Broad-spectrum Delta-BA.2 tandem-fused heterodimer mRNA vaccine delivered by lipopolyplex.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to mutate and generates new variants with increasingly severe immune escape, urging the upgrade of COVID-19 vaccines. Here, based on a similar dimeric RBD design as our previous ZF2001 vaccine, we developed a novel broad-spectrum COVID-19 mRNA vaccine, SWIM516, with chimeric Delta-BA.2 RBD dimer delivered by lipopolyplex (LPP). Unlike the popular lipid nanoparticle (LNP), this LPP-delivered mRNA expresses only in the injection site, which avoids potential toxicity to the liver. We demonstrated the broad-spectrum humoral and cellular immunogenicity of this vaccine to Delta and Omicron sub-variants in naïve mice and as booster shots. When challenged with Delta or Omicron live virus, vaccinated human angiotensin-converting enzyme (hACE2) transgenic mice and rhesus macaques were both protected, displaying significantly reduced viral loads and markedly relieved pathological damages. We believe the SWIM516 vaccine qualifies as a candidate for the next-generation broad-spectrum COVID-19 vaccine.

The impact of anxiety on gait impairments in Parkinson's disease: insights from sensor-based gait analysis.

BACKGROUND: Sensor-based gait analysis provides a robust quantitative tool for assessing gait impairments and their associated factors in Parkinson's disease (PD). Anxiety is observed to interfere with gait clinically, but this has been poorly investigated. Our purpose is to utilize gait analysis to uncover the effect of anxiety on gait in patients with PD. METHODS: We enrolled 38 and 106 PD patients with and without anxiety, respectively. Gait parameters were quantitively examined and compared between two groups both in single-task (ST) and dual-task (DT) walking tests. Multiple linear regression was applied to evaluate whether anxiety independently contributed to gait impairments. RESULTS: During ST, PD patients with anxiety presented significantly shorter stride length, lower gait velocity, longer stride time and stance time, longer stance phase, smaller toe-off (TO) and heel-strike (HS) angles than those without anxiety. While under DT status, the differences were diminished. Multiple linear regression analysis demonstrated that anxiety was an independent factor to a serials of gait parameters, particularly ST-TO (B = -2.599, (-4.82, -0.38)), ST-HS (B = -2.532, (-4.71, -0.35)), ST-TO-CV (B = 4.627, (1.71, 7.64)), ST-HS-CV(B = 4.597, (1.66, 7.53)), ST stance phase (B = 1.4, (0.22, 2.58)), and DT stance phase (B = 1.749, (0.56, 2.94)). CONCLUSION: Our study discovered that anxiety has a significant impact on gait impairments in PD patients, especially exacerbating shuffling steps and prolonging stance phase. These findings highlight the importance of addressing anxiety in PD precision therapy to achieve better treatment outcomes.

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma.

OBJECTIVE: The roles of MTFR1 in the drug resistance of lung adenocarcinoma (LAC) to cisplatin remain unexplored. In this study, the expression, clinical values and mechanisms of MTFR1 were explored, and the relationship between MTFR1 expression and immune microenvironment was investigated in LAC using bioinformatics analysis, cell experiments, and meta-analysis. METHODS: MTFR1 expression and clinical values, and the relationship between MTFR1 expression and immunity were explored, through bioinformatics analysis. The effects of MTFR1 on the growth, migration and cisplatin sensitivity of LAC cells were identified using cell counting kit-8, wound healing and Transwell experiments. Additionally, the mechanisms of drug resistance of LAC cells involving MTFR1 were investigated using western blotting. RESULTS: MTFR1 was elevated in LAC tissues. MTFR1 overexpression was associated with sex, age, primary therapy outcome, smoking, T stage, unfavourable prognosis and diagnostic value and considered an independent risk factor for an unfavourable prognosis in patients with LAC. MTFR1 co-expressed genes involved in the cell cycle, oocyte meiosis, DNA replication and others. Moreover, interfering with MTFR1 expression inhibited the proliferation, migration and invasion of A549 and A549/DDP cells and promoted cell sensitivity to cisplatin, which was related to the inhibition of p-AKT, p-P38 and p-ERK protein expression. MTFR1 overexpression was associated with stromal, immune and estimate scores along with natural killer cells, pDC, iDC and others in LAC. CONCLUSIONS: MTFR1 overexpression was related to the unfavourable prognosis, diagnostic value and immunity in LAC. MTFR1 also participated in cell growth and migration and promoted the drug resistance of LAC cells to cisplatin via the p-AKT and p-ERK/P38 signalling pathways.

Tau Phosphorylation Patterns in the Rat Cerebral Cortex After Traumatic Brain Injury and Sodium Selenate Effects: An Epibios4rx Project 2 Study.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser202/Thr205-immunoreactivity (AT8-ir) and pTAU-Ser199/202-ir at 2 days, and pTAU-Thr231-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

HLA-DPA1 overexpression inhibits cancer progression, reduces resistance to cisplatin, and correlates with increased immune infiltration in lung adenocarcinoma.

PURPOSE: Human Leukocyte Antigen-DP alpha 1 (HLA-DPA1) is a critical gene in antigen-presenting cells and plays a significant role in immune regulation. The objective of this study was to comprehensively analyze the roles of HLA-DPA1 and its association with lung adenocarcinoma (LUAD). METHODS: We utilized bioinformatics and conducted a meta-analysis to examine the roles of HLA-DPA1 expression on the progression and immunity of LUAD. We also performed CCK-8, wound healing, and Transwell assays to validate the functions of HLA-DPA1 in LUAD. RESULTS: HLA-DPA1 expression is downregulated in LUAD tissues and is associated with gender, race, age, smoking history, clinical stage, histological type, lymph node metastasis, and prognosis of patients with LUAD. HLA-DPA1 is involved in immune responses, leukocyte cell-cell adhesion, and antigen processing and presentation. Overexpression of HLA-DPA1 inhibits cancer cell proliferation, migration, and invasion while promoting cell sensitivity to cisplatin in A549 and A549/DDP cells. Additionally, overexpression of HLA-DPA1 correlates with tumor purity, stromal, immune, and ESTIMATE scores, the abundance of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, dendritic cells, and neutrophils), and immune cell markers (programmed cell death 1, cytotoxic T-lymphocyte-associated protein 4, and cluster of differentiation 8A). CONCLUSIONS: Decreased HLA-DPA1 expression is associated with poor prognosis and immune infiltration in LUAD while HLA-DPA1 overexpression inhibits cancer cell proliferation and progression. Therefore, HLA-DPA1 shows potential as a prognostic biomarker and a therapeutic target for LUAD.

Multi-Level Biomarkers for Early Diagnosis of Ischaemic Stroke: A Systematic Review and Meta-Analysis.

Blood biomarkers hold potential for the early diagnosis of ischaemic stroke (IS). We aimed to evaluate the current weight of evidence and identify potential biomarkers and biological pathways for further investigation. We searched PubMed, EMBASE, the Cochrane Library and Web of Science, used R package meta4diag for diagnostic meta-analysis and applied Gene Ontology (GO) analysis to identify vital biological processes (BPs). Among 8544 studies, we included 182 articles with a total of 30,446 participants: 15675 IS, 2317 haemorrhagic stroke (HS), 1798 stroke mimics, 846 transient ischaemic attack and 9810 control subjects. There were 518 pooled biomarkers including 203 proteins, 114 genes, 108 metabolites and 88 transcripts. Our study generated two shortlists of biomarkers for future research: one with optimal diagnostic performance and another with low selection bias. Glial fibrillary acidic protein was eligible for diagnostic meta-analysis, with summary sensitivities and specificities for differentiating HS from IS between 3 h and 24 h after stroke onset ranging from 73% to 80% and 77% to 97%, respectively. GO analysis revealed the top five BPs associated with IS. This study provides a holistic view of early diagnostic biomarkers in IS. Two shortlists of biomarkers and five BPs warrant future investigation.

New Insights into Phospholipid Profile Alteration of Bigeye Tuna (Thunnus obesus) during Daily Cooking Processes Using Rapid Evaporative Ionization Mass Spectrometry.

Bigeye tuna (BET, Thunnus obesus) is one of the most nutritious and luxurious cosmopolitan fish. The cooked BET products are capturing the interests of consumers by enhancing flavor and ensuring microbiological safety; however, the lipidomic fingerprints during daily cooking processes have not been investigated. In this work, lipid phenotypic data variation in BET during air-frying, roasting, and boiling was studied comprehensively using iKnife rapid evaporative ionization mass spectrometry (REIMS). The outstanding lipid ions mainly including fatty acids (FAs) and phospholipids (PLs) were identified structurally. It was demonstrated that the rates of heat transfer and lipid oxidation in air-fried BET were slower than those in roasted and boiled BET by elucidating the lipid oxidation and PL hydrolysis mechanism. Furthermore, multivariate REIMS data analysis (e.g., discriminant analysis, support vector machine, neutral network, and machine learning models) was used to characterize the lipid profile change in different cooked BET samples, among which FAC22:6, PL18:3/22:6, PL18:1/22:6, and others were the salient contributing features for determining the cooked BET samples. These results may provide a potential strategy for a healthy diet by controlling and improving functional food quality in daily cooking.

CENPH overexpression promotes the progression, cisplatin resistance, and poor prognosis of lung adenocarcinoma via the AKT and ERK/P38 pathways.

Overexpression of centromere protein H (CENPH) promotes cancer growth and progression. However, the roles and underlying mechanisms have not been elucidated. Therefore, we aim to explore the roles and mechanisms of CENPH in lung adenocarcinoma (LUAD) progression by using comprehensive data analysis and cell experiments. In this study, the relationship between CENPH expression, which was obtained from the TCGA, and GTEx databases, and the prognosis and clinical characteristics of LUAD patients was analyzed, and the diagnostic values of CENPH was evaluated. CENPH-related risk models and nomograms were constructed to evaluate the prognosis of LUAD via Cox and LASSO regression analysis. The roles and mechanisms of CENPH in LUAD cells were studied using CCK-8 assay, wound healing and migration tests, and western blotting. The relationship between CENPH expression and immune microenvironment and RNA modifications was explored through correlation analysis. We found that CENPH was overexpressed in LUAD tissues, and tumors with diameter >3 cm, lymph node metastasis, distant metastasis, late stage, men, and dead cancer patients. Increased expression of CENPH was related to the diagnosis, poor survival rate, disease specific survival rate, and progression of LUAD. CENPH-related nomograms and risk models could predict the survival rate of LUAD patients. Inhibiting the expression of CENPH in LUAD cells decreased their migration, proliferation, and invasion, and promoted their sensitivity to cisplatin, which was related to the downregulation of p-AKT, p-ERK, and p-P38. However, there was no effect on AKT, ERK, and P38. Enhanced expression of CENPH was significantly correlated with immune score, immune cells, cell markers, and RNA modifications. In conclusion, CENPH was strongly expressed in LUAD tissues and was associated with poor prognosis, immune microenvironment, and RNA modifications. CENPH overexpression could enhance cell growth and metastasis and promote resistance to cisplatin via the AKT and ERK/P38 pathways, indicating its potential as a biomarker for the prognosis of LUAD.

Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat Model.

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies.

A new prognostic model for RHOV, ABCC2, and CYP4B1 to predict the prognosis and association with immune infiltration of lung adenocarcinoma.

Background: Lymph node metastasis is one of the important factors affecting the prognosis of lung adenocarcinoma (LUAD) patients. The key molecules in lymph node metastasis have not yet been fully revealed. Therefore, we aimed to construct a prognostic model based on lymph node metastasis-related genes to evaluate the prognosis of LUAD patients. Methods: The differentially expressed genes (DEGs) in the process of LUAD metastasis were identified in The Cancer Genome Atlas (TCGA) database, and the biological roles of the DEGs were depicted using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and a protein-protein interaction (PPI) network. Survival analysis and Cox regression analysis were used to identify the genes related to the prognosis of patients with LUAD, and a nomogram and a prognostic model were constructed. The potential prognostic value, immune escape, and regulatory mechanisms of the prognostic model in LUAD progression were explored through survival analysis and gene set enrichment analysis (GSEA). Results: A total of 75 genes were upregulated, and 138 genes were downregulated in tissues of lymph node metastasis. The expression levels of STC1, CYP17A1, RHOV, GUCA2B, TM4SF20, DEFB1, CRHR2, ABCC2, CYP4B1, KRT16, and NTS were revealed as risk factors for a poor prognosis in LUAD patients. High-risk LUAD patients had a poor prognosis in the prognostic model based on RHOV, ABCC2, and CYP4B1. The clinical stage and the risk score were found to be independent risk factors for a poor prognosis in LUAD patients, and the risk score was associated with the tumor purity, T cell, natural killer (NK) cell, and other immune cells. The prognostic model might affect the progression of LUAD using DNA replication, the cell cycle, P53, and other signaling pathways. Conclusions: Lymph node metastasis-related genes RHOV, ABCC2, and CYP4B1 are associated with a poor prognosis in LUAD. A prognostic model based on RHOV, ABCC2, and CYP4B1 might predict the prognosis of LUAD patients and be associated with immune infiltration.

Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam.

OBJECTIVE: We used the lateral fluid percussion injury (LFPI) model of moderate-to-severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post-traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. METHODS: Adult male Sprague-Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post-LFPI, and were continuously video-EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post-LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d-to-7d neuroscore recovery, using machine learning. RESULTS: Low 2d plasma levels of Thr231 -phosphorylated tau protein (pTAU-Thr231 ) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam-treated LFPI rats were differentiated from vehicle treated by the 2d-HMGB1, 2d-pTAU-Thr231 , and 2d-UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle-treated LFPI rats: pTAU-Thr231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle-treated LFPI rats). Levetiracetam-resistant early seizures were predicted by high 2d-IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d-to-7d neuroscore recovery was best predicted by higher 2d-S100B, lower 2d-HMGB1, and 2d-to-7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers). SIGNIFICANCE: Antiseizure medications and early seizures need to be considered in the interpretation of early post-traumatic biomarkers.

Lipidomic fingerprinting of plasmalogen-loaded zein nanoparticles during in vitro multiple-stage digestion using rapid evaporative ionization mass spectrometry.

Plasmalogens (Pls) as the hydrophobic bioactive compound have shown potential in enhancing neurological disorders. However, the bioavailability of Pls is limited because of their poor water solubility during digestion. Herein, the hollow dextran sulfate/chitosan - coated zein nanoparticles (NPs) loaded with Pls was prepared. Subsequently, a novel in situ monitoring method utilizing rapid evaporative ionization mass spectrometry (REIMS) coupled with electric soldering iron ionization (ESII) was proposed to assess the lipidomic fingerprint alteration of Pls-loaded zein NPs during in vitro multiple-stage digestion in real time. A total of 22 Pls in NPs were structurally characterized and quantitatively analyzed, and the lipidomic phenotypes at each digestion stage were evaluated by multivariate data analysis. During multiple-stage digestion, Pls were hydrolyzed to lyso-Pls and free fatty acids by phospholipases A2, while the vinyl ether bond was retained at the sn-1 position. The result revealed that the contents of Pls groups were significantly reduced (p < 0.05). The multivariate data analysis results indicated that the ions at m/z 748.28, m/z 750.69, m/z 774.38, m/z 836.58, and etc. were the significant candidate contributors for monitoring the variation of Pls fingerprints during digestion. Results demonstrated that the proposed method exhibited potential for real-time tracking the lipidomic characteristics of nutritional lipid NPs digestion in the human gastrointestinal tract.

The simulation, regulation capacity assessment and coping strategy of rainstorm runoff waterlogging in Zhu pai-chong Basin of Nanning, China.

Currently, China is experiencing a phase of rapid urbanization. With the frequent occurrence of extreme rainfall events within the context of climate change, the problem of heavy rainfall and waterlogging in many cities is very prominent. In November 2020, China issued a proposal for the construction of sponge cities across the entire region to significantly enhance the rainfall flood prevention and drainage capacity of cities and effectively improve the resilience of sponge city systems for flooding management. Therefore, this paper selected the Zhu pai-chong watershed in Nanning with frequent waterlogging disasters as an example. Based on underlying surface information, We used a coupled SWMM-LISFOOD model to simulate runoff and waterlogging processes and analyze the spatial and temporal evolution characteristics of the basin under 10 designed rainstorm return periods (0.25a-50a). The results confirm the substantial spatial and temporal variabilities of the runoff coefficient in the study area; impermeability was the main factor contributing to high runoff coefficient values. The spatial distribution characteristics of inundation area was general dispersion and local linear aggregation. Furthermore, this study assessed the effect of the control rate of blue‒green‒gray facilities on the actual storms, and the value ranged from only 48.6% (0.25a)-24.05% (50a). This study quantified the two-dimensional distribution of rainfall storage volume thresholds with or without considering the discharged from the pipe network. Quantitative mapping between the elements of "rainfall-storage volume of blue‒green‒gray facilities-runoff-drainage capacity of the pipe network-waterlogging level" was conducted within the study area as an example. Finally, an overall technical process scheme for rainfall and waterlogging management was proposed. The scheme covered the hydrological‒hydraulic mechanism, storage function of sponge facilities, engineering control response, nonengineering measures and intelligent management of rainfall and waterlogging during sponge city construction, which could provide critical scientific support for effective promotion of the construction of sponge cities in China.

The circ_0002538/miR-138-5p/plasmolipin axis regulates Schwann cell migration and myelination in diabetic peripheral neuropathy.

Circular RNAs (circRNAs) play a vital role in diabetic peripheral neuropathy. However, their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood. Here, we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls. Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group. Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation. A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs. circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy. Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin (PLLP) expression. Moreover, overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function. The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p, while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration. These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients, improving myelin sheath structure and nerve function. Thus, this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.

A new risk model for CSTA, FAM83A, and MYCT1 predicts poor prognosis and is related to immune infiltration in lung squamous cell carcinoma.

OBJECTIVES: To create a prognostic model based on differentially expressed genes (DEGs) in early lung squamous cell carcinoma (LUSC) and characterize the relationship between risk scores and tumor immune infiltration. METHODS: We identified DEGs in normal and tumor tissues that overlapped between LUSC-related data sets from the Gene Expression Omnibus and the Cancer Genome Atlas and evaluated their roles in the diagnosis and prognosis of LUSC by Kaplan-Meier survival analysis, receiver operating characteristic (ROC) analysis, meta-analysis and nomogram analysis. We then constructed a risk model based on Cox regression analysis and the Akaike information criterion and identified the relationship between LUSC risk scores and immune infiltration. RESULTS: Sixty-two overlapping DEGs were involved with keratinocyte differentiation, epidermal cell differentiation, neutrophil migration, granulocyte chemotaxis, granulocyte migration, leukocyte aggregation, and positive regulation of nuclear factor-κB (NF-κB) activity. Overexpression of family with sequence similarity 83 member A (FAM83A) and MYC target 1 (MYCT1), kallikrein related peptidase 8 (KLK8), and downregulation of ADP ribosylation factor like GTPase 14 (ARL14), caspase recruitment domain family member 14 (CARD14), cystatin A (CSTA), dickkopf WNT signaling pathway inhibitor 4 (DKK4), desmoglein 3 (DSG3), and keratin 6B (KRT6B) were associated with a poor prognosis in LUSC and had significant value for LUSC diagnosis. The expression of CSTA, FAM83A, and MYCT1 and high-risk scores were independent risk factors for a poor prognosis in LUSC. A risk nomogram revealed that risk scores could predict the prognosis of LUSC. The risk score was associated with neutrophils, naive B cells, helper follicular T cells, and activated dendritic cells. CONCLUSIONS: The expression levels of CSTA, FAM83A, and MYCT1 are related to the diagnosis and prognosis of LUSC and may have potential as therapeutic targets in LUSC. A risk model and nomogram based on CSTA, FAM83A, and MYCT1 can predict the prognosis of LUSC.

Exosomes from Adipose Stem Cells Promote Diabetic Wound Healing through the eHSP90/LRP1/AKT Axis.

Oxidative damage is a critical cause of diabetic wounds. Exosomes from various stem cells could promote wound repair. Here, we investigated the potential mechanism by which exosomes from adipose-derived stem cells (ADSC-EXOs) promote diabetic wound healing through the modulation of oxidative stress. We found that ADSC-EXOs could promote proliferation, migration, and angiogenesis in keratinocytes, fibroblasts, and endothelial cells. Furthermore, ADSC-EXOs reduced the reactive oxygen species (ROS) levels in these cells and protected them against hypoxic and oxidative stress damage. Finally, the local injection of ADSC-EXOs at wound sites significantly increased collagen deposition and neovascularization while reducing ROS levels and cell death; thus, it led to accelerated diabetic wound closure. The mechanism underlying ADSC-EXO functions involved heat-shock protein 90 (HSP90) expressed on the cell surface; these functions could be inhibited by an anti-HSP90 antibody. Exosomal HSP90 could bind to the low-density lipoprotein receptor-related protein 1 (LRP1) receptor on the recipient cell membrane, leading to activation of the downstream AKT signaling pathway. Knockdown of LRP1 and inhibition of the AKT signaling pathway by LY294002 in fibroblasts was sufficient to impair the beneficial effect of ADSC-EXOs. In summary, ADSC-EXOs significantly accelerated diabetic wound closure through an exosomal HSP90/LRP1/AKT signaling pathway.

A structural MRI study of global developmental delay in infants (<2 years old).

Objective: To use structural magnetic resonance imaging (3D-MRI) to evaluate the abnormal development of the cerebral cortex in infants with global developmental delay (GDD). Methods: The GDD group includes 67 infants aged between 112 and 699 days with global developmental delay and who underwent T1-weighted MRI scans in Shanxi Children's Hospital from December 2019 to March 2022. The healthy control (HC) group includes 135 normal developing infants aged between 88 and 725 days in Shanxi Children's Hospital from September 2020 to August 2021. Whole-brain T1-weighted MRI scans were carried out with a 3.0-T magnetic resonance scanner, which was later processed using InfantSurfer to perform MR image processing and cortical surface reconstruction. Two morphological features of the cortical surface of the 68 brain regions were computed, i.e., the cortical thickness (CT) and cortical surface area (SA), and compared between the GDD and HC groups. Results: With regard to the CT, the HC group showed a rapid decrease at first and then a slow increase after birth, and the CT of the GDD group decreased slowly and then became relatively stable. The GDD group showed bilaterally higher hemispherical average CT than those in the HC group. In detail, for the left hemisphere, except in the entorhinal and temporal poles in which the average CT values of the two brain regions were lower than those of the HC group, the CT of the 26 brain regions in the GDD group was higher than those of the HC group (p < 0.05). For the right hemisphere, the CT of the entorhinal in the GDD group was lower than that in the HC group. Otherwise, the CT of the remaining 28 brain regions was higher than those in the HC group (p < 0.05). With regard to the SA, both groups showed a rapid increase after birth till 23 months and remained quite stable afterward. The GDD group shows lower SA bilaterally than that in the HC group. In detail, SA in the GDD group was lower in most cortical regions of both hemispheres than in the HC group (p < 0.05), except for the right temporal pole and entorhinal. When testing for brain asymmetry, we found that the HC group showed obvious asymmetry of CT and SA, while only a few cortical regions in the GDD group showed asymmetry.

Green Innovation and Enterprise Sustainable Development Performance Based on the SBM-DEA Model.

Since the introduction of a low-carbon economy, corporate performance is no longer limited to the evaluation of internal economic benefits but has become the performance of corporate sustainable development, adding environmental and social factors. Now, the whole world is paying attention to low consumption and low emission. As the main economic pillar of society, the enterprise undertakes the biggest low-carbon task. In order to develop the economy in the longer term and meet the needs of society, enterprises must combine green innovation to evaluate the performance of sustainable development. However, because the previous model's analysis of performance will produce distortion effects, the data error is also relatively large. Therefore, in order to solve these problems and make performance analysis more realistic, this paper deeply discusses the issue of green innovation and enterprise sustainable development performance. Using the method of the SBM-DEA model, it analyzes the performance comparison of enterprises without and with the expected output and conducts a comparison experiment. The result shows that in 2017, the efficiency of company A without unexpected output was 0.6943. The efficiency with undesired output is 0.6643. In 2018, the efficiency of the enterprise without undesired output is 1, and the efficiency with undesired output is 1. After applying the model, it is obvious that the efficiency of computing performance has been greatly improved. Therefore, in order to better study the sustainable development performance of enterprises, the SBM-DEA model should be focused on.

Paired Box Gene 6 Regulates Heme Oxygenase-1 Expression and Mitigates Hydrogen Peroxide-Induced Oxidative Stress in Lens Epithelial Cells.

PURPOSE: This study aimed to investigate the regulation of heme oxygenase-1 (HO-1) by paired box gene 6 (Pax6) and their roles in hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in lens epithelial cells (LECs) (SRA01/04, HLE-B3). METHODS: Lens anterior capsule membranes of mice of different ages were obtained to compare differences in the expression of Pax6 and HO-1 using Western blotting. Pax6-overexpressing plasmid and small interfering RNA were designed to overexpress and silence Pax6, respectively. Cobalt protoporphyrin (CoPP) was used to promote the expression of HO-1. Oxidative damage in LECs was induced by treatment with H2O2 (400 µM) for 24 h. Cell viability was measured using the Cell Counting Kit-8 assay. Intracellular reactive oxygen species (ROS) were detected using flow cytometry and immunofluorescence. Superoxide dismutase (SOD) level was measured using SOD Assay Kit and apoptotic cells were quantified using annexin V-fluorescein isothiocyanate/propidium iodide staining. RESULTS: Pax6 and HO-1 expression levels showed an age-dependent decrease in LECs of mouse. Overexpressing Pax6 upregulated HO-1 expression level. Silencing Pax6 downregulated the HO-1 expression level, resulting in increased generation of ROS, reduced SOD activity, decreased cell viability, and increased apoptotic cells of LECs under H2O2-induced oxidative stress. Overexpressing Pax6 and CoPP both mitigates H2O2-induced oxidative stress by increasing the expression of HO-1 of LECs. CONCLUSION: Pax6 and HO-1 expression levels showed an age-dependent decrease in LECs in mouse anterior capsules. Pax6 could regulate the expression of HO-1 in LECs. The decrease of Pax6 weakened the antioxidant ability of LECs under H2O2-induced oxidative stress by downregulating HO-1, which may be a potential mechanism for the formation of age-related cataract.

ADSC-exo@MMP-PEG smart hydrogel promotes diabetic wound healing by optimizing cellular functions and relieving oxidative stress.

Diabetic wound complications are financially costly and difficult to heal in worldwide. Whereas the therapies of diabetic wound, such as wound dressing, endocrine therapy or flap-transplantations, were not satisfied. Based on our previous study of exosome secreted by adipose-derived stem cell (ADSC-exo), we loaded ADSC-exo into the matrix metalloproteinase degradable polyethylene glycol (MMP-PEG) smart hydrogel. Physical and chemical properties of ADSC-exo@MMP-PEG smart hydrogel were tested by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), weight loss examination, etc. As the hydrogel degraded in response to MMP, ADSC-exo was released and subsequently enhanced cell function via Akt signaling. Moreover, treatment with ADSC-exo@MMP-PEG smart hydrogel significantly relieved the H2O2-induced oxidative stress, which was widely recognized as a major cause of diabetic wound nonhealing. Similar results were achieved in mice diabetic wound models, in which the ADSC-exo@MMP-PEG treatment group displayed a significantly accelerated wound healing. To summarize, the present smart hydrogel with enzyme-response and exosome-release was proved to be benefit for diabetic wounds healing, which provides a reliable theoretical basis for application of ADSC-exo in treatment of diabetic wounds.