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Abstract Background Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. Objectives Investigate the therapeutic effects and the mechanism of SAL on PAH. Methods Monocrotaline was used to establish a PAH rat model. SAL’s impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL’s metabolic regulatory mechanisms. Results SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. Conclusions SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling.

Abstract Ustilago maydis is a pathogenic fungus in Basidiomycota causing corn smut disease. A strain of U. maydis YZZF202006 was isolated from the tumor of corn smut collected from Jingzhou city in China. The intracellular bacteria were confirmed inner hyphal of the strain YZZF202006 by PCR amplification and fluorescence in situ hybridization (FISH) and SYTO-9. An endohyphal bacterium YZUMF202001 was isolated from the protoplasts of the strain YZZF202006. It was gram-negative, short rod-shaped with smooth light yellow colony. The endohyphal bacterium was genomic evidenced as Klebsiella michiganensis on the basis of average nucleotide identity (ANI) analysis and the phylogram. Then K. michiganensis was GFP-Labeled and reintroduced into U. maydis, which confirmed the bacterium can live in hyphae of U.maydis. The bacterium can grow on N-free culture media. Its nitrogenase activity was reached av. 646.25 ± 38.61 nmol·mL− 1·h− 1 C2H4 by acetylene reduction assay. A cluster of nitrogen fixation genes (nifJHDKTXENXUSVWZMFLABQ) was found from its genome. The endohyphal K. michiganensis may play an important role to help nitrogen fixation for fungi in the future.

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Spin effect of the small diameter shaped charge results in the centrifugal stress during the jet stretching process. Consequently, the jet scatters, which deceases the jet penetration capability. In the present study, a multi-section method was proposed to design the spin-compensation liner. The spin-compensation rate (SCR) of the liner was defined as the specific angular velocity that a fluted liner can offset. Based on the plain stress theory, SPH numerical method was applied to study the converging process of the 2D fluted structure. The spin-compensation mechanism of the fluted structure was illustrated. Then, nine cross sections were chosen along the liner axis equidistantly. On each of the section, a 2D fluted structure was designed to offset a given initial angular velocity. After, the optimized fluted structures were integrated into a 3D fluted liner. Jet appearances of the normal liner and the fluted liners under different initial angular velocities were compared, which verifies the practicality of the multi-sectional method. The multi-section optimization method provides a new efficient method of designing the shaped charge liner for a specific usage.

The identification of aging- and longevity-associated genes is important for promoting healthy aging. By analyzing a large cohort of Chinese centenarians, we previously found that single-nucleotide polymorphisms (SNPs) in the SLC39A11 gene (also known as ZIP11) are associated with longevity in males. However, the function of the SLC39A11 protein remains unclear. Here, we found that SLC39A11 expression is significantly reduced in patients with Hutchinson–Gilford progeria syndrome (HGPS). In addition, we found that zebrafish with a mutation in slc39a11 that significantly reduces its expression have an accelerated aging phenotype, including a shortened average lifespan, muscle atrophy and reduced swimming, impaired muscle regeneration, gut damage, and abnormal morphology in the reproductive system. Interestingly, these signs of premature aging were more pronounced in male zebrafish than in females. RNA-sequencing analysis revealed that cellular senescence may serve as a potential mechanism for driving this slc39a11 deficiency-induced phenotype in mutant zebrafish. Moreover, immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in slc39a11 mutant zebrafish. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that manganese significantly accumulates in slc39a11 mutant zebrafish, as well as in the serum of both global Slc39a11 knockout and hepatocyte-specific Slc39a11 knockout mice, suggesting that this metal transporter regulates systemic manganese levels. Finally, using cultured human fibroblasts, we found that both knocking down SLC39A11 and exposure to high extracellular manganese increased cellular senescence. These findings provide compelling evidence that SLC39A11 serves to protect against the aging process, at least in part by regulating cellular manganese homeostasis.

Lichens exist in an organismal organization of mycobiont, photobiont, and non-photoautotrophic bacteria. These organisms contribute to the growth of lichens even in poor nutrition substrates. However, studies on the isolation and application of non-photoautotrophic bacteria in plant growth and biocontrol are scanty. Therefore, a study was conducted to isolate and evaluate the potential of non-photoautotrophic bacteria from lichen tissues in maize plant growth promotion and biocontrol of plant pathogens (fungi and bacteria). Five bacterial strains were isolated and tested for their ability to produce indole-3-Acetic Acid (IAA). One bacterium named YZCUO202005 produced IAA, siderophores and biofilms, solubilized phosphate and potassium and exhibited extracellular enzymes (cellulases, proteases, amylase, and β −1,3-Glucanase). Based on the 16S rRNA sequence analysis results, YZCUO202005 was identified as Bacillus licheniformis. The strain inhibited the growth of five pathogenic fungi with an inhibition percent of between 58.7% and 71.7% and two pathogenic bacteria. Under greenhouse conditions, YZCUO202005 was tested for its abilities to enhance maize seed germination, and vegetative growth. Compared with the control treatment, the strain significantly enhanced the growth of stem length (i.e. 18 ± 0.64 cm, 78 ± 0.92 cm), leaf length (i.e. 10 ± 0.36 cm, 57 ± 1.42 cm), leaf chlorophyll levels (i.e., 13 ± 0.40, 40 ± 0.43 SPAD), and root length (i.e, 9.8 ± 2.25 cm, 22.5 ± 6.59 cm). Our results demonstrated that B. licheniformis YZCUO202005 from lichens has the potential to promote plant growth and reduce fungal and bacterial pathogens’ growth. Furthermore, the results suggest that lichens are naturally rich sources of plant growth promotion and biocontrol agents that would be used in agriculture.

Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates.

Abstract Aiming at solving the trouble that digital image information is easily intercepted and tampered during transmission, we proposed a color image encryption scheme based on alternate quantum random walk and controlled Rubik’s Cube transformation. At the first, the color image is separated into three channels: channel R, channel G and channel B. Besides, a random sequence is generated by alternate quantum walk. Then the six faces of the Rubik’s Cube are decomposed and arranged in a specific order on a two-dimensional plane, and each pixel of the image is randomly mapped to the Rubik’s Cube. The whirling of the Rubik’s Cube is controlled by a random sequence to realize image scrambling and encryption. The scrambled image acquired by Rubik’s Cube whirling and the random sequence received by alternate quantum walk are bitwise-XORed to obtain a single-channel encrypted image. Finally the three-channel image is merged to acquire the final encrypted image. The decryption procedure is the reverse procedure of the encryption procedure. The key space of this scheme is theoretically infinite. After simulation experiments, the information entropy after encryption reaches 7.999, the NPCR is 99.5978%, and the UACI is 33.4317%. The encryption scheme with high robustness and security has a excellent encryption effect which is effective to resist statistical attacks, force attacks, and other differential attacks.

INTRODUCTION: Connections between environmental factors and mental health issues have been postulated in many different countries around the world. Previously undertaken research has shown many possible connections between these fields, especially in relation to air quality and extreme weather events. However, research on this subject is lacking in New Zealand, which is difficult to analyse as an overall nation due to its many micro-climates and regional differences. OBJECTIVES: The aim of this study and subsequent analysis is to explore the associations between environmental factors and poor mental health outcomes in New Zealand by region and predict the number of people with mental health-related illnesses corresponding to the environmental influence. METHODS: Data are collected from various public-available sources, e.g., Stats NZ and Coronial services of New Zealand, which comprised four environmental factors of our interest and two mental health indicators data ranging from 2016 up until 2020. The four environmental factors are air pollution, earthquakes, rainfall and temperature. Two mental health indicators include the number of people seen by District Health Boards (DHBs) for mental health reasons and the statistics on suicide deaths. The initial analysis is carried out on which regions were most affected by the chosen environmental factors. Further analysis using Auto-Regressive Integrated Moving Average(ARIMA) creates a model based on time series of environmental data to generate estimation for the next two years and mental health projected from the ridge regression. RESULTS: In our initial analysis, the environmental data was graphed along with mental health outcomes in regional charts to identify possible associations. Different regions of New Zealand demonstrate quite different relationships between the environmental data and mental health outcomes. The result of later analysis predicts that the suicide rate and DHB mental health visits may increase in Wellington, drop-in Hawke's Bay and slightly increase in Canterbury for the year 2021 and 2022 with different environmental factors considered. CONCLUSION: It is evident that the relationship between environmental and mental health factors is regional and not national due to the many micro-climates that exist around the nation. However, it was observed that not all factors displayed a good relationship between the regions. We conclude that our hypotheses were partially correct, in that increased air pollution was found to correlate to increased mental health-related DHB visits. Rainfall was also highly correlated to some mental health outcomes. Higher levels of rainfall reduced DHB visits and suicide rates in some areas of the country.

PurposeThis study examined the methodological quality of radiomics to predict the effectiveness of neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC). We performed a meta-analysis of radiomics studies evaluating the bias risk and treatment response estimation.MethodsOur study was conducted through a literature review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included radiomics-related papers, published prior to January 31, 2022, in our analysis to examine the effectiveness of neoadjuvant chemotherapy in NPC. The methodological quality was assessed using the radiomics quality score. The intra-class correlation coefficient (ICC) was employed to evaluate inter-reader reproducibility. The pooled area under the curve (AUC), pooled sensitivity, and pooled specificity were used to assess the ability of radiomics to predict response to neoadjuvant chemotherapy in NPC. Lastly, the Quality Assessment of Diagnostic Accuracy Studies technique was used to analyze the bias risk.ResultsA total of 12 studies were eligible for our systematic review, and 6 papers were included in our meta-analysis. The radiomics quality score was set from 7 to 21 (maximum score: 36). There was satisfactory ICC (ICC = 0.987, 95% CI: 0.957–0.996). The pooled sensitivity and specificity were 0.88 (95% CI: 0.71–0.95) and 0.82 (95% CI: 0.68–0.91), respectively. The overall AUC was 0.91 (95% CI: 0.88–0.93).ConclusionPrediction response of neoadjuvant chemotherapy in NPC using machine learning and radiomics is beneficial in improving standardization and methodological quality before applying it to clinical practice.

BackgroundPrimary small cell breast carcinoma (SCBC) is an uncommon malignancy with highly invasive behavior. The aim of this study was to find out more about the incidence, clinicopathologic characteristics and identify potential prognostic factors of SCBC.MethodsData of patients with primary diagnosis of SCBC between 1975 and 2018 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The incidence after adjustment for age and percentage change per year in incidence were calculated. Disease-specific survival (DSS) and overall survival (OS) were analyzed among these SCBC patients identified from the SEER database. The whole cohorts were randomized into training and validation cohorts as ratio of 7: 3. Cox regression analysis was performed to determine predictors of survival with the training cohorts. Predictive models were constructed with training cohorts, and nomogram validation was performed using receiver operating characteristic curves, concordance indices and calibration curves in both training and validation cohorts.Results323 SCBC patients were enrolled finally during the research period. The overall incidence after adjustment for age between 1990 and 2018 was 0.14 per million per year, and the prevalence of the incidence has plateaued. Most of these tumors were poorly differentiated or undifferentiated. The most prevalent presenting stage was Stage II. Patients identified in this study were randomly divided into training (n = 226) and testing (n = 97) cohorts. Multivariate Cox proportional hazards model showed that chemotherapy, surgery and stage were important predictors of DSS and OS.ConclusionSCBC is considered an infrequent breast neoplasm with aggressive characteristics. Tumor stage is associated with poor prognosis. Combination of surgery and chemotherapy is the main treatment for SCBC.

Coronary artery disease (CAD) is a major contributor to morbidity and mortality worldwide. Myocardial ischemia may occur in patients with normal or non-obstructive CAD on invasive coronary angiography (ICA). The comprehensive evaluation of coronary CT angiography (CCTA) integrated with fractional flow reserve derived from CCTA (CT-FFR) to CAD may be essential to improve the outcomes of patients with non-obstructive CAD. China CT-FFR Study-2 (ChiCTR2000031410) is a large-scale prospective, observational study in 29 medical centers in China. The primary purpose is to uncover the relationship between the CCTA findings (including CT-FFR) and the outcome of patients with non-obstructive CAD. At least 10,000 patients with non-obstructive CAD but without previous revascularization will be enrolled. A 5-year follow-up will be performed. The primary endpoint is the occurrence of major adverse cardiovascular events (MACE), including all-cause mortality, non-fatal myocardial infarct, unplanned revascularization, and hospitalization for unstable angina. Clinical characteristics, laboratory and imaging examination results will be collected to analyze their prognostic value.

IMMH-010 is a prodrug of YPD-29B, which is a novel PD-L1 inhibitor. A specific and sensitive LC-MS/MS method with polarity switching was developed and validated for the simultaneous determination of IMMH-010 and YPD-29B in rat plasma, liver, brain, urine and fecal samples. Method validation was investigated to demonstrate the lower limit of quantification linearity, precision and accuracy, matrix effect and recovery, stability and dilution reliability for IMMH-010 and YPD-29B. This validated method was successfully applied to investigate the pharmacokinetics, tissue distribution, and excretion of IMMH-010 and YPD-29B in rats. After oral administration of IMMH-010 maleate to rats, IMMH-010 was rapidly and extensively converted to the active metabolite YPD-29B. The areas under the plasma concentration-time curve (AUC) of IMMH-010 and YPD-29B were proportional to the dose in the range of 10–100 mg/kg. IMMH-010 was primarily distributed in the adrenal gland, lymph nodes, heart, liver and spleen. YPD-29B was mainly observed in the liver, lymph, kidney, and lung. Approximately 28.81% of the IMMH-010 dose was recovered in the urine and feces within 72 h, including unchanged IMMH-010 (7.99%) and YPD-29B (20.82%). The results of this study may be useful as a reference for further development of IMMH-010 and PD-L1 inhibitors.Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT04343859?term=IMMH-010&draw=2&rank=1], identifier [NCT04343859]."

The synthesis of Au nanocubes is used to label alpha-fetoprotein antibody (anti-AFP) and horseradish peroxidase (HRP) to form an immune complex for antibody detection. Graphene oxide-methylene blue-gold nanoparticles (GO-MB-AuNPs) nanocomposites were used as the immunosensing platform. This proposed sandwich-type immunoassay shows good performance. This method establishes a feasible amperometric immunoassay method for sensitive analysis of AFP in serum samples. Under the optimal experimental conditions, the DPV current response of the immunosensor is proportional to the logarithmic value of the AFP concentration. The linear detection range can achieve to 0.005–20 ng/mL with a detection limit of 1.5 pg/mL. The proposed immunosensor has good precision, selectivity and stability, and can be used for AFP determination in clinical tests.

IMM-H004, a derivative of coumarin, is a promising candidate for the treatment of cerebral ischemia. The pharmacodynamic mechanisms of IMM-H004 are still under exploration. The present study was conducted to explore the pharmacoactive substances of IMM-H004 from the perspective of drug metabolism. Four metabolites of IMM-H004 including demethylated metabolites M1 and M2, glucuronide conjugate IMM-H004G (M3), and sulfated conjugate M4 were found in rats in vivo. IMM-H004G was the major metabolite in rats and cultured human hepatocytes, and uridine diphosphate-glucuronosyltransferase (UGT) was found to catalyze the metabolism of IMM-H004 in human liver microsomes (HLMs) and rat liver microsomes (RLMs) with high capacity (Vmax at 3.25 and 5.04 nmol/min/mg protein). Among 13 recombinant human UGT isoforms, UGT1A7, 1A9, 1A8, and 1A1 appeared to be primarily responsible for IMM-H004G formation. The exposure and duration of IMM-H004G (28,948 h × ng/ml of area under the plasma concentration–time curve (AUC), 6.61 h of t1/2β) was much higher than that of the parent drug (1,638 h × ng/ml of AUC, 0.42 h of t1/2β) in transient middle cerebral artery occlusion/reperfusion (MCAO/R) rats, consistent with the malondialdehyde (MDA) inhibition effect for at least 10 h. Further pharmacological study revealed that IMM-H004G exhibited a similar neuroprotective activity to that of the parent drug on both oxygen-glucose deprivation injured PC12 cells and transient MCAO/R injured rats. These results demonstrate that both prototype and IMM-H004G are the active pharmaceutical substances, and IMM-H004G, at least in part, contributes to the maintenance of anti-cerebral ischemia efficacy of IMM-H004.

Objectives Paris polyphylla 26 (PP-26) is a monomer purified from Paris polyphylla , which has traditionally been used as an antimicrobial, hemostatic, and anticancer agent in China. The anti-proliferation effect and underlying molecular mechanism of PP-26 were investigated in vitro. Methods The effects of PP-26 on various tumor cells were detected by MTT assay. PP-26-affected cell cycle and cell cycle-related proteins in HepG2 cells were detected by flow cytometry and western blotting, respectively. Apoptosis in response to PP-26 was assessed by Hoechst 33258 staining and flow cytometry. PP-26-affected apoptosis-related proteins and Akt signaling were detected by western blotting. The inhibitory effect of PP-26 on HepG2 cells, when combined with 5-fluorouracil (5-FU), was also assessed. Results PP-26 inhibited proliferation of HepG2 cells in a dose-dependent manner by triggering G2/M-phase arrest. Moreover, PP-26 induced apoptosis of HepG2 cells. Expression levels of apoptosis proteins caspase 9, caspase 3, PARP, Bcl-2, Bcl-xL, and Mcl-1 were downregulated, while the expression level of apoptosis protein Bax was upregulated. Expression levels of p-Akt, p-GSK-3β, and p-Foxo3 were downregulated. Combination with PP-26 enhanced 5-FU inhibition of HepG2 cell proliferation. Conclusions PP-26 triggers G2/M-phase arrest and induces apoptosis in HepG2 cells via inhibition of the Akt signaling pathway.