Poria cocos Attenuated DSS-Induced Ulcerative Colitis via NF-κB Signaling Pathway and Regulating Gut Microbiota.

Ulcerative colitis (UC), as a chronic inflammatory disease, presents a global public health threat. However, the mechanism of Poria cocos (PC) in treating UC remains unclear. Here, LC-MS/MS was carried out to identify the components of PC. The protective effect of PC against UC was evaluated by disease activity index (DAI), colon length and histological analysis in dextran sulfate sodium (DSS)-induced UC mice. ELISA, qPCR, and Western blot tests were conducted to assess the inflammatory state. Western blotting and immunohistochemistry techniques were employed to evaluate the expression of tight junction proteins. The sequencing of 16S rRNA was utilized for the analysis of gut microbiota regulation. The results showed that a total of fifty-two nutrients and active components were identified in PC. After treatment, PC significantly alleviated UC-associated symptoms including body weight loss, shortened colon, an increase in DAI score, histopathologic lesions. PC also reduced the levels of inflammatory cytokines TNF-α, IL-6, and IL-1ß, as evidenced by the suppressed NF-κB pathway, restored the tight junction proteins ZO-1 and Claudin-1 in the colon, and promoted the diversity and abundance of beneficial gut microbiota. Collectively, these findings suggest that PC ameliorates colitis symptoms through the reduction in NF-κB signaling activation to mitigate inflammatory damage, thus repairing the intestinal barrier, and regulating the gut microbiota.

Layer-by-Layer Assembly of Renal-Targeted Polymeric Nanoparticles for Robust Arginase-2 Knockdown and Contrast-Induced Acute Kidney Injury Prevention.

The mitochondrial enzyme arginase-2 (Arg-2) is implicated in the pathophysiology of contrast-induced acute kidney injury (CI-AKI). Therefore, Arg-2 represents a candid target for CI-AKI prevention. Here, layer-by-layer (LbL) assembled renal-targeting polymeric nanoparticles are developed to efficiently deliver small interfering RNA (siRNA), knockdown Arg-2 expression in renal tubules, and prevention of CI-AKI is evaluated. First, near-infrared dye-loaded poly(lactic-co-glycolic acid) (PLGA) anionic cores are electrostatically coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg-2 siRNA. Next, nanoparticles are coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential electrostatic layering of CS and HA improves loading capacity of Arg-2 siRNA and yields LbL-assembled nanoparticles. Renal targeting and accumulation is enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA-KTP). The resultant kidney-targeting and siRNA loaded nanoparticles (PLGA/CS/HA-KTP siRNA) exhibit proprietary accumulation in kidneys and proximal tubular cells at 24 h post-tail vein injection. In iohexol-induced in vitro and in vivo CI-AKI models, PLGA/CS/HA-KTP siRNA delivery alleviates oxidative and nitrification stress, and rescues mitochondrial dysfunction while reducing apoptosis, thereby demonstrating a robust and satisfactory therapeutic effect. Thus, PLGA/CS/HA-KTP siRNA nanoparticles offer a promising candidate therapy to protect against CI-AKI.

Safety assessment of Brexpiprazole: Real-world adverse event analysis from the FAERS database.

OBJECTIVE: This study aims to analysis adverse drug events (ADE) related to Brexpiprazole from the third quarter of 2015 to the first quarter of 2023 from FAERS database. METHODS: The ADE data related to Brexpiprazole from 2015 Q3 to 2023 Q1 were collected. After standardizing the data, a variety of signal quantification techniques, including ROR, PRR, BCPNN, and MGPS were used for analysis. RESULTS: Among the 8559 ADE reports with Brexpiprazole as the primary suspected drug, 178 preferred terms (PT) of adverse reactions spanning 27 different system organ classes (SOC) were identified. Specifically, Metabolism and nutrition disorders and Reproductive system and breast disorders were unique adverse reactions to Brexpiprazole, with the latter not mentioned in the official drug label. Moreover, uncommon but significantly strong ADE signals, such as Egocentrism, Pharmacophobia, and Compulsions were observed. Notably, Tardive dyskinesia (n = 317, ROR 103.87, PRR 102.21, IC 6.21, EBGM 96.17) and Extrapyramidal disorder (n = 104, ROR 31.17, PRR 31.00, IC 4.57, EBGM 30.44) exhibited relatively high occurrence rates and signal strengths. Additionally, Lactation disorder (n = 6, ROR 48.09, PRR 48.07, IC 2.63, EBGM 46.71) and Breast discharge (n = 10, ROR 23.18, PRR 23.17, IC 2.94, EBGM 22.86) were observed, both presenting strong ADE signals. CONCLUSION: Brexpiprazole poses risks of various adverse reactions while providing therapeutic effects. In clinical applications, practitioners should closely monitor occurrences of Psychiatric disorders, Metabolism and nutrition disorders, Reproductive system and breast disorders, and other events.

Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance.

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.

Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma.

BACKGROUND: Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS: 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS: Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated ß-catenin signaling pathway in LCSCs. CONCLUSIONS: LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.

Differential regulation of hair cell actin cytoskeleton mediated by SRF and MRTFB.

The MRTF-SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various cell types. However, the specific contribution of MRTF-SRF in hair cells remains unknown. In this study, we showed that hair cell-specific deletion of Srf or Mrtfb, but not Mrtfa, leads to similar defects in the development of stereocilia dimensions and the maintenance of cuticular plate integrity. We used fluorescence-activated cell sorting-based hair cell RNA-Seq analysis to investigate the mechanistic underpinnings of the changes observed in Srf and Mrtfb mutants, respectively. Interestingly, the transcriptome analysis revealed distinct profiles of genes regulated by Srf and Mrtfb, suggesting different transcriptional regulation mechanisms of actin cytoskeleton activities mediated by Srf and Mrtfb. Exogenous delivery of calponin 2 using Adeno-associated virus transduction in Srf mutants partially rescued the impairments of stereocilia dimensions and the F-actin intensity of cuticular plate, suggesting the involvement of Cnn2, as an Srf downstream target, in regulating the hair bundle morphology and cuticular plate actin cytoskeleton organization. Our study uncovers, for the first time, the unexpected differential transcriptional regulation of actin cytoskeleton mediated by Srf and Mrtfb in hair cells, and also demonstrates the critical role of SRF-CNN2 in modulating actin dynamics of the stereocilia and cuticular plate, providing new insights into the molecular mechanism underlying hair cell development and maintenance.

Safety, tolerability, and immunogenicity of a CpG/Alum adjuvanted SARS-CoV-2 recombinant protein vaccine (ZR202-CoV) in healthy adults: Preliminary report of a phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial.

This was a phase 1 dose-escalation study of ZR202-CoV, a recombinant protein vaccine candidate containing a pre-fusion format of the spike (S)-protein (S-trimer) combined with the dual-adjuvant system of Alum/CpG. A total of 230 participants were screened and 72 healthy adults aged 18-59 years were enrolled and randomized to receive two doses at a 28-day interval of three different ZR202-CoV formulations or normal saline. We assessed the safety for 28 days after each vaccination and collected blood samples for immunogenicity evaluation. All formulations of ZR202-CoV were well-tolerated, with no observed solicited adverse events ≥ Grade 3 within 7 days after vaccination. No unsolicited adverse events ≥ Grade 3, or serious adverse events related to vaccination occurred as determined by the investigator. After the first dose, detectable immune responses were observed in all subjects. All subjects that received ZR202-CoV seroconverted at 14 days after the second dose by S-binding IgG antibody, pseudovirus and live-virus based neutralizing antibody assays. S-binding response (GMCs: 2708.7 ~ 4050.0 BAU/mL) and neutralizing activity by pseudovirus (GMCs: 363.1 ~ 627.0 IU/mL) and live virus SARS-CoV-2 (GMT: 101.7 ~ 175.0) peaked at 14 days after the second dose of ZR202-CoV. The magnitudes of immune responses compared favorably with COVID-19 vaccines with reported protective efficacy.

Brevibacillus brevis HNCS-1: a biocontrol bacterium against tea plant diseases.

As a biocontrol bacteria, Brevibacillus has been the subject of extensive research for agricultural applications. Antibacterial peptides (AMPs) are the main antibacterial products of Brevibacillus. This study isolated a strain of Br. brevis HNCS-1 from tea garden soil, and the strain has an antagonistic effect against five types of pathogens of tea diseases, namely Gloeosporium theae-sinensis, Elsinoe leucospira, Phyllosticta theaefolia, Fusarium sp., and Cercospora theae. To determine the genetic characteristics implicated in the biocontrol mechanism, the genome sequence of the HNCS-1 strain was obtained and analyzed further, and the data are deposited in the GenBank repository (No. CP128411). Comparative genomics analyses revealed that the HNCS-1 strain and 17 public Br. brevis share a core genome composed of 3,742 genes. Interestingly, only one non-ribosomal peptide synthetase (NRPS) gene cluster annotated as edeine is present in the core genome. And UHPLC-MS/MS detection results showd that edeine B and edeine A were the principal antibacterial peptides in the HNCS-1 strain. This study proves that edeine is the main antibacterial peptide of Br. brevis, and provides a new strategy for the identification of antibacterial products from other biocontrol bacteria.

Arginase2 mediates contrast-induced acute kidney injury via facilitating nitrosative stress in tubular cells.

Contrast-induced acute kidney injury(CI-AKI) is the third cause of AKI. Although tubular injury has been regarded as an important pathophysiology of CI-AKI, the underlying mechanism remains elusive. Here, we found arginase2(ARG2) accumulated in the tubules of CI-AKI mice, and was upregulated in iohexol treated kidney tubular cells and in blood samples of CI-AKI mice and patients, accompanied by increased nitrosative stress and apoptosis. However, all of the above were reversed in ARG2 knockout mice, as evidenced by the ameliorated kidney dysfunction and the tubular injury, and decreased nitrosative stress and apoptosis. Mechanistically, HO-1 upregulation could alleviate iohexol or ARG2 overexpression mediated nitrosative stress. Silencing and overexpressing ARG2 was able to upregulate and downregulate HO-1 expression, respectively, while HO-1 siRNA had no effect on ARG2 expression, indicating that ARG2 might inhibit HO-1 expression at the transcriptional level, which facilitated nitrosative stress during CI-AKI. Additionally, CREB1, a transcription factor, bound to the promoter region of ARG2 and stimulated its transcription. Similar findings were yielded in cisplatin- or vancomycin-induced AKI models. Taken together, ARG2 is a crucial target of CI-AKI, and activating CREB1/ARG2/HO-1 axis can mediate tubular injury by promoting nitrosative stress, highlighting potential therapeutic strategy for treating CI-AKI.

Exploring CAR-T Cell Therapy Side Effects: Mechanisms and Management Strategies.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of malignancies, especially hematological tumors, but toxicities have tempered its success. The main impediments to the development of CAR-T cell therapies are the following: cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), tumor lysis syndrome (TLS), and on-target/off-tumor toxicity (OTOT). This review summarizes these side effects' underlying mechanisms and manifestations over time. It provides potential prevention and treatment according to the consensus grading, stressing the significance of establishing strategies that anticipate, reduce, and navigate the beginning of these side effects. It is essential to fully comprehend the mechanisms underlying these toxicities to create efficient treatment and preventive approaches.

Boosting the ammonia synthesis activity of ceria-supported Ru catalysts achieved through trace Pr addition.

The amount of dopant used in conventional cases for improving catalytic performance is higher than 5%. In this work, a strategy to enhance the ammonia synthesis performance of a Ru/CeO2 catalyst by using trace Pr (0.1 mol%) is reported. Owing to the improvement of oxygen defects, Ce3+ concentration and interfaced Ru species, the hydrogen adsorption was enhanced, and the desorption of hydrogen species would be promoted. As a result, Ru/CeO2 with 0.1 mol% Pr shows 1.4 times higher ammonia synthesis rate and excellent stability compared to Ru/CeO2 or the sample with high Pr loading (50 mol% Pr). This study provides a new idea for the design of high-efficiency ammonia synthesis catalysts.

The Morphologically Controlled Synthesis and Application of Mesoporous Alumina Spheres.

The control of alumina morphology is crucial yet challenging for its various applications. Unfortunately, traditional methods for preparing alumina particles suffer from several limitations such as irregular morphology, poor dispersibility, and restricted application areas. In this study, we develop a novel method for preparing spherical mesoporous alumina using chitin and Pluronic P123 as mixed templates. The effects of reaction temperature, time, and the addition of mixed templates on the phase structure, micromorphology, and optical absorption properties of the samples were investigated. The experimental results indicate that lower temperature and shorter reaction time facilitated the formation of spherical mesoporous alumina with excellent CO2 adsorption capacity. The periodic density functional theory (DFT) calculations demonstrate that both the (110) and (100) surfaces of γ-Al2O3 can strongly adsorb CO2. The difference in the amount of CO2 adsorbed by Al2O3 is mainly due to the different surface areas, which give different numbers of exposed active sites. This approach introduces a novel strategy for utilizing biological compounds to synthesize spherical alumina and greatly enhances mesoporous alumina's application efficiency in adsorption fields. Moreover, this study explored the electrochemical performance of the synthesized product using cyclic voltammetry, and improved loading of electrocatalysts and enhanced electrocatalytic activity were discovered.

Strong positive light chain immunostaining in a patient with transthyretin amyloidosis.

The two most common systemic amyloidosis types are immunoglobulin light chain (AL) and amyloid transthyretin (ATTR) amyloidosis, in which the precursor proteins responsible for amyloidosis are light chain and transthyretin, respectively. Identification of precursor proteins is paramount to determine the type of amyloidosis, given that both amyloidosis types lack specificity in clinical presentation. Congo red staining followed by immunohistochemistry or immunofluorescence using fibril protein-specific antibodies is crucial for the diagnosis of amyloidosis. Here we describe a patient who was initially diagnosed with AL amyloidosis due to strong positive kappa light chain staining results. However, the diagnosis was corrected to hereditary ATTR amyloidosis using mass spectrometry and gene sequencing, confirming the important role of mass spectrometry in identifying the amyloid precursor protein and ruling out false-positive result from immunohistochemistry.

Nanofluidic diodes based on asymmetric bio-inspired surface coatings in straight glass nanochannels.

In this study, we present nanofluidic diodes fabricated from straight glass nanochannels and functionalized using bio-inspired polydopamine (PDA) and poly-L-lysine (PLL) coatings. The resulting PDA coatings are shown to be asymmetric due to a combination of transport considerations which can be leveraged to provide a measure of control over the effective channel geometry. By subsequently introducing a layer of amine-bearing PLL chains covalently bound to the PDA, we enhance heterogeneities in the charge and ion distributions within the channel and enable significant current rectification between forward-bias and reverse-bias modes; our PDA-PLL-coated channels yielded a rectification ratio greater than 1000 in a 100 nm channel filled with 0.01× phosphate-buffered saline solution (PBS). We further demonstrated that at higher ionic strength conditions, reducing the solution pH increased the number of protonated amines within the PLL layer, amplifying the charge disparities along the channel and leading to greater rectification. As nanofluidic diodes with bipolar surface charge distributions tend to provide superior performance compared to those with a single wall charge polarity, we imposed a more bipolar charge distribution in our devices by partially coating our PDA-PLL-coated channels with negatively charged polyacrylic acid (PAA). These enhanced bipolar channels exhibited greater current rectification than the PDA-PLL-coated channels, reaching rectification ratios in excess of 100 even in more physiologically-relevant 1× PBS solutions. Our fabrication approach and the results herein provide a promising platform from which the scientific community can build upon in the relentless endeavor for improved sensitivity in biosensors and other analytical devices.

Trends of the burden of type 2 diabetes mellitus attributable to high body mass index from 1990 to 2019 in China.

Background: Overweight and obesity are well-known risk factors for developing type 2 diabetes (T2DM). However, details on the evolution of the T2DM burden attributed to China's high body mass index (BMI) in China have not been thoroughly studied. This study aimed to investigate the temporal trends of the T2DM burden attributable to a high BMI in China from 1990 to 2019 and to evaluate the independent effects of age, period, and cohort on the burden of T2DM attributed to a high BMI. Methods: Data on T2DM burden attributable to a high BMI from 1990 to 2019 were obtained from the Global Burden of Disease Study 2019. Deaths, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) of T2DM attributable to a high BMI were estimated by age and sex. The joinpoint regression model was performed to calculate the annual percentage change (APC) and the average annual percentage change (AAPC) in the burden of T2DM attributed to a high BMI. The age-period-cohort analysis was applied to estimate the independent effects of age, period, and cohort on the temporal trends of mortality and the DALY rate. Results: In 2019, deaths and DALYs from T2DM attributable to a high BMI in China were 47.53 thousand and 3.74 million, respectively, five times higher than in 1990. Among those under 60 years of age, men had higher deaths and DALYs than women, while the gender differences reversed in those over 60 years of age. Furthermore, the ASMR and ASDR in 2019 were 2.39 per 100,000 (95%UI 1.12-3.90) and 181.54 per 100,000 (95%UI 93.71-286.33), respectively, representing a 91% and 126% increase since 1990. In China, women previously had a higher ASMR and ASDR than men, while the differences in the ASMR and ASDR between the sexes were reversed in recent years. From 1990 to 2019, the ASMR in women increased before 2004 and then decreased from 2004 to 2015, and increased again after, with an overall AAPC value of 1.6%. In contrast, the ASMR in men continued to increase, with an overall AAPC value of 3.2%. The ASDR continued to increase in men and women, with AAPCs of 2.2% and 3.5%, respectively. The age effect showed that the relative risk of mortality increased with age in both men and women, except for the 75-84 age group. The impact of the age on the DALY rate revealed a trend of first rising and then decreasing, peaking at 65-69 years. The effect of the period on the burden of T2DM attributable to a high BMI increased from 1990 to 2019. The cohort effect generally showed a downward trend. Conclusion: The burden of T2DM attributed to a high BMI in China increased substantially from 1990 to 2019, particularly in men. Therefore, there is an urgent need for gender- and age-based public health guidelines on prevention strategies, early diagnosis, and effective management of T2DM, overweight, and obesity in China.

Safety and immunogenicity of a bivalent HPV16/18 vaccine in Chinese females.

As global supply is still inadequate to address the worldwide requirements for HPV vaccines, we assessed the safety and immunogenicity of a new bivalent HPV16/18 vaccine. In this randomized, double-blind, placebo-controlled, phase 2 trial, healthy 9-45-year-old Chinese females in three age cohorts (600 aged 9-17 years; 240 aged 18-26 years; 360 aged 27-45 years) were randomized 1:1 to receive three doses (0,2,6 months) of HPV16/18 vaccine or placebo. We measured neutralizing antibodies against HPV 16 and 18 at 7 months and monitored safety to 12 months in all age cohorts; 9-17-year-old girls were monitored for safety and immunogenicity to 48 months. In vaccinees, 99.8% seroconverted for HPV 16 and 18 types at 7 months; respective GMTs of 5827 (95% CI: 5249, 6468) and 4223 (3785, 4713) were significantly (p < .001) higher than controls for all comparisons. GMTs in the 9-17-year-olds, which were significantly higher than in older women at 7 months, gradually declined to 48 months but remained higher than placebo with seropositivity rates maintained at 98.5% and 97.6% against HPV 16 and 18, respectively. Adverse events occurred at similar rates after vaccine and placebo (69.8% vs. 72.5%, p = .308), including solicited local reactions and systemic adverse events which were mainly mild-to-moderate. The bivalent HPV16/18 vaccine was well tolerated and induced high levels of neutralizing antibodies in all age groups which persisted at high levels to 48 months in the 9-17-year-old age group which would be the target for HPV vaccination campaigns.

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis.

Background: Drug-induced acute kidney damage (DI-AKI) is a clinical phenomenon of rapid loss of kidney function over a brief period of time as a consequence of the using of medicines. The lack of a specialized treatment and the instability of traditional kidney injury markers to detect DI-AKI frequently result in the development of chronic kidney disease. Thus, it is crucial to continue screening for DI-AKI hub genes and specific biomarkers. Methods: Differentially expressed genes (DEGs) of group iohexol, cisplatin, and vancomycin's were analyzed using Limma package, and the intersection was calculated. DEGs were then put into String database to create a network of protein-protein interactions (PPI). Ten algorithms are used in the Cytohubba plugin to find the common hub genes. Three DI-AKI models' hub gene expression was verified in vivo and in vitro using PCR and western blot. To investigate the hub gene's potential as a biomarker, protein levels of mouse serum and urine were measured by ELISA kits. The UUO, IRI and aristolochic acid I-induced nephrotoxicity (AAN) datasets in the GEO database were utilized for external data verification by WGCNA and Limma package. Finally, the Elisa kit was used to identify DI-AKI patient samples. Results: 95 up-regulated common DEGs and 32 down-regulated common DEGs were obtained using Limma package. A PPI network with 84 nodes and 24 edges was built with confidence >0.4. Four hub genes were obtained by Algorithms of Cytohubba plugin, including TLR4, AOC3, IRF4 and TNFAIP6. Then, we discovered that the protein and mRNA levels of four hub genes were significantly changed in the DI-AKI model in vivo and in vitro. External data validation revealed that only the AAN model, which also belonged to DI-AKI model, had significant difference in these hub genes, whereas IRI and UUO did not. Finally, we found that plasma TLR4 levels were higher in patients with DI-AKI, especially in vancomycin-induced AKI. Conclusion: The immune system and inflammation are key factors in DI-AKI. We discovered the immunological and inflammatory-related genes TLR4, AOC3, IRF4, and TNFAIP6, which may be promising specific biomarkers and essential hub genes for the prevention and identification of DI-AKI.

Safety and immunogenicity of a pichia pastoris-expressed bivalent human papillomavirus (types 16 and 18) L1 virus-like particle vaccine in healthy Chinese women aged 9-45 years: A randomized, double-blind, placebo-controlled phase 1 clinical trial.

BACKGROUND: We evaluated the safety and immunogenicity of high and low doses of a novel pichia pastoris-expressed bivalent (types 16 and 18) human papillomavirus (HPV) virus-like particle vaccine. METHODS: In this randomized, double-blind, placebo-controlled phase 1 trial, we enrolled 160 healthy females aged 9-45 years in Guangxi, China who were randomized (1:1:2) to receive either low (0.5 mL) or high (1.0 mL) dosages of bivalent HPV vaccine, or placebo (aluminum adjuvant) in a 0, 2, 6 months schedule. Adverse events and other significant conditions that occurred within 30 days after each vaccination were recorded throughout the trial. Sera were collected at days 0, 60, 180 and 210 to measure anti-HPV 16/18 neutralizing antibodies. RESULTS: A total of 160 participants received at least one dose of the HPV vaccine and 152 completed the three dose vaccination series. Reporting rates of adverse events in placebo, low dose (0.5 mL) and high dose (1.0 mL) groups were 47.5 %, 55.0 % and 55.0 %, respectively. No serious adverse events occurred during this trial. 100 % of the participants who received three doses of the HPV vaccine produced neutralizing antibodies against HPV 16/18 vaccine. For HPV 16 and HPV 18, the geometric mean titers (GMTs) were similar between the low dose group (GMTHPV 16 = 10816 [95 % CI: 7824-14953]), GMTHPV 18 = 3966 [95 % CI: 2693-5841]) and high dose group (GMT HPV 16 = 14482 [95 % CI: 10848-19333], GMT HPV 18 = 3428 [95 % CI: 2533-4639]). CONCLUSION: The pichia pastoris-expressed bivalent HPV vaccine was safe and immunogenic in Chinese females aged 9-45 years. The low dosage (0.5 mL) was selected for further immunogenicity and efficacy study.

Atp8a1 deletion increases the proliferative activity of hematopoietic stem cells by impairing PTEN function.

PURPOSE: The eukaryotic cell plasma membrane contains several asymmetrically distributed phospholipids, which is maintained by the P4-ATPase flippase complex. Herein, we demonstrated the biological effects and mechanisms of asymmetrical loss in hematopoietic stem cells (HSCs). METHODS: An Atp8a1 knockout mouse model was employed, from which the HSC (long-term HSCs and short-term HSCs) population was analyzed to assess their abundance and function. Additionally, competitive bone marrow transplantation and 5-FU stress assays were performed. RNA sequencing was performed on Hematopoietic Stem and Progenitor Cells, and DNA damage was assayed using immunofluorescence staining and comet electrophoresis. The protein abundance for members of key signaling pathways was confirmed using western blotting. RESULTS: Atp8a1 deletion resulted in slight hyperleukocytosis, associated with the high proliferation of HSCs and BCR/ABL1 transformed leukemia stem cells (LSCs). Atp8a1 deletion increased the repopulation capability of HSCs with a competitive advantage in reconstitution assay. HSCs without Atp8a1 were more sensitive to 5-FU-induced apoptosis. Moreover, Atp8a1 deletion prevented HSC DNA damage and facilitated DNA repair processes. Genes involved in PI3K-AKT-mTORC1, DNA repair, and AP-1 complex signaling were enriched and elevated in HSCs with Atp8a1 deletion. Furthermore, Atp8a1 deletion caused decreased PTEN protein levels, resulting in the activation of PI3K-AKT-mTORC1 signaling, further increasing the activity of JNK/AP-1 signaling and YAP1 phosphorylation. CONCLUSION: We identified the role of Atp8a1 on hematopoiesis and HSCs. Atp8a1 deletion resulted in the loss of phosphatidylserine asymmetry and intracellular signal transduction chaos.