteSpace software, were used to investigate and visualize parameters, including yearly publications, country/region, institution, and authors, to collate and quantify information. Analysis of keywords and co-cited references explored trends and hotspots. There was a significant increase in the number of publications addressing the non-motor symptoms of PD, with a total of 3,521 articles retrieved. The United States was ranked first in terms of publications (n = 763) and citations (n = 11,269), maintaining its leadership position among all countries. King’s College London (United Kingdom) was the most active institution among all publications (n = 133) and K Ray Chaudhuri was the author with the most publications (n = 131). Parkinsonism & Related Disorders published the most articles, while Movement Disorders was the most cited journal. Reference explosions have shown that early diagnosis, biomarkers, novel magnetic resonance imaging techniques, and deep brain stimulation have become research “hotspots” in recent years. Keyword clustering revealed that alpha-synuclein is the largest cluster for PD. The keyword heatmap revealed that non-motor symptoms appeared most frequently (n = 1,104), followed by quality of life (n = 502), dementia (n = 403), and depression (n = 397). Results of the present study provide an objective, comprehensive, and systematic analysis of these publications, and identifies trends and “hot” developments in this field of research. This work will inform investigators worldwide to help them conduct further research and develop new therapies.

Rab7 is a small GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. In this study, full-length cDNA sequences of Rab7 were cloned from Yellow River Carp Cyprinus carpio, which were designated as CcRab7, and its function during pathogen infection was also investigated. The results showed that the full-length cDNA of CcRab7 was composed of 1511 bp, and open reading frame is 618 bp encoding 205 amino acids with 23.10 kDa. The deduced amino acid sequence of CcRab7 shared high similarity to that of Pimephales promelas (99.02%). In this paper, real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression levels in 11 tissues and organs of healthy Yellow River Carp, and the tissue distribution of CcRab7 as well as its defense mechanism against Spring viremia of carp virus (SVCV) and Aeromonas hydrophila in Yellow River Carp C. carpio was investigated. The results revealed that the mRNA transcripts of CcRab7 were widely detected in various tissues of C. carpio, with the highest expression levels in head kidney and blood, indicating that CcRab7 was involved in the innate immune process. Yellow River Carp was immunized with A. hydrophila and SVCV respectively, and the expression changes of CcRab7 were detected in gill, spleen, liver and skin of Yellow River Carp. The mRNA transcripts of CcRab7 in the main organs (gill, and liver, skin and spleen) were significantly affected by SVCV and A. hydrophila infection. The results showed that the CcRab7 expression levels was obviously up-regulated at different time points. The eukaryotic recombinant plasmids of CcRab7 and pEGFP-N3 transfected into Grass carp ovary cell lines (GCO) cells for subcellular localization. The results provide a basis for further investigation into the immunological role of CcRab7 in Yellow River Carp.

The Gram-negative bacterium Pseudomonas plecoglossicida has caused visceral granulomas disease in several farmed fish species, including large yellow croaker (Larimichthys crocea), which results in severe economic losses. Type III secretion systems (T3SS) are protein secretion and translocation nanomachines widely employed by many Gram-negative bacterial pathogens for infection and pathogenicity. However, the exact role of T3SS in the pathogenesis of P. plecoglossicida infection is still unclear. In this study, a T3SS translocators deletion strain (△popBD) of P. plecoglossicida was constructed to investigate the function of T3SS. Then comparative secretome analysis of the P. plecoglossicida wild-type (WT) and △popBD mutant strains was conducted by label-free quantitation (LFQ) mass spectrometry. The results show that knockout of T3SS translocators popB and popD has an adverse effect on the effector protein ExoU secretion, flagella assembly, and biofilm formation. Further experimental validations also confirmed that popB-popD deletion could affect the P. plecoglossicida flagella morphology/formation, adherence, mobility, and biofilm formation. These data indicate that a cross-talk exists between the P. plecoglossicida T3SS and the flagella system. Our results, therefore, will facilitate the further under-standing of the pathogenic mechanisms leading to visceral granulomas disease caused by P. plecoglossicida.

Acidifier has become one of the most important substitutes for antibiotics, and its beneficial effects on growth performance and digestive ability have been evidenced. Sodium benzoate is a commonly used acidifier. A 56-day feeding test was carried out to elucidate the effects of dietary sodium benzoate on growth performance, morphology, antioxidant activity and intestinal microflora of juvenile Litopenaeus vannamei with an average initial body weight of 0.55 ± 0.01 g. Six experimental diets were prepared by adding 0, 750, 1000, 1250, 1500 and 1750 mg/kg sodium benzoate to the control diet. The results showed that: The final body weight (FBW) and weight gain (WG) of juvenile shrimp were significantly improved by diet supplemented with 1750 mg/kg sodium benzoate. Dietary 1750 mg/kg sodium benzoate significantly increased the trypsin activity. The activities of catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST) in the intestine and hepatopancreas of the 1750 mg/kg sodium benzoate group were markedly higher than those of the control group. Furthermore, the expression levels of trypsin (TRY), amylase (AMS), lysozyme (LZM), interleukin-8 (IL8) and interleukin-10 (IL10) genes in the intestine significantly increased when the content of sodium benzoate in the diet was greater than or equal to 1000 mg/kg. The addition of 1500 and 1750 mg/kg sodium benzoate to the feed improved the intestinal and hepatopancreatic tissue structures of juvenile shrimp and enriched the diversity of intestinal microbiota. Sodium benzoate residues were not detected in each sodium benzoate supplemented group. At the end of the Aeromonas hydrophila challenge test, juvenile shrimp in the 1500 and 1750 mg/kg group exhibited significantly higher cumulative survival rates than that in the control group. Conclusively, dietary 1750 mg/kg sodium benzoate could improve the growth performance, antioxidant capacity, morphology, intestinal microflora and disease resistance of juvenile shrimp.

Background and aims: Clostridioides difficile infection (CDI) induces intense acute inflammatory responses through toxin release. A combination of antibiotic and anti-inflammatory agents is sometimes recommended in severe, non-responsive cases, although clinical trials have been inconclusive, raising concerns about potential complications. This study aims to investigate the effect of budesonide and mesalamine in the treatment of CDI in a murine model, by evaluating the combination of fidaxomicin and these anti-inflammatory drugs. Method: C57BL/6 J female mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or culture media by gavage. After the challenge, mice received placebo, fidaxomicin alone (20 mg/kg), or fidaxomicin combined with mesalamine (200, 400 mg/kg) or budesonide (0.2, 1, 10 mg/kg) for 5 days. The mice were monitored for 7 days with weight and survival. Colon and cecum tissues were harvested for histological assessment. Results: CDI of mice caused 80% mortality. Fidaxomicin completely protected against CDI in all parameters (weight, survival and pathscores). Mortality rates were up to 90%, 70% in budesonide(10 mg/kg) and mesalamine (400 mg/kg) treatment group, respectively. Budesonide (0.02,0.1 and 1 mg/kg) adjunction to fidaxomicin worsened the disease outcome according to all tested parameters. While mesalamine in combination with fidaxomicin (200, 400 mg/kg) did not lead to any deaths during CDI treatment, it did not provide additional benefits. Conclusions: Anti-inflammatory drugs including corticosteroid therapy may worsen the incidence and severity of CDI in this mouse model. These studies may have important clinical implications for understanding the role of anti-inflammatory/ corticosteroid therapy in CDI and inflammatory bowel disease management.

Dimethyl disulfide (DMDS) is a relatively new soil fumigant used in agro-industrial crop production to control soil-borne pests that damage crops and reduce yield. The emissions of DMDS after fumigation reduce soil concentrations thus reducing the risk of phytotoxicity to newly planted crops. However, the factors affecting the desorption of DMDS from soil are unclear. In our study, the desorption characteristics of DMDS from soil were measured in response to continuous ventilation. The degradation of DMDS in soil was examined by thermal incubation. The phytotoxic response of newly-planted cucumber (Cucumis sativus) seedlings to DMDS residues was measured by a sand culture experiment. The results showed DMDS desorption and degradation rates fit a first-order model; that 92% of the DMDS desorption occurred in the first hour after fumigant application; and that residue concentrations in the soil at the end of the ventilation period were unlikely to be phytotoxic to newly-planted cucumber seedlings. By the third day of ventilation, the average desorption rate (ADR) of DMDS in Wenshan soil was 4.0 and 3.6 times, respectively, faster than that in Shunyi and Suihua soils and the ADR of DMDS in soil decreased by 40.0% when the soil moisture content increased from 3% to 12% (wt/wt). Moreover, within one hour of ventilation, the ADR of DMDS in soil decreased by 20.1% when the soil bulk density increased from 1.1 to 1.3 g cm-3. The degradation of DMDS in soil, however, was mostly influenced by soil type and moisture content. A slow degradation rate resulted in a high initial desorption concentration of DMDS in soil. Our results indicated that DMDS desorption from soil in response to continuous ventilation was affected by the soil type, moisture content and bulk density. Rapid degradation of DMDS in soil will lower the risk of phytotoxic residues remaining in the soil and reduce emissions during the waiting period. Acceleration of emissions early in the waiting period by managing soil moisture content or increasing soil porosity may shorten the duration of emissions. Alternatively, soil extraction technology could be developed to recover and reduce fumigant emissions.

Abstract Anti‐angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti‐angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4‐acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF‐1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP‐sequencing, Ribosome profiling sequencing, RNA‐sequencing, and functional studies confirm that NAT10 in turn activates the HIF‐1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF‐1α positive feedback loop leads to excessive activation of the HIF‐1 pathway and induces glycolysis addiction. Combined anti‐angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti‐angiogenic therapy by combining apatinib with ac4C inhibition.

Abstract Background Peritoneal metastasis (PM) is not uncommon in patients with gastric cancer(GC), which affects clinical treatment decisions, but the relevant examination measures are not efficiently detected. Our goal was to develop a clinical radiomics nomogram to better predict peritoneal metastases. Methods A total of 3480 patients from 2 centers were divided into 1 training, 1 internal validation, and 1 external validation cohort(1949 in the internal training set, 704 in the validation set, and 827 in the external validation cohort) with clinicopathologically confirmed GC. We recruited 11 clinical factors, including age, sex, smoking status, tumor size, differentiation, Borrmann type, location, clinical T stage, and serum tumor markers (STMs) comprising carbohydrate antigen 19–9 (CA19-9), carbohydrate antigen 72–4 (CA72-4), and carcinoembryonic antigen (CEA), to develop the radiomics nomogram. For clinical predictive feature selection and the establishment of clinical models, statistical methods of analysis of variance (ANOVA), relief and recursive feature elimination (RFE) and logistic regression analysis were used. To develop combined predictive models, tumor diameter, type, and location, clinical T stage and STMs were finally selected. The discriminatory ability of the nomogram to predict PM was evaluated by the area under the receiver operating characteristic curve(AUC), and decision curve analysis (DCA) was conducted to evaluate the clinical usefulness of the nomogram. Results The AUC of the clinical models was 0.762 in the training cohorts, 0.772 in the internal validation cohort, and 0.758 in the external validation cohort. However, when combined with STMs, the AUC was improved to 0.806, 0.839 and 0.801, respectively. DCA showed that the combined nomogram was of good clinical evaluation value to predict PM in GC. Conclusions The present study proposed a clinical nomogram with a combination of clinical risk factors and radiomics features that can potentially be applied in the individualized preoperative prediction of PM in GC patients.

An outbreak of COVID-19 caused by the SARS-CoV-2 Omicron BA.2 sublineage occurred in Shanghai, China from February 26 to June 30, 2022. We use official reported data retrieved from Shanghai municipal Health Commissions to estimate the incidence of infections, severe/critical infections, and deaths to assess the disease burden. By adjusting for right censoring and RT-PCR sensitivity, we provide estimates of clinical severity, including the infection fatality ratio, symptomatic case fatality ratio, and risk of developing severe/critical disease upon infection. The overall infection rate, severe/critical infection rate, and mortality rate were 2.74 (95% CI: 2.73-2.74) per 100 individuals, 6.34 (95% CI: 6.02-6.66) per 100,000 individuals and 2.42 (95% CI: 2.23-2.62) per 100,000 individuals, respectively. The severe/critical infection rate and mortality rate increased with age, noted in individuals aged 80 years or older. The overall fatality ratio and risk of developing severe/critical disease upon infection were 0.09% (95% CI: 0.09-0.10%) and 0.27% (95% CI: 0.24-0.29%), respectively. Having received at least one vaccine dose led to a 10-fold reduction in the risk of death for infected individuals aged 80 years or older. Under the repeated population-based screenings and strict intervention policies implemented in Shanghai, our results found a lower disease burden and mortality of the outbreak compared to other settings and countries, showing the impact of the successful outbreak containment in Shanghai. The estimated low clinical severity of this Omicron BA.2 epidemic in Shanghai highlight the key contribution of vaccination and availability of hospital beds to reduce the risk of death.

Rumen microbes play an important role in ruminant energy supply and animal performance. Previous studies showed that yak (Bos grunniens) rumen microbiome and fermentation differ from other ruminants. However, little is understood about the features of the rumen microbiome that make yak adapted to their unique environmental and dietary conditions. This study was to investigate the rumen microbiome and metabolome to understand how yak adapt to the coarse forage and harsh environment in the Qinghai-Tibetan plateau. Nine female Qaidam yellow cattle (Bos taurus), 9 dzomo (hybrids of cattle and yak) and 9 female plateau yak (B. grunniens), about 5 to 6 years old, were used in this study. Rumen fermentation parameters, fibrolytic enzyme activities, and rumen metataxonomic were determined. Then 18 (6 samples per group) were selected for rumen metagenomic and metabolome analysis. Metataxonomic analysis revealed that the rumen microbiota was significantly different among plateau yak, Qaidam yellow cattle, and dzomo (P

SARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. Over 92% of the Chinese population aged ≥12 years has been fully vaccinated against COVID-19 (albeit with vaccines developed against historical lineages). At the end of October 2021, the vaccination programme has been extended to children aged 3–11 years. Here, we aim to assess whether, in this vaccination landscape, the importation of Delta variant infections could shift COVID-19 burden from adults to children. We developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission to simulate epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalizations, intensive care unit admissions, and deaths. In the context of the vaccination programme targeting individuals aged ≥12 years, and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could have led to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 89% across the eligible age groups. Extending the vaccination roll-out to include children aged 3–11 years (as it was the case since the end of October 2021) is estimated to dramatically decrease the burden of symptomatic infections and hospitalizations within this age group (39% and 68%, respectively, when considering a vaccination coverage of 87%), but would have a low impact on protecting infants. Our findings highlight the importance of including children among the target population and the need to strengthen vaccination efforts by increasing vaccine effectiveness.

Abstract Background A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. Methods Two population-based longitudinal cohorts in southern China were studied during 2013–2018. Participants were enrolled in autumn 2013, including 2475 children aged 1–9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. Results The average maternal antibody transfer ratio was 0.88 (95% CI 0.80–0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9–2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. Conclusions Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0–5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

Abstract Background Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we investigated the effect of raltitrexed on the proliferation of HGC-27 human gastric cancer cells and its potential underlying molecular mechanism(s). Methods RT-qPCR and western blotting were used to quantify RSK4 levels. Colony formation and flow cytometry assays were used to assess HGC-27 cell proliferation, cell cycle progression, mitochondrial membrane potential, and apoptosis. The expression of cell cycle and apoptosis markers were determined by western blotting. Results Our results demonstrate that raltitrexed upregulated RSK4 mRNA and protein levels in HGC-27 cells. Moreover, raltitrexed significantly inhibited tumor cell colony formation, arrested the cell cycle, decreased the mitochondrial membrane potential, and induced apoptosis. We observed that raltitrexed was capable of upregulating the expression of Bax, cyclin A1, and CDK3, and downregulating the expression of Bcl-2 and cleaved caspase-3. Importantly, siRNA-mediated RSK4 knockdown significantly reduced the inhibitory effect of raltitrexed on cell proliferation and its promotion of cell apoptosis. Moreover, silencing of RSK4 inhibited the raltitrexed-induced upregulation of cytochrome C. In addition, the changes in molecular markers related to the cell cycle and apoptosis induced by raltitrexed were reduced upon RSK4 depletion. Conclusion Our study shows that RSK4 is a key target of raltitrexed in the regulation of gastric cancer cell proliferation, cell cycle progression, and apoptosis.

BackgroundTension-type headache (TTH) is one of the most common primary headaches. Several studies have confirmed the efficacy of acupuncture therapies for TTH, but it is uncertain which treatment is most effective.ObjectiveThis study aimed to compare the effectiveness and safety of different acupuncture therapies for TTH using Bayesian Network Meta-analysis to provide new ideas for treating TTH.MethodsNine databases were searched for randomized controlled trials (RCTs) about different acupuncture therapies for TTH up to December 1, 2022. The outcome indicators analyzed in our study were total effective rate, visual analog scale (VAS), headache frequency, and safety. Pairwise meta-analysis and risk of bias assessment were performed using Review Manager 5.4. Stata 15.0 generated a network evidence plot and detected publication bias. Finally, a Bayesian network meta-analysis of the data was used by RStudio.ResultsThe screening process resulted in 30 RCTs that met the inclusion criteria, including 2,722 patients. Most studies failed to report details of trials and were therefore assessed as unclear risks. Two studies were considered high risk because they did not report on all pre-specified outcome indicators or had incomplete data on outcome indicators. The NMA results showed that for total effective rate, bloodletting therapy had the most considerable SUCRA value (0.93156136), for VAS, head acupuncture combined with Western medicine ranked first (SUCRA = 0.89523571), and acupuncture combined with herbal medicine was the most effective in improving headache frequency (p > 0.05).ConclusionAcupuncture can be used as one of the complementary or alternative therapies for TTH; bloodletting therapy better improves the overall symptoms of TTH, head acupuncture combined with Western medicine is more effective in reducing VAS scores, and acupuncture combined with herbal medicine seems to reduce headache frequency, but the difference is not statistically significant. Overall, acupuncture for TTH is effective with mild side effects, but future high-quality studies are still necessary.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, PROSPERO [CRD42022368749].

An 8 weeks feeding trail was conducted to evaluate the potential of poultry by-product meal (PBM) replacing fish meal (FM) in the diet of juvenile large yellow croaker (Larimichthys crocea). Five iso-nitrogenous (45% crude protein), iso-lipidic (10% crude lipid) and iso-energetic (about kcal 400 g diet −1) diets were formulated with 0, 25%, 50% 75% and 100% FM being replaced by PBM (marked as FM, PBM25, PBM50, PBM75 and PBM100). Crystal methionine and lysine were added into PBM-containing diets to match its concentration in FM diet. Each diet was randomly assigned to triplicate groups of 30 fish (initial weight 18.43 ± 1.28 g) in floating sea cages. The weight gain, specific growth rate and feed efficiency of L. crocea decreased significantly when the replacement level of FM was higher than 25%. The feed intake of fish fed PBM100 was significantly lower than those fed FM, PBM25 and PBM50. Juveniles fed PBM-containing diets showed significantly lower value of muscular thickness in intestine when compared to those fed FM. Villi length decreased significantly when the replacement of FM in diets was more than 50%. Fish fed FM diet had the relative higher abundances of Exiguobacterium (from order to genus), Bacillus (from order to genus), Pseudomonadales (from order to genus) and Acinetobacter genus, those fed PBM25, PBM50 and/or PBM75 showed higher abundance of Peptostreptococcaceae and Vibrio. Overall, PBM replacing dietary FM may inhibit growth performance of L. crocea through reducing digestibility via declining the abundance of intestinal bacteria that producing digestive enzyme, and improving the abundance of pathogen. Peptostreptococcaceae and Vibrio could be the indicator in the intestinal of L. crocea fed high PBM diets. The optimum dietary FM replacement level by PBM was 25% for L. crocea.

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. Nanosecond pulsed electric fields (nsPEFs) have emerged as a new treatment for cancer. This study aims to identify the effectiveness of nsPEFs in the treatment of HCC and analyze the alterations in the gut microbiome and serum metabonomics after ablation.Methods: C57BL/6 mice were randomly divided into three groups: healthy control mice (n = 10), HCC mice (n = 10), and nsPEF-treated HCC mice (n = 23). Hep1-6 cell lines were used to establish the HCC model in situ. Histopathological staining was performed on tumor tissues. The gut microbiome was analyzed by 16S rRNA sequencing. Serum metabolites were analyzed by liquid chromatography–mass spectrometry (LC-MS) metabolomic analysis. Spearman’s correlation analysis was carried out to analyze the correlation between the gut microbiome and serum metabonomics.Results: The fluorescence image showed that nsPEFs were significantly effective. Histopathological staining identified nuclear pyknosis and cell necrosis in the nsPEF group. The expression of CD34, PCNA, and VEGF decreased significantly in the nsPEF group. Compared with normal mice, the gut microbiome diversity of HCC mice was increased. Eight genera including Alistipes and Muribaculaceae were enriched in the HCC group. Inversely, these genera decreased in the nsPEF group. LC-MS analysis confirmed that there were significant differences in serum metabolism among the three groups. Correlation analysis showed crucial relationships between the gut microbiome and serum metabolites that are involved in nsPEF ablation of HCC.Conclusion: As a new minimally invasive treatment for tumor ablation, nsPEFs have an excellent ablation effect. The alterations in the gut microbiome and serum metabolites may participate in the prognosis of HCC ablation.

Shanghai and Hong Kong, China, experienced an outbreak of COVID-19 in early 2022. Both cities had similar dynamic prevention policies and population-level immunity, but showed differences in the numbers of cases and deaths. We collected data from official websites to estimate and compare the infection rates, mortality rates, and infection fatality ratios (IFRs) between cities. We further performed univariable analysis and used two tree models to explore the factors affecting the differences. The infection rate in Hong Kong, China, was 42.45 (95% CI: 42.41–42.48) per 100 individuals (15.49 times higher than that in Shanghai). The mortality rate was 124.90 (95% CI: 122.33–127.46) per 100,000 individuals (51.61 times higher than that in Shanghai). The adjusted IFR was 0.29% (95% CI: 0.29–0.30%) (3.30 times higher than that in Shanghai). The infection rate was negatively correlated with the stringency of nonpharmaceutical interventions. The mortality rate and IFR negatively correlated with the vaccination rate. However, positive correlations were observed between the median age and both mortality and IFR, as well as between the proportion of people ≥65 and IFR. Overall, a lack of medical resources, lower vaccination rates, and higher median age were associated with a higher infection rate, mortality rate, and IFR in Hong Kong.

Following a booster dose of CoronaVac in two single-centre phase 2 clinical trials, the authors show that neutralising antibody titres decline approximately 4-fold and 2.5-fold from day 28 to day 180 in adults aged 18-59 years and in adults aged 60 years and older, respectively.

Abstract. Background:. Previous studies have revealed that diabetes mellitus (DM) promotes disease progress of gastric cancer (GC). This study aimed to further investigating whether DM advanced lymph nodes (LNs) metastasis in GC. Methods:. The clinicopathologic data of GC patients with >15 examined LN (ELN) between October 2004 and December 2019 from a prospectively maintained database were included. The observational outcomes included the number (N3b status) and anatomical distribution (N3 stations) of metastatic LN (MLN). Results:. A total of 2142 eligible patients were included in the study between October 2004 and December 2019. N3 stations metastasis (26.8% in DM vs. 19.3% in non-DM, P = 0.026) and N3b status (18.8% in DM vs. 12.8% in non-DM, P = 0.039) were more advanced in the DM group, and multivariate logistic regression analyses confirmed that DM was an independent factor of developing N3 stations metastasis (odds ratio [OR] = 1.771, P = 0.011) and N3b status (OR = 1.752, P = 0.028). Also, multivariate analyses determined DM was independently associated with more MLN (β = 1.424, P = 0.047). The preponderance of N3 stations metastasis (DM vs. non-DM, T1–2: 2.2% vs. 4.9%, T3: 29.0% vs. 20.3%, T4a: 38.9% vs. 25.8%, T4b: 50.0% vs. 36.6%; ELN16–29: 8.6% vs. 10.4%, ELN30–44: 27.9% vs. 20.5%, ELN ≥ 45: 37.7% vs. 25.3%), N3b status (DM vs. non-DM, T1–2: 0% vs. 1.7%, T3: 16.1% vs. 5.1%, T4a: 27.8% vs. 19.1%, T4b: 44.0% vs. 28.0%; ELN16–29: 8.6% vs. 7.9%, ELN30–44: 18.0% vs. 11.8%, ELN ≥ 45: 26.4% vs. 17.3%), and the number of MLN (DM vs. non-DM, T1–2: 0.4 vs. 1.1, T3: 8.6 vs. 5.2, T4a: 9.7 vs. 8.6, T4b: 17.0 vs. 12.8; ELN16–29: 3.6 vs. 4.6, ELN30–44: 5.8 vs. 5.5, ELN ≥ 45: 12.0 vs. 7.7) of DM group increased with the advancement of primary tumor depth stage and raising of ELN. Conclusions:. DM was an independent risk factor for promoting LN metastasis. The preponderance of LN involvement in the DM group was aggravated with the advancement of tumor depth.

Masson pine (Pinus massoniana Lamb.) is a major fast-growing woody tree species and pioneer species for afforestation in barren sites in southern China. However, the regulatory mechanism of gene expression in P. massoniana under drought remains unclear. To uncover candidate microRNAs, their expression profiles, and microRNA-mRNA interactions, small RNA-seq was used to investigate the transcriptome from seedling roots under drought and rewatering in P. massoniana. A total of 421 plant microRNAs were identified. Pairwise differential expression analysis between treatment and control groups unveiled 134, 156, and 96 differential expressed microRNAs at three stages. These constitute 248 unique microRNAs, which were subsequently categorized into six clusters based on their expression profiles. Degradome sequencing revealed that these 248 differentially expressed microRNAs targeted 2069 genes. Gene Ontology enrichment analysis suggested that these target genes were related to translational and posttranslational regulation, cell wall modification, and reactive oxygen species scavenging. miRNAs such as miR482, miR398, miR11571, miR396, miR166, miRN88, and miRN74, along with their target genes annotated as F-box/kelch-repeat protein, 60S ribosomal protein, copper-zinc superoxide dismutase, luminal-binding protein, S-adenosylmethionine synthase, and Early Responsive to Dehydration Stress may play critical roles in drought response. This study provides insights into microRNA responsive to drought and rewatering in Masson pine and advances the understanding of drought tolerance mechanisms in Pinus.

Abstract Background Evidence on vaccine-specific protection over time, in particular against the Delta variant, and protection afforded by a homologous third dose is urgently needed. Methods We used a previously published model and neutralization data for five vaccines—mRNA-1273, BNT162b2, NVX-CoV2373, V01, and CoronaVac— to evaluate long-term neutralizing antibody dynamics and predict time-varying efficacy against the Delta variant by specific vaccine, age group, and clinical severity. Results We found that homologous third-dose vaccination produces higher neutralization titers compared with titers observed following primary-series vaccination for all vaccines studied. We estimate the efficacy of mRNA-1273 and BNT162b2 against Delta variant infection to be 63.5% (95% CI: 51.4–67.3%) and 78.4% (95% CI: 72.2–83.5%), respectively, 14–30 days after the second dose, and that efficacy decreases to 36.0% (95% CI: 24.1–58.0%) and 38.5% (95% CI: 28.7–49.1%) 6–8 months later. Fourteen to 30 days after administration of homologous third doses, efficacy against the Delta variant would be 97.0% (95% CI: 96.4–98.5%) and 97.2% (95.7–98.1%). All five vaccines are predicted to provide good protection against severe illness from the Delta variant after both primary and homologous third dose vaccination. Conclusions Timely administration of third doses of SARS-CoV-2-prototype-based vaccines can provide protection against the Delta variant, with better performance from mRNA vaccines than from protein and inactivated vaccines. Irrespective of vaccine technology, a homologous third dose for all types of vaccines included in the study will effectively prevent symptomatic and severe COVID-19 caused by the Delta variant. Long-term monitoring and surveillance of antibody dynamics and vaccine protection, as well as further validation of neutralizing antibody levels or other markers that can serve as correlates of protection against SARS-CoV-2 and its variants, are needed to inform COVID-19 pandemic responses.

Abstract Background To allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs. Methods We developed a compartmental model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. Two vaccination programs were tested and model-based estimates of the immunity level in the population were provided. Results We found that it is unlikely to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021 and the lack of prior natural immunity. We estimated that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 50–62% in case of an all-or-nothing vaccine model and an epidemic starts to unfold on December 1, 2021. Conclusions Efforts should be taken to increase population’s confidence and willingness to be vaccinated and to develop highly efficacious vaccines for a wide age range.

The present study investigated the growth performance, feed utilization, intestinal morphology, and microbiota communities of juvenile large yellow croaker (Larimichthys crocea) fed diets containing different proportions of soy protein concentrate (SPC) (0, 15%, 30%, and 45%, namely FM, SPC15, SPC30, and SPC45) as a substitute for fish meal (FM) for 8 weeks. The weight gain (WG) and specific growth rate (SGR) in fish fed SPC45 were significantly lower than those fed FM and SPC15 but not differ with these fed SPC30. The feed efficiency (FE) and protein efficiency ratio (PER) decreased sharply when the dietary SPC inclusion level was higher than 15%. The activity of alanine aminotransferase (ALT) and expression of alt and aspartate aminotransferase (ast) were significantly higher in fish fed SPC45 than those fed FM. The activity and mRNA expression of acid phosphatase were opposite. The villi height (VH) in distal intestine (DI) showed a significant quadratic response to increasing dietary SPC inclusion levels and was highest in SPC15. The VH in proximal intestine, middle intestine decreased significantly with increasing dietary SPC levels. The 16S rRNA sequences in intestine revealed that fish fed SPC15 had higher bacterial diversity and abundance of Phylum Firmicutes such as order Lactobacillales and order Rhizobiaceae than those fed other diets. Genus vibrio, family Vibrionaceae and order Vibrionales within phylum Proteobacteria were enriched in fish fed FM and SPC30 diets. Tyzzerella and Shewanella that belongs to phylum Firmicutes and Proteobacteria, respectively, were enriched in fish fed SPC45 diet. Our results indicated that SPC replacing more than 30% FM could lead to lower quality diet, retard growth performance, ill health, disordered intestine structure, and microbiota communities. Tyzzerella could be the bacteria indicator of intestinal in large yellow croaker fed low quality diet due to high SPC content. Based on the quadratic regression analysis of WG, the best growth performance could be observed when the replacement of FM with SPC was 9.75%.

The overuse of antibiotics leads to the emergence of bacterial resistance, which poses a serious threat to aquaculture. Antimicrobial peptides (AMPs) display excellent antimicrobial activity and are thought to be the most feasible replacements for antibiotics. The usage of AMPs as feed additives has great application prospects in aquaculture. In this study, large yellow croaker interferon-γ related gene (IFNG1R) was cloned, and a 17-amino acids (aa) short peptide named SKL17-2 was synthesized based on its protein sequence. The synthesized SKL17-2 peptide possessed a strong antimicrobial activity against Pseudomonas plecoglossicida, which could cause visceral white nodules disease (VWND) in cultured marine fish, with a minimum inhibitory concentration (MIC) of 2 μM. SKL17-2 peptide also showed weak antimicrobial activities against other tested bacteria, indicating its narrow-spectrum antimicrobial activity. This suggested that SKL17-2 peptide may not kill probiotics in intestinal flora when used as the feed additive. Furthermore, SKL17-2 had broad temperature and pH stability, low cytotoxicity, and negligible hemolysis, indicating its good biosafety and stability. Mechanistically, the synthesized SKL17-2 peptide can form α-helical structure in a membrane environment and destroy P. plecoglossicida through membrane disruption. Thus, our data showed that SKL17-2 peptide may represent a potential feed additive used for prevention and treatment of VWND.

Summary: How organisms cope with coldness and high pressure in the hadal zone remains poorly understood. Here, we sequenced and assembled the genome of hadal sea cucumber Paelopatides sp. Yap with high quality and explored its potential mechanisms for deep-sea adaptation. First, the expansion of ACOX1 for rate-limiting enzyme in the DHA synthesis pathway, increased DHA content in the phospholipid bilayer, and positive selection of EPT1 may maintain cell membrane fluidity. Second, three genes for translation initiation factors and two for ribosomal proteins underwent expansion, and three ribosomal protein genes were positively selected, which may ameliorate the protein synthesis inhibition or ribosome dissociation in the hadal zone. Third, expansion and positive selection of genes associated with stalled replication fork recovery and DNA repair suggest improvements in DNA protection. This is the first genome sequence of a hadal invertebrate. Our results provide insights into the genetic adaptations used by invertebrate in deep oceans.

Tris (2-chloroethyl) phosphate (TCEP), an emerging environmental pollutant, has been frequently detected in natural waters. The objective of this study was to investigate possible parental transfer of TCEP and transgenerational effects on the early development and thyroid hormone homeostasis in F1 larvae following parental whole life-cycle exposure to TCEP. To this end, zebrafish (Danio rerio) embryos were exposed to environmentally relevant concentrations (0.8, 4, 20 and 100 μg/L) of TCEP for 120 days until sexual maturation. Parental exposure to TCEP resulted in significant levels of TCEP, developmental toxicity including decreased survival and final hatching rates, accelerated heart rate and elevated malformation rate, as well as induction of oxidative stress and cell apoptosis in F1 offspring. In F1 eggs, declined thyroxin (T4) levels were observed, consistent with those in plasma of F0 adult females, indicating the maternal transfer of thyroid endocrine disruption to the offspring. In addition, mRNA levels of several genes along the hypothalamic-pituitary-thyroid (HPT) axis were significantly modified in F1 larvae, which could be linked to transgenerational developmental toxicity and thyroid hormone disruption. For the first time, we revealed that the parental exposure to environmentally relevant levels of TCEP could cause developmental toxicity and thyroid endocrine disruption in subsequent unexposed generation.

BackgroundThe specific efficacy of immunotherapy for patients with liver metastases of gastric cancer is unclear. This study set out to explore the treatment response and related prognostic factors for patients with liver metastases of gastric cancer treated with immunotherapy.Patients and methodsThis retrospective cohort study included 135 patients with unresectable advanced gastric cancer. According to the presence of liver metastases and/or first-line treatment with immunotherapy, patients were divided into the following three groups: I-LM(-) group(patients without liver metastases treated with immunotherapy, n=66), I-LM(+) group(patients with liver metastases treated with immunotherapy, n=36), C-LM(+) group(patients with liver metastases treated with chemotherapy and/or target therapy, n=33). Cox regression analyses were used to identify factors associated with survival in all patients and the three groups, respectively.ResultsFor the patients with liver metastases treated with immunotherapy, multivariate analysis showed that only the presence of peritoneal metastases was significantly associated with shorter PFS [hazard ratios (HR), 3.23; 95% CI, 1.12-9.32; P=0.030] and the patients with peritoneal metastases had shorter median PFS than patients without peritoneal metastases(3.1 vs 18.4 months; P=0.004), while the objective response rate was 100% in patients with HER2-positive (2 complete radiographic responses and 2 partial responses; 3 of 4 patients were still ongoing benefits [median follow-up time, 15.3 months ; interquartile range(IQR), 6.3-17.9 months]).ConclusionsThe findings suggest that patients with various types of gastric cancer liver metastases respond differently to immune checkpoint inhibitors, HER2-positive patients may derive clinical benefits from immune checkpoint inhibitors, while the presence of peritoneal metastases is associated with resistance.

ObjectiveWe investigate the characteristics of histological damage to myocardial cells in the ablation region and surrounding areas of the left ventricular epicardium in rabbits using our self-developed cardiac pulsed electric field (PEF) ablation instrument and ablation catheter.MethodsForty eight New Zealand rabbits underwent ablation on the left ventricular myocardium after open-heart exposure with a cardiac arrhythmia PEF ablation device and ablation catheter developed by the Medical Translation Laboratory of Pulsed Electric Field Technology in Zhejiang Province. The ablation parameters were set as biphasic electrical pulses; voltage, ±800 V; pulse width, 10 μs; interphase delay, 500 us. Six rabbits were included in the sham group and 42 other rabbits were randomly divided into immediately, 6-h, 1-, 3-day, 1-, 2-, and 4-week post-ablation groups, with six rabbits in each group. Creatine kinase- (CK)-MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were measured before and at different time points after PEF ablation to analyze their dynamic evolution. Masson staining of tissue block sections of left ventricular myocardial ablation and adjacent tissue heart specimens was performed, and the occurrence of TUNEL apoptosis in myocardium tissue was analyzed.ResultsAll rabbits completed the PEF ablation procedure and the follow-up process. After PEF ablation, the levels of cardiac enzymes, including CK-MB, CK, and AST, increased significantly, peaking 1–3 days after the procedure. In particular, those of CK and CK-MB increased by 15–20 times but returned to the preoperative level after 2 weeks. Based on general observation, it was found that the myocardium in the ablation area was swollen immediately after PEF ablation. Masson staining analysis revealed that cardiomyocytes were broken and infiltrated by erythrocytes after 6 h. After 1 day, the cells started to experience atrophy and necrosis; after 3 days, fibrotic replacement of the necrotic area became obvious. Then, by 4 weeks, the myocardial cells were completely replaced by hyperplasia. Apoptosis occurred significantly at 6 h and peaked at 24 h post-ablation, demonstrating a 37.7-fold increase; apoptotic cell counts decreased significantly at 3 days post-ablation, and no significant apoptotic cardiomyocytes were seen after 1 week.ConclusionAfter PEF ablation, cardiomyocytes showed apoptotic process and dyed, at least partially, through a secondary necrosis, the ablation boundary was clear, the ablation area was replaced by structurally intact fibroblasts, no island myocardium tissue were seen, and the ablation area vessels and nerves were not affected.