The Biodistribution of Replication-Defective Simian Adenovirus 1 Vector in a Mouse Model.

The administration route affects the biodistribution of a gene transfer vector and the expression of a transgene. A simian adenovirus 1 vector carrying firefly luciferase and GFP reporter genes (SAdV1-GFluc) were constructed, and its biodistribution was investigated in a mouse model by bioluminescence imaging and virus DNA tracking with real-time PCR. Luciferase activity and virus DNA were mainly found in the liver and spleen after the intravenous administration of SAdV1-GFluc. The results of flow cytometry illustrated that macrophages in the liver and spleen as well as hepatocytes were the target cells. Repeated inoculation was noneffective because of the stimulated serum neutralizing antibodies (NAbs) against SAdV-1. A transient, local expression of low-level luciferase was detected after intragastric administration, and the administration could be repeated without compromising the expression of the reporter gene. Intranasal administration led to a moderate, constant expression of a transgene in the whole respiratory tract and could be repeated one more time without a significant increase in the NAb titer. An immunohistochemistry assay showed that respiratory epithelial cells and macrophages in the lungs were transduced. High luciferase activity was restricted at the injection site and sustained for a week after intramuscular administration. A compromised transgene expression was observed after a repeated injection. When these mice were intramuscularly injected for a third time with the human adenovirus 5 (HAdV-5) vector carrying a luciferase gene, the luciferase activity recovered and reached the initial level, suggesting that the sequential use of SAdV-1 and HAdV-5 vectors was practicable. In short, the intranasal inoculation or intramuscular injection may be the preferred administration routes for the novel SAdV-1 vector in vaccine development.

Effect of hydrogen sulfide (H2S) on the growth and development of tobacco seedlings in absence of stress.

BACKGROUND: Hydrogen sulfide (H2S) is a novel signaling molecule involved in the growth and development of plants and their response to stress. However, the involvement of H2S in promoting the growth and development of tobacco plants is still unclear. RESULTS: In this study, we explored the effect of pre-soaking or irrigating the roots of tobacco plants with 0.0, 2.0, 4.0, 6.0, and 8.0 mM of sodium hydrosulfide (NaHS) on endogenous H2S production, antioxidant enzymatic and cysteine desulfhydrase activities, seed germination, agronomic traits, photosynthetic pigments contents, and root vigor. The results revealed that exogenous NaHS treatment could significantly promote endogenous H2S production by inducing gene expression of D/L-CD and the activities of D/L-CD enzymes. Additionally, a significant increase in the agronomic traits and the contents of photosynthetic pigments, and no significant difference in carotenoid content among tobacco plants treated with 0.0 to 8.0 mM of NaHS was observed. Additionally, a significant increase in the germination speed, dry weight, and vigor of tobacco seeds, whereas no significant effect on the percentage of seed germination was observed on NaHS treatment. Furthermore, NaHS treatment could significantly increase the activity of superoxide dismutase (SOD) and peroxidase (POD) enzymes, which reduces damage due to oxidative stress by maintaining reactive oxygen species homeostasis. CONCLUSIONS: These results would aid in enhancing our understanding of the involvement of H2S, a novel signaling molecule to promote the growth and development of tobacco plants.

Association of sleep quality on the night of operative day with postoperative delirium in elderly patients: A prospective cohort study.

BACKGROUND: Sleep disturbances in the peri-operative period have been associated with adverse outcomes, including postoperative delirium (POD). However, research on sleep quality during the immediate postoperative period is limited. OBJECTIVES: This study aimed to investigate the association between sleep quality on the night of the operative day assessed using the Sleep Quality Numeric Rating Scale (SQ-NRS), and the incidence of POD in a large cohort of surgical patients. DESIGN: A prospective cohort study. SETTING: A tertiary hospital in China. PATIENTS: This study enrolled patients aged 65 years or older undergoing elective surgery under general anaesthesia. The participants were categorised into the sleep disturbance and no sleep disturbance groups according to their operative night SQ-NRS. MAIN OUTCOME MEASURES: The primary outcome was delirium incidence, whereas the secondary outcomes included acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. RESULTS: In total, 3072 patients were included in the analysis of this study. Among them, 791 (25.72%) experienced sleep disturbances on the night of operative day. Patients in the sleep disturbance group had a significantly higher risk of developing POD (adjusted OR 1.43, 95% CI 1.11 to 1.82, P  = 0.005). Subgroup analysis revealed that age 65-75 years; male sex; ASA III and IV; haemoglobin more than 12 g l -1 ; intra-operative hypotension; surgical duration more than 120 min; and education 9 years or less were significantly associated with POD. No interaction was observed between the subgroups. No significant differences were observed in the secondary outcomes, such as acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. CONCLUSIONS: The poor subjective sleep quality on the night of operative day was independently associated with increased POD risk, especially in certain subpopulations. Optimising peri-operative sleep may reduce POD. Further research should investigate potential mechanisms and causal relationships. TRIAL REGISTRY: chictr.org.cn: ChiCTR1900028545.

Ovarian Tumor Domain-Containing 7B Attenuates Pathological Cardiac Hypertrophy by Inhibiting Ubiquitination and Degradation of Krüppel-Like Factor 4.

BACKGROUND: Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently, no pharmacological interventions have been specifically tailored to treat CH. OTUD7B (ovarian tumor domain-containing 7B) is a member of the ovarian tumor-related protease (OTU) family that regulates many important cell signaling pathways. However, the role of OTUD7B in the development of CH is unclear. Therefore, we investigated the role of OTUD7B in CH. METHODS AND RESULTS: OTUD7B knockout mice were used to assay the role of OTUD7B in CH after transverse aortic coarctation surgery. We further assayed the specific functions of OTUD7B in isolated neonatal rat cardiomyocytes. We found that OTUD7B expression decreased in hypertrophic mice hearts and phenylephrine-stimulated neonatal rat cardiomyocytes. Furthermore, OTUD7B deficiency exacerbated transverse aortic coarctation surgery-induced myocardial hypertrophy, abnormal cardiac function, and fibrosis. In cardiac myocytes, OTUD7B knockdown promoted phenylephrine stimulation-induced myocardial hypertrophy, whereas OTUD7B overexpression had the opposite effect. An immunoprecipitation-mass spectrometry analysis showed that OTUD7B directly binds to KLF4 (Krüppel-like factor 4). Additional molecular experiments showed that OTUD7B impedes KLF4 degradation by inhibiting lysine residue at 48 site-linked ubiquitination and suppressing myocardial hypertrophy by activating the serine/threonine kinase pathway. CONCLUSIONS: These results demonstrate that the OTUD7B-KLF4 axis is a novel molecular target for CH treatment.

Klebsiella michiganensis: a nitrogen-fixing endohyphal bacterium from Ustilago maydis.

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.

Mechanistic basis for mitigating drought tolerance by selenium application in tobacco (Nicotiana tabacum L.): a multi-omics approach.

The lack of irrigation water in agricultural soils poses a significant constraint on global crop production. In-depth investigation into microRNAs (miRNAs) has been widely used to achieve a comprehensive understanding of plant defense mechanisms. However, there is limited knowledge on the association of miRNAs with drought tolerance in cigar tobacco. In this study, a hydroponic experiment was carried out to identify changes in plant physiological characteristics, miRNA expression and metabolite profile under drought stress, and examine the mitigating effects of selenium (Se) application. The shoot dry weight of drought-stressed plants was approximately half (50.3%) of that in non-stressed (control) conditions. However, plants supplied with Se attained 38.8% greater shoot dry weight as compared to plants with no Se supply under drought stress. Thirteen miRNAs were identified to be associated with drought tolerance. These included 7 known (such as nta-miR156b and nta-miR166a) and 6 novel miRNAs (such as novel-nta-miR156-5p and novel-nta-miR209-5p) with the target genes of squamosa promoter-binding-like protein 4 (SPL4), serine/threonine protein phosphatase 2A (PPP2A), cation/calcium exchanger 4-like (CCX4), extensin-1-like (EXT1) and reduced wall acetylation 2 (RWA2). Further investigation revealed that the expression levels of Ext1 and RWA2 were significantly decreased under drought stress but increased with Se addition. Moreover, key metabolites such as catechin and N-acetylneuraminic acid were identified, which may play a role in the regulation of drought tolerance. The integrated analysis of miRNA sequencing and metabolome highlighted the significance of the novel-nta-miR97-5p- LRR-RLK- catechin pathway in regulating drought tolerance. Our findings provide valuable insights into the molecular mechanisms underlying drought tolerance and Se-induced stress alleviation in cigar tobacco.

Heterogeneity changes of active bacterial community on cigar filler leaves after fermentation based on metagenome.

Microorganisms play an important role in cigar fermentation. To further explore the dynamic changes of bacterial community composition, the changes of surface bacterial diversity of cigar filler leaves were investigated in the present study by high-throughput sequencing technology. It was found that the surface bacterial richness was declined after fermentation, and the dominant microorganisms on the surface of cigar filler leaves evolved from Pseudomonas spp. and Sphingomonas spp. before fermentation to Staphylococcus spp. after fermentation. The chemical composition and sensory quality evaluation of cigar filler leaves were closely related to the changes of surface bacterial community. The changes of the dominant surface bacterial community led to the differences of metabolic functions, among which the metabolic pathways such as the synthesis of secondary metabolites, carbon metabolism, and amino acid biosynthesis were significantly different. The results provide a basis for clarifying the roles of bacteria in fermentation of cigar filler leaves.

Frailty in hypertensive population and its association with all-cause mortality: data from the National Health and Nutrition Examination Survey.

Objectives: This study aimed to investigate the relationship between frailty and all-cause mortality in hypertensive population. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 and mortality data from the National Death Index. Frailty was assessed using the revised version of the Fried frailty criteria (weakness, exhaustion, low physical activity, shrinking, and slowness). This study aimed to evaluate the association between frailty and all-cause mortality. Cox proportional hazard models were used to evaluate the association between frailty category and all-cause mortality, adjusted for age, sex, race, education, poverty-income ratio, smoking, alcohol, diabetes, arthritis, congestive heart failure, coronary heart disease, stroke, overweight, cancer or malignancy, chronic obstructive pulmonary disease, chronic kidney disease, and taking medicine for hypertension. Results: We gathered data of 2,117 participants with hypertension; 17.81%, 28.77%, and 53.42% were classified as frail, pre-frail, and robust, respectively. We found that frail [hazard ratio (HR) = 2.76, 95% confidence interval (CI) = 2.33-3.27] and pre-frail (HR = 1.38, 95% CI = 1.19-1.59] were significantly associated with all-cause mortality after controlling for variables. We found that frail (HR = 3.02, 95% CI = 2.50-3.65) and pre-frail (HR = 1.35, 95% CI = 1.15-1.58) were associated with all-cause mortality in the age group ≥65 years. For the frailty components, weakness (HR = 1.77, 95% CI = 1.55-2.03), exhaustion (HR = 2.25, 95% CI = 1.92-2.65), low physical activity (HR = 2.25, 95% CI = 1.95-2.61), shrinking (HR = 1.48, 95% CI = 1.13-1.92), and slowness (HR = 1.44, 95% CI = 1.22-1.69) were associated with all-cause mortality. Conclusion: This study demonstrated that frailty and pre-frailty were associated with an increased risk of all-cause mortality in patients with hypertension. More attention should be paid to frailty in hypertensive patients, and interventions to reduce the burden of frailty may improve outcomes in these patients.

Rhizosphere Microbial Community and Metabolites of Susceptible and Resistant Tobacco Cultivars to Bacterial Wilt.

Soil-borne diseases are closely related to rhizosphere microecosystem. While, plant species and genotypes are important factors affected rhizosphere microecosystem. In this study, the rhizosphere soil microbial community and metabolites of susceptible and resistant tobacco cultivars were investigated. The results showed that there were significant differences in the rhizosphere microbial community and metabolites between susceptible cultivar Yunyan87 and resistant cultivar Fandi3. Furthermore, the rhizosphere soil of Fandi3 showed a higher microbial diversity than that of Yunyan87. The abundance of R. solanacearum was much higher in the rhizosphere soil of Yunyan87 than in the rhizosphere soil of Fandi3, resulting in a higher disease incidence and index. While the abundance of beneficial bacteria in the rhizosphere soil of Fandi3 were higher than that of Yunyan87. Additionally, there were significant differences in metabolites between Yunyan87 and Fandi3 cultivars, and 4-hydroxybenzaldehyde, 3-hydroxy-4-methoxybenzoic acid, vamillic aldehyde, benzoic acid, 4-hydroxybenzyl alcohol, p-hydroxybenzoic acid and phthalic acid were notably high in Yunyan87. Redundancy analysis (RDA) indicated that the rhizosphere microbial community of Fandi3 and Yunyan87 were highly correlated with various environmental factors and metabolites. Overall, susceptible and resistant tobacco cultivars had different impact on rhizosphere microbial community and metabolites. The results expand our understanding of the roles of tobacco cultivars in plant-micro-ecosystem interactions, and provide a basis for the control of tobacco bacterial wilt.

Effect and mechanism of NaHS on tobacco bacterial wilt caused by Ralstonia solanacearum.

Since its discovery as a third unique gaseous signal molecule, hydrogen sulfide (H2S) has been extensively employed to resist stress and control pathogens. Nevertheless, whether H2S can prevent tobacco bacterial wilt is unknown yet. We evaluated the impacts of the H2S donor sodium hydrosulfide (NaHS) on the antibacterial activity, morphology, biofilm, and transcriptome of R. solanacearum to understand the effect and mechanism of NaHS on tobacco bacterial wilt. In vitro, NaHS significantly inhibited the growth of Ralstonia solanacearum and obviously altered its cell morphology. Additionally, NaHS significantly inhibited the biofilm formation and swarming motility of R. solanacearum, and reduced the population of R. solanacearum invading tobacco roots. In field experiments, the application of NaHS dramatically decreased the disease incidence and index of tobacco bacterial wilt, with a control efficiency of up to 89.49%. The application of NaHS also influenced the diversity and structure of the soil microbial community. Furthermore, NaHS markedly increased the relative abundances of beneficial microorganisms, which helps prevent tobacco bacterial wilt. These findings highlight NaHS's potential and efficacy as a powerful antibacterial agent for preventing tobacco bacterial wilt caused by R. solanacearum.

18F-FDG PET and a classifier algorithm reveal a characteristic glucose metabolic pattern in adult patients with moyamoya disease and vascular cognitive impairment.

Vascular cognitive impairment (VCI) is a critical issue in moyamoya disease (MMD). However, the glucose metabolic pattern in these patients is still unknown. This study aimed to identify the metabolic signature of cognitive impairment in patients with MMD using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) and establish a classifier to identify VCI in patients with MMD. One hundred fifty-two patients with MMD who underwent brain 18F-FDG PET scans before surgery were enrolled and classified into nonvascular cognitive impairment (non-VCI, n = 52) and vascular cognitive impairment (VCI, n = 100) groups according to neuropsychological test results. Additionally, thirty-three health controls (HCs) were also enrolled. Compared to HCs, patients in the VCI group exhibited extensive hypometabolism in the bilateral frontal and cingulate regions and hypermetabolism in the bilateral cerebellum, while patients in the non-VCI group showed hypermetabolism only in the cerebellum and slight hypometabolism in the frontal and temporal regions. In addition, we found that the patients in the VCI group showed hypometabolism mainly in the left basal ganglia compared to those in the non-VCI group. The sparse representation-based classifier algorithm taking the SUVr of 116 Anatomical Automatic Labeling (AAL) areas as features distinguished patients in the VCI and non-VCI groups with an accuracy of 82.4%. This study demonstrated a characteristic metabolic pattern that can distinguish patients with MMD without VCI from those with VCI, namely, hypometabolic lesions in the left hemisphere played a more important role in cognitive decline in patients with MMD.

Metabolomic analysis reveals key metabolites alleviating green spots under exogenous sucrose spraying in air-curing cigar tobacco leaves.

Cigar variety CX-010 tobacco leaves produce localized green spots during the air-curing period, and spraying exogenous sucrose effectively alleviates the occurrence of the green spots. To investigate the alleviation effect of exogenous sucrose spraying, the total water content and the number and size of green spots on tobacco leaves were investigated during the air-curing period under four treatments; CK (pure water), T1 (0.1 M sucrose), T2 (0.2 M sucrose) and T3 (0.4 M sucrose). The results showed that the total water content of tobacco leaves showed a trend of T3 < CK < T2 < T1 in the early air-curing stage, and the number and size of green spots showed a trend of T3 < T2 < T1 < CK. All sucrose treatments alleviated the green spot phenomenon, and T3 had the fewest green spots. Thus, the tobacco leaves of the T3 and CK treatments at two air-curing stages were used to perform metabolomics analysis with nontargeted liquid chromatography‒mass spectrometry to determine the physiological mechanism. A total of 259 and 178 differentially abundant metabolites (DAMs) between T3- and CK-treated tobacco leaves were identified in the early air-curing and the end of air-curing stages, respectively. These DAMs mainly included lipid and lipid-like molecules, carbohydrates, and organic acids and their derivatives. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the T3 treatment significantly altered carbohydrate metabolism (pentose phosphate pathway, sucrose and starch metabolism and galactose metabolism) and amino acid metabolism (tyrosine metabolism and tryptophan metabolism) in air-curing tobacco leaves. Sucrose treatment alleviated green spots by altering DAMs that affected chlorophyll degradation, such as tyrosine and citric acid, to promote the normal degradation of chlorophyll.

Mitigation of tobacco bacteria wilt with microbial degradation of phenolic allelochemicals.

Long-term continuous monoculture cropping of tobacco leads to high incidence of tobacco bacterial wilt (TBW) caused by Ralstonia solanacearum, which threatening world tobacco production and causing great economy loss. In this study, a safe and effective way to control TBW by microbial degradation of phenolic allelochemicals (PAs) was explored. Eleven kinds of PAs were identified from continuous tobacco cropping soil. These PAs exhibited various effects on the growth, chemotaxis and biofilm formation of R. solanacearum. Then we isolated eight strains of Bacillus, one strain of Brucella, one strain of Enterobacter and one strain of Stenotrophomonas capable of degrading these PAs. The results of degradation assay showed that these isolated strains could degrade PAs both in culture solutions and soil. Besides, the incidence of TBW caused by R. solanacearum and deteriorated by PAs were significantly decreased by treating with these degrading strains. Furthermore, six out of eleven isolated strains were combined to degrade all the identified PAs and ultimately sharply reduced the incidence of TBW by 61.44% in pot experiment. In addition, the combined degrading bacteria could promote the plant growth and defense response. This study will provide a promising strategy for TBW control in tobacco production.

CELO Fiber1 Knob Is a Promising Candidate to Modify the Tropism of Adenoviral Vectors.

Fowl adenovirus 4 (FAdV-4) has the potential to be constructed as a gene transfer vector for human gene therapy or vaccine development to avoid the pre-existing immunity to human adenoviruses. To enhance the transduction of FAdV-4 to human cells, CELO fiber1 knob (CF1K) was chosen to replace the fiber2 knob in FAdV-4 to generate recombinant virus F2CF1K-CG. The original FAdV4-CG virus transduced 4% human 293 or 1% HEp-2 cells at the multiplicity of infection of 1000 viral particles per cell. In contrast, F2CF1K-CG could transduce 98% 293 or 60% HEp-2 cells under the same conditions. Prokaryotically expressed CF1K protein blocked 50% transduction of F2CF1K-CG to 293 cells at a concentration of 1.3 µg/mL while it only slightly inhibited the infection of human adenovirus 5 (HAdV-5), suggesting CF1K could bind to human cells in a manner different from HAdV-5 fiber. The incorporation of CF1K had no negative effect on the growth of FAdV-4 in the packaging cells. In addition, CF1K-pseudotyped HAdV-41 could transduce HEp-2 and A549 cells more efficiently. These data indicated that CF1K had the priority to be considered when there is a need to modify adenovirus tropism.

Physiological Responses of Cigar Tobacco Crop to Nitrogen Deficiency and Genome-Wide Characterization of the NtNPF Family Genes.

Tobacco prefers nitrate as a nitrogen (N) source. However, little is known about the molecular components responsible for nitrate uptake and the physiological responses of cigar tobacco to N deficiency. In this study, a total of 117 nitrate transporter 1 (NRT1) and peptide transporter (PTR) family (NPF) genes were comprehensively identified and systematically characterized in the whole tobacco genome. The NtNPF members showed significant genetic diversity within and across subfamilies but showed conservation between subfamilies. The NtNPF genes are dispersed unevenly across the chromosomes. The phylogenetic analysis revealed that eight subfamilies of NtNPF genes are tightly grouped with their orthologues in Arabidopsis. The promoter regions of the NtNPF genes had extensive cis-regulatory elements. Twelve core NtNPF genes, which were strongly induced by N limitation, were identified based on the RNA-seq data. Furthermore, N deprivation severely impaired plant growth of two cigar tobaccos, and CX26 may be more sensitive to N deficiency than CX14. Moreover, 12 hub genes respond differently to N deficiency between the two cultivars, indicating the vital roles in regulating N uptake and transport in cigar tobacco. The findings here contribute towards a better knowledge of the NtNPF genes and lay the foundation for further functional analysis of cigar tobacco.

Morusin Protected Ruminal Epithelial Cells against Lipopolysaccharide-Induced Inflammation through Inhibiting EGFR-AKT/NF-κB Signaling and Improving Barrier Functions.

Using phytogenic extracts for preventing or treating rumen epithelial inflammatory injury is a potential alternative to antibiotic use due to their residue-free characteristics. In this study, the efficacy of Morus root bark extract Morusin on ruminal epithelial cells (RECs) against pathogenic stimulus was investigated for the first time. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and quantitative real-time polymerase chain reaction (qPCR) results showed that the Morusin did not affect the cell viability of RECs and exerted anti-inflammatory effects in a concentration-dependent manner. Transcriptome analysis further revealed that the Morusin significantly downregulated the inflammatory-response-related cell signaling, while it upregulated the cell-proliferation-inhibition- and barrier-function-related processes in RECs upon lipopolysaccharide (LPS) stimulation. The epidermal growth factor receptor (EGFR) blocking and immunoblotting analysis further confirmed that the Morusin suppressed LPS-induced inflammation in RECs by downregulating the phosphorylation of protein kinase B (AKT) and nuclear factor-kappaB (NF-κB) p65 protein via inhibiting the EGFR signaling. These findings demonstrate the protective roles of Morusin in LPS-induced inflammation in RECs.

Socioeconomic deprivation and survival outcomes in primary central nervous system lymphomas.

Objective: To our knowledge, the impact of area-level socioeconomic status (SES) has not yet been described in primary central nervous system lymphomas (PCNSLs). Current study sought to explore the association of socioeconomic deprivation, measured using the Area Deprivation Index (ADI), with PCNSL outcomes. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify PCNSL patients diagnosed between 2006 and 2015 for our analyses. The impact of ADI on overall survival (OS) and cancer-specific survival (CSS) were investigated. Survival analyses were conducted using Kaplan-Meier method with log-rank tests. The Inverse Probability Weighting (IPW) analysis and multivariate cox proportional hazards regression analysis were employed to make covariate adjustments. Multiple mediation analysis (MMA) was performed to estimate the mediating effects. Results: A total of 3159 PCNSL patients classified into low and high ADI subgroups according to the median ADI score were studied. The Kaplan-Meier analyses showed that low ADI was significantly associated with higher OS rates (HR 1.15, 95%CI 1.06-1.26, P<0.01) and CSS rates (HR 1.15, 95%CI 1.05-1.27, P<0.01). Similar results were observed in analyses adjusted via IPW and multivariate cox methods. Subgroup analyses revealed that ADI could remain a prognostic indictor among different subsets. MMA revealed that several factors including chemotherapy and HIV status making up about 40% of the overall effect, mediated PCNSL survival disparities related to the ADI. Finally, multivariable logistic regression analysis showed that ADI as well as several other factors were independently related to receipt of chemotherapy. Conclusions: Our study highlights the role of area-level SES in prognosis of PCNSLs. And several factors including chemotherapy and HIV status of PCNSL patents contributed to the CSS disparities between ADI subgroups were uncovered by MMA. Such relationships would highlight the importance of policies development to enhance healthcare delivery and promote awareness of HIV prevention and treatment in low-resource neighborhoods.

Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Ameliorates Cardiac Hypertrophy by Targeting TLR4 in Macrophages.

Background: Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been reported to regulate inflammation and apoptosis. The role of TIPE2 in cardiovascular disease, especially cardiac hypertrophy, has not been elucidated. Thus, the aim of the present study was to explore the role of TIPE2 in cardiac hypertrophy. Methods: Mice were subjected to aortic banding (AB) to induce an adverse hypertrophic model. To overexpress TIPE2, mice were injected with a lentiviral vector expressing TIPE2. Echocardiographic and hemodynamic analyses were used to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) and mouse peritoneal macrophages (MPMs) were isolated and stimulated with angiotensin II. NRCMs and MPM were also cocultured and stimulated with angiotensin II. Cells were transfected with Lenti-TIPE2 to overexpress TIPE2. Results: TIPE2 expression levels were downregulated in hypertrophic mouse hearts and in macrophages in heart tissue. TIPE2 overexpression attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, we found that TIPE2 overexpression in neonatal cardiomyocytes did not relieve the angiotensin II-induced hypertrophic response in vitro. Furthermore, TIPE2 overexpression downregulated TLR4 and NF-κB signaling in macrophages but not in cardiomyocytes, which led to diminished inflammation in macrophages and consequently reduced the activation of hypertrophic Akt signaling in cardiomyocytes. TLR4 inhibition by TAK-242 did not enhance the antihypertrophic effect of TIPE2 overexpression. Conclusions: The present study indicated that TIPE2 represses macrophage activation by targeting TLR4, subsequently inhibiting cardiac hypertrophy.

Impact of Gut Microbiota on Radiation-Associated Cognitive Dysfunction and Neuroinflammation in Mice.

Radiation-induced brain injury is a common complication of brain irradiation that eventually leads to irreversible cognitive impairment. Evidence has shown that the gut microbiome may play an important role in radiation-induced cognitive function. However, the effects of gut microbiota on radiation-induced brain injury (RIBI) remain poorly understood. Here we studied the link between intestinal microbes and radiation-induced brain injury to further investigate the effects of intestinal bacteria on neuroinflammation and cognitive function. We first verified the differences in gut microbes between male and female mice and administered antibiotics to C57BL/6 male mice to deplete the gut flora and then expose mice to radiation. We found that depletion of intestinal flora after irradiation may act as a protective modulator against radiation-induced brain injury. Moreover, we found that pretreatment with depleted gut microbes in RIBI mice suppressed brain pro-inflammatory factor production, and high-throughput sequencing analysis of mouse feces at 1-month postirradiation revealed microbial differences. Interestingly, a proportion of Verrucomicrobia Akkermansia showed partial recovery. Additionally, short-chain fatty acid treatments increased neuroinflammation in the radiation-induced brain injury model. Although a further increase in cognitive function was not observed, brain injury was aggravated in whole-brain irradiated mice to some extent. The protective effects of depleted intestinal flora and the utilization of the brain-gut axis open new avenues for development of innovative therapeutic strategies for radiation-induced brain injury.

Screening and characterisation of potential antioxidant, hypoglycemic and hypolipidemic components revealed in Portulaca oleracea via multi-target affinity ultrafiltration LC-MS and molecular docking.

INTRODUCTION: Portulaca oleracea is a commonly used nutritional vegetable and traditional herbal medicine with plenty of nutrients and manifold pharmacological activities. However, the potential active ingredients for its remarkable antioxidant, hypoglycemic and hypolipidemic activities remain unexplored. OBJECTIVES: The present study aims to systematically evaluate the antioxidant activities of different extracts of P. oleracea and screen bioactive ligands that can interact with α-glucosidase, pancreatic lipase, and superoxide dismutase (SOD). METHODS: In this research, the antioxidant activities of different parts of P. oleracea and their corresponding total phenolic content (TPC) and total flavonoid content (TFC) were systematically determined. Subsequently, a multi-target affinity ultrafiltration method was developed using affinity ultrafiltration with SOD, α-glucosidase, and pancreatic lipase coupled to liquid chromatography-mass spectrometry (UF-LC-MS). Later, molecular docking was used to further investigate the possible interaction mechanism between these ligands and target enzymes. RESULTS: Among them, the ethyl acetate (EA) fraction showed the highest antioxidant activity along with the highest TPC and TFC, and four compounds in the EA fraction were quickly retrieved as potential SOD, α-glucosidase, and pancreatic lipase ligands, respectively. Molecular docking revealed that these potential ligands exhibited strong binding ability and inhibitory activities on SOD, α-glucosidase, and pancreatic lipase. CONCLUSION: The present study revealed that P. oleracea can be used as a functional food with excellent antioxidant, hypoglycemic and hypolipidemic effects. Meanwhile, the integrated strategy based on multi-target UF-LC-MS and molecular docking also provided a powerful tool and a multidimensional perspective for further exploration of active ingredients in P. oleracea responsible for the antioxidant, hypoglycemic and hypolipidemic activities.