IL-13/IL-13RA2 signaling promotes colorectal cancer stem cell tumorigenesis by inducing ubiquitinated degradation of p53.

Cancer stem cells (CSCs) are considered tumor-initiating cells and the main drivers of disease progression. Targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the up-regulation of IL-13RA2 expression in colorectal cancer (CRC) tissues and spheroid cells. The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC. We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients. Biologically, recombinant IL-13 (rIL-13) stimulation promoted the sphere formation, proliferation, and migration of CRC cells in vitro and enhanced tumorigenesis in vivo. This phenotype could be reversed by knocking down IL-13RA2. Mechanistically, IL-13 activated autophagy by inducing LC3I/LC3II transformation in CRC-CSCs, which was crucial for the biological functions of IL-13. We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein, enhancing the interaction of UBE3C and p53, thereby inducing the K48-linked ubiquitination of p53. In conclusion, the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination, adding an important layer to the connection between IL-13 and p53, which can be translated into novel targeted therapies.

Using the photo-enhanced barrier effect on electrochemical response for highly sensitive detection of melamine.

Melamine added to milk powder can lead to kidney injury and even death, but rapid detection is still hard due to the strong interference of milk powder solution. Herein, the CC/CeO2/CNPs mesh was constructed to detect melamine by using the photo-enhanced barrier effects on electrochemical response. Schottky barrier was regulated effectively to produce electrochemical response to melamine by photo-induced electrostatic interaction, which exhibited strong resistance to interference in milk powder solution. Sensitivity was enhanced by nearly 5 times and the lowest detection limit was reduced as low as 0.274 nM. The obtained high recovery (100%-104%) and good stability in milk powder solution indicated the good potential for practical applications. It provides a new opportunity for achieving strong resistance to interference by using the photo-enhanced barrier driving effect on electrochemical response.

The mortality trends analysis of ischemic heart disease attributed to (PM) 2.5 exposure in China from 1990 to 2019 in APC model.

OBJECTIVE: To analyze the mortality trend of ischemic heart disease (IHD) attributed to particulate matter (PM) 2.5 exposure among Chinese populations from 1990 to 2019. To evaluate the influences of cohort, period, and age on long-term of IHD mortality trends. METHODS: Global burden of disease (GBD) data in 2019 regarding IHD death rate attributed to exposure to (PM) 2.5 in China from 1990 to 2019 were adopted. The age-period-cohort (APC) model based on the R language produced by the National Cancer Institute of the United States was used for statistical analysis to investigate the influences of different ages, periods, and cohorts on IHD death rate attributed to exposure to (PM) 2.5. RESULTS: The age-standardized death rate of IHD attributed to exposure to ambient (PM) 2.5 in China revealed an uptrend from 1990 to 2019. This increased from 8.63/100,000 in 1990 to 21.31/100,000 in 2019. This was an increase of 1.47%. The age-standardized IHD death rate attributed to exposure to household (PM) 2.5 showed a decreasing trend. This decreased from 19.61/100,000 in 1990 to 8.72/100,000 in 2019. This was a decrease of 0.74%. The results of the APC model indicated that the annual net drift of IHD mortality attributed to exposure to (PM) 2.5 was -0.10%. The annual net drifts of exposure to household and ambient (PM) 2.5 were -4.54% and 3.44%, respectively. The IHD death rate attributed to ambient and household (PM) 2.5 exposure in the same birth cohort enhanced with age. With time, the rate ration (RR) of period effects of IHD mortality attributed to ambient (PM) 2.5 exposure for both male and female showed an upward trend. The RR of period effects of IHD death rate attributed to household (PM) 2.5 exposure suggested a downtrend. In the consecutive birth cohorts, the population in China with a later birth cohort presented a higher risk of IHD death attributed to exposure to ambient (PM) 2.5 and a lower risk of IHD death attributed to household (PM) 2.5 exposure. CONCLUSIONS: In China for the burden of IHD attributed to exposure to (PM) 2.5, the primary environmental risk was ambient (PM) 2.5 exposure compared to exposure to household PM2.5. IHD exposure to environmental air pollution posed a greater risk to young people.

Constitutive photomorphogenic protein 1 ubiquitinates interleukin-1 receptor accessory protein in human liver cancer.

BACKGROUND: Constitutive photomorphogenic protein 1 (COP1) plays a pivotal role in the development and progression of several human cancers and is reported to be upregulated in liver cancer. However, the role of COP1 in human liver cancer is unclear. METHODS: We analyzed the COP1 expression in normal liver and liver cancer tissue samples using western blot and immunohistochemical analysis. We overexpressed and silenced COP1 in HepG2 and Huh7 cells and analyzed the effect on liver cancer cell proliferation. Additionally, COP1 was used as a bait to screen COP1-interacting proteins in a human cDNA library in a yeast two-hybrid screen and the results were confirmed with co-immunoprecipitation (co-IP) assays. Moreover, immunofluorescence staining was performed to assess co-localization. The protein levels of COP1 and mIL1RAcP were determined in clinical samples. RESULTS: COP1 was upregulated in liver cancer samples compared to that in normal tissue samples. COP1 overexpression promoted proliferation of liver cancer cells, while COP1 knockdown exerted the opposite effect. Yeast two-hybrid screen identified interleukin-1 receptor accessory protein (IL1RAP) as a potential COP1-interacting protein. Co-IP assays further confirmed that COP1 interacts with both preIL1RAP and membrane-bound form of IL1RAP (mIL1RAP). Furthermore, COP1 upregulated mIL1RAP protein levels and promoted nuclear translocation and activation of the nuclear factor kappa B (NF-κB) (p50/p65) dimer. Additionally, we demonstrated that COP1 regulated mIL1RAP expression through K63-linked polyubiquitination, suggesting that COP1 plays a role in stabilizing mIL1RAP. Finally, the protein levels of COP1 and mIL1RAcP were found to be positively correlated in clinical samples. CONCLUSION: COP1 regulates IL1RAP, which in turn results in activation of the NF-κB signaling. Our findings suggest that the COP1/IL1RAP/NF-κB axis promotes proliferation of liver cancer cells and is a potential target for the treatment of liver cancer.

The predictive value of advanced lung cancer inflammation index for short-term outcomes and prognosis of colorectal cancer patients who underwent radical surgery.

PURPOSE: The purpose of this study was to investigate the predictive value of advanced lung cancer inflammation index (ALI) for short-term outcomes and prognosis of colorectal cancer (CRC) patients who underwent radical surgery. METHODS: CRC patients who underwent radical resection were included from Jan 2011 to Jan 2020 in our single clinical centre. Short-term outcomes, overall survival (OS), and disease-free survival (DFS) were compared in different groups. Cox analysis was conducted to identify independent risk factors for OS and DFS. RESULTS: A total of 4010 patients who underwent radical CRC surgery were enrolled in the current study. As a result, the low ALI group had longer operation time (p = 0.02), more intra-operative blood loss (p < 0.01), longer postoperative hospital stay (p < 0.01), and more overall complications (p < 0.01). Moreover, ALI (p < 0.01, OR = 0.679, 95% CI = 0.578-0.798) was an independent risk factor for overall complications. As for survival, the low ALI group had worse OS in all TNM stages (p < 0.01), stage II (p < 0.01) and stage III (p < 0.01). Similarly, the low ALI group had worse DFS in all TNM stages (p < 0.01), stage II (p < 0.01), and stage III (p < 0.01). In Cox analysis, ALI was an independent risk factors for OS (p < 0.01, HR = 0.707, 95% CI = 0.589-0.849) and DFS (p < 0.01, HR = 0.732, 95% CI = 0.622-0.861). CONCLUSION: Lower ALI was associated with more postoperative complications, worse OS, and DFS for CRC patients who underwent radical surgery. Furthermore, ALI was an independent risk factor for overall complications, OS, and DFS. Surgeons should pay close attention to patients with low ALI before surgery and make clinical strategies cautiously.

Physical Resilience as a Predictor of Lifespan and Late-Life Health in Genetically Heterogeneous Mice.

Dynamic measures of resilience-the ability to resist and recover from a challenge-may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed between young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females that had more weight loss between days 15-20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.

Starch-entrapped microspheres enhance gut microbiome-mediated anti-obesity effects of resistant starch in high-fat diet induced obese C57BL/6J mice.

The prevalence of obesity is growing worldwide and has been extensively linked to gut microbiota dysbiosis. In addition to exercise and physical activity, fiber-rich foods may be a first-line prophylactic to manage obesity. This study investigated in vivo dietary intervention with high-amylose maize starch (HAMS) and starch-entrapped microspheres (MS) to treat high-fat diet induced metabolic disorder and gut microbiome dysbiosis in mice. MS more efficiently controlled body weight as well as adipose tissue mass compared to HAMS. Furthermore, MS significantly reduced blood glucose, insulin, lipid and pro-inflammatory cytokine levels compared to the high-fat diet, while the effects of HAMS were less pronounced. The MS-altered gut microbiota composition favoring Streptococcaceae, Bacilli, Firmicutes and unclassified Clostridiales was predicted to promote fatty acid, pantothenate and Coenzyme A biosynthesis. In line with this, elevated fecal short chain fatty acid (SCFA), in particular, propionate concentration was observed in MS-fed mice. Our study provides novel insights into the mechanistic action of MS on intestinal homeostasis, providing a basis for future dietary therapeutic applications.

Safety profile evaluation of different herbicides used on peach rootstock seedlings.

To screen out suitable herbicides for peach nurseries, we treated the potted seedlings of the peach rootstock 'Nemaguard' with eleven herbicides under recommended doses to investigate the changes of physiological indices and comprehensively evaluate the safety of different herbicides using principal component analysis (PCA). The results showed that soil application of quizalofop-p exhibited no detectable phytotoxicity on rootstock seedlings, while the remaining herbicides generated multiple symptoms, including green loss, wilting, spot, and withering. Starane caused rapid wilting and death, with a 100.0% phytotoxicity index (PI). Soil application of n-(phosphonomethyl)glycine, glufosinate-ammonium, acetochlor, and MCPA-Na showed a PI＞65.0%. As compared with the control, all herbicides inhibited leaf area growth to varying degrees, with a 10.0%-56.2% and 5.8%-44.4% reduction in young leaf area and mature leaf area, respectively. All herbicides, except quizalofop-p, increased the electrolyte permeability of leaf and root tip cells by 21.2%-145.0% and 36.9%-291.4%, respectively, and significantly inhibited root growth. The total root length, root surface area, root volume, and the number of root tips significantly decreased by 37.3%-75.3%, 35.7%-83.0%, 44.3%-89.9%, and 42.6%-73.7%, respectively. Although net photosynthetic rate (Pn) and transpiration rate (Tr) of leaves were not significantly affected by quizalofop-p, mesotrione-atrazine, MCPA-Na·bentazone, bensulfuron-methyl·quinclorac, and bensulfuron-methyl·acetochlor, there was significant reduction of 29.6%, 28.9%, 28.4% and 27.9% in Pn and 21.9%, 29.2%, 26.4%, and 19.7% in Tr post soil application of n-(phosphonomethyl)glycine, glufosinate-ammonium, acetochlor, and MCPA-Na. The overall safety ranking of the 11 examined herbicides is as follows: quizalofop-p>bensulfuron-methyl·acetochlor>bensulfuron-methyl·quinclorac>esotrione·atrazine> auizalofop-p·fluoroglycofen>acetochlor>MCPA-Na·bentazone>MCPA-Na>n-(phosphonomethyl)glycine>glufosinate-ammonium>sterane.

Preliminary study of noninvasive prenatal screening for 22q11.2 deletion/duplication syndrome using multiplex dPCR assay.

OBJECTIVE: This study aimed to establish a cell-free fetal DNA (cffDNA) assay using multiplex digital PCR (dPCR) for identifying fetuses at increased risk of 22q11.2 deletion/duplication syndrome. METHODS: Six detection sites and their corresponding probes were designed for the 22q11.2 recurrent region. A dPCR assay for the noninvasive screening of 22q11.2 deletion/duplication syndrome was established. A total of 130 plasma samples from pregnant women (including 15 samples with fetal 22q11.2 deletion/duplication syndrome) were blindly tested for evaluating the sensitivity and specificity of the established assay. RESULTS: DNA with different sizes of 22q11.2 deletion/duplication was detected via dPCR, indicating that the designed probes and detection sites were reasonable and effective. In the retrospective clinical samples, 11 out of 15 samples of pregnant women with 22q11.2 deletion/duplication were detected during the cffDNA assay, and accurate regional localization was achieved. Among the 115 normal samples, 111 were confirmed to be normal. Receiver operating characteristic curves were used for assessing the cut-off values and AUC for these samples. The sensitivity, specificity, and positive as well as negative predictive values were 73.3%, 96.5%, 73.3%, and 96.5%, respectively. CONCLUSION: The cffDNA assay based on dPCR technology for the noninvasive detection of 22q11.2 recurrent copy number variants in fetuses detected most affected cases, including smaller but relatively common nested deletions, with a low false-positive rate. It is a potential, efficient and simple method for the noninvasive screening of 22q11.2 deletion/duplication syndrome.

The Expression of P35 Plays a Key Role in the Difference in Apoptosis Induced by AcMNPV Infection in Different Spodoptera exigua Cell Lines.

Baculovirus infection induces apoptosis in host cells, and apoptosis significantly affects virus production. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) can regulate apoptosis, but the regulatory mechanism is unclear. Here, we found that AcMNPV infection induced different apoptosis responses in different Spodoptera exigua cell lines. In the early stages of viral infection (1-6 h), Se-1 cells underwent severe apoptosis, while Se-3 cells underwent very slight apoptosis. In the late stages of viral infection (12-72 h), Se-1 cells continued to undergo apoptosis and formed a large number of apoptotic bodies, while the apoptosis of Se-3 cells was inhibited and no apoptotic bodies were formed. To determine the reasons for the apoptosis differences in the two cell lines, we measured the expression of the six S. exigua cysteine-dependent aspartate specific protease genes (SeCaspase-1 to -6) and the three AcMNPV antiapoptotic protein genes (iap1, iap2 and p35) during viral infection. We found that SeCaspase-1 to -6 were all activated in Se-1 cells and inhibited in Se-3 cells, whereas iap1, iap2 and p35 were all inhibited in Se-1 cells and normally expressed in Se-3 cells. And p35 was expressed earlier than iap1 and iap2 in Se-3 cells. Otherwise, Se-1 and Se-3 cells would all be apoptotic when infected with the recombinant p35 knockout AcMNPV, whereas only Se-1 cells were apoptotic, but Se-3 cells were not apoptotic when infected with the recombinant p35 repair AcMNPV. Combined with the fact that the expression of P35 protein is inhibited in Se-1 cells but normally expressed in Se-3 cells during the infection of recombinant p35 repair AcMNPV, we proposed that the different expression of P35 is an important reason for the apoptosis differences between the two cell lines. We also found that some genes associated with apoptosis can probably regulate the expression of P35. However, the major upstream regulators of P35 and their mechanisms are still unclear and will be studied in the future.

Fabrication of AIE Polymer-Functionalized Reduced Graphene Oxide for Information Storage.

Reduced graphene oxide (RGO) has been extensively studied and applied in optoelectronic systems, but its unstable dispersion in organic solvents has limited its application. To overcome this problem, the newly designed and developed aggregation-induced emission (AIE) material poly[(9,9-bis(6-azidohexyl)-9H-fluorene)-alt-(9-(4-(1,2,2-triphenylvinyl)phenyl)-9H-carbazole)] (PAFTC) was covalently grafted onto RGO to produce (PFTC-g-RGO). The solubility of two-dimensional graphene was improved by incorporating it into the backbone of PAFTC to form new functional materials. In resistive random access memory (RRAM) devices, PFTC-g-RGO was used as the active layer material after it was characterized. The fabricated Al/PFTC-g-RGO/ITO device exhibited nonvolatile bistable resistive switching performances with a long retention time of over 104 s, excellent endurance of over 200 switching cycles, and an impressively low turn-ON voltage. This study provides important insights into the future development of AIE polymer-functionalized nanomaterials for information storage.

Identification of Copper Metabolism Related Biomarkers, Polygenic Prediction Model, and Potential Therapeutic Agents in Alzheimer's Disease.

BACKGROUND: The underlying pathogenic genes and effective therapeutic agents of Alzheimer's disease (AD) are still elusive. Meanwhile, abnormal copper metabolism is observed in AD brains of both human and mouse models. OBJECTIVE: To investigate copper metabolism-related gene biomarkers for AD diagnosis and therapy. METHODS: The AD datasets and copper metabolism-related genes (CMGs) were downloaded from GEO and GeneCards database, respectively. Differentially expressed CMGs (DE-CMGs) performed through Limma, functional enrichment analysis and the protein-protein interaction were used to identify candidate key genes by using CytoHubba. And these candidate key genes were utilized to construct a prediction model by logistic regression analysis for AD early diagnosis. Furthermore, ROC analysis was conducted to identify a single gene with AUC values greater than 0.7 by GSE5281. Finally, the single gene biomarker was validated by quantitative real-time polymerase chain reaction (qRT-PCR) in AD clinical samples. Additionally, immune cell infiltration in AD samples and potential therapeutic drugs targeting the identified biomarkers were further explored. RESULTS: A polygenic prediction model for AD based on copper metabolism was established by the top 10 genes, which demonstrated good diagnostic performance (AUC values). COX11, LDHA, ATOX1, SCO1, and SOD1 were identified as blood biomarkers for AD early diagnosis. 20 agents targeting biomarkers were retrieved from DrugBank database, some of which have been proven effective for the treatment of AD. CONCLUSIONS: The five blood biomarkers and copper metabolism-associated model can differentiate AD patients from non-demented individuals and aid in the development of new therapeutic strategies.

Development and validation of a score predicting mortality for older patients with mitral regurgitation.

OBJECTIVE: To develop and validate a user-friendly risk score for older mitral regurgitation (MR) patients, referred to as the Elder-MR score. METHODS: The China Senile Valvular Heart Disease (China-DVD) Cohort Study functioned as the development cohort, while the China Valvular Heart Disease (China-VHD) Study was employed for external validation. We included patients aged 60 years and above receiving medical treatment for moderate or severe MR (2274 patients in the development cohort and 1929 patients in the validation cohort). Candidate predictors were chosen using Cox's proportional hazards model and stepwise selection with Akaike's information criterion. RESULTS: Eight predictors were identified: age ≥ 75 years, body mass index < 20 kg/m2, NYHA class III/IV, secondary MR, anemia, estimated glomerular filtration rate < 60 mL/min per 1.73 m2, albumin < 35 g/L, and left ventricular ejection fraction < 60%. The model displayed satisfactory performance in predicting one-year mortality in both the development cohort (C-statistic = 0.73, 95% CI: 0.69-0.77, Brier score = 0.06) and the validation cohort (C-statistic = 0.73, 95% CI: 0.68-0.78, Brier score = 0.06). The Elder-MR score ranges from 0 to 15 points. At a one-year follow-up, each point increase in the Elder-MR score represents a 1.27-fold risk of death (HR = 1.27, 95% CI: 1.21-1.34, P < 0.001) in the development cohort and a 1.24-fold risk of death (HR = 1.24, 95% CI: 1.17-1.30, P < 0.001) in the validation cohort. Compared to EuroSCORE II, the Elder-MR score demonstrated superior predictive accuracy for one-year mortality in the validation cohort (C-statistic = 0.71 vs. 0.70, net reclassification improvement = 0.320, P < 0.01; integrated discrimination improvement = 0.029, P < 0.01). CONCLUSIONS: The Elder-MR score may serve as an effective risk stratification tool to assist clinical decision-making in older MR patients.

Chemokine receptor 5 signaling in PFC mediates stress susceptibility in female mice.

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

Dynamic simulation of carbon emission under different policy scenarios in Pearl River Delta urban agglomeration, China.

Global climate continues to warm; by reducing carbon emission (CE) to cope with climate warming has become a global consensus. The influencing factors of CE exhibit diversification and spatial characteristics, and the complexity of the CE system poses challenges to green and low-carbon development and the realization of China's dual-carbon goals. Taking the Pearl River Delta urban agglomeration as an example, this study explored the influencing factors of CE and designed emission reduction schemes with the help of multi-scale geographically weighted regression (MGWR). Based on this, the system dynamics model was used to construct a CE system framework considering multi-dimensional driving factors, so as to combine the complex CE system with the emission reduction countermeasures considering spatial heterogeneity, and realize the dynamic simulation of CE reduction policies. The results showed that the urban agglomeration as a whole will reach carbon peak by 2025. Shenzhen, Zhuhai, and Dongguan have achieved carbon peak before 2020, while other cities will reach carbon peak by 2025-2030. The government policy constraints can effectively curb CE, but if government constraints were relaxed, CE will rise and individual cities will not reach carbon peak. Comprehensive CE reduction policies are better than a single CE reduction policy. The study found that this model framework provides a systematic analysis of carbon reduction strategies for urban agglomerations, offering decision-makers various combinations of economic development and green low-carbon objectives. This will further contribute to a multi-faceted mitigation of high emission in urban agglomeration and promote regional sustainable development.

Whole-tumor histogram analysis of multi-parametric MRI for differentiating brain metastases histological subtypes in lung cancers: relationship with the Ki-67 proliferation index.

This study aims to investigate the predictive value of preoperative whole-tumor histogram analysis of multi-parametric MRI for histological subtypes in patients with lung cancer brain metastases (BMs) and explore the correlation between histogram parameters and Ki-67 proliferation index. The preoperative MRI data of 95 lung cancer BM lesions obtained from 73 patients (42 men and 31 women) were retrospectively analyzed. Multi-parametric MRI histogram was used to distinguish small-cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC), and adenocarcinoma (AC) from squamous cell carcinoma (SCC), respectively. The T1-weighted contrast-enhanced (T1C) and apparent diffusion coefficient (ADC) histogram parameters of the volumes of interest (VOIs) in all BMs lesions were extracted using FireVoxel software. The following histogram parameters were obtained: maximum, minimum, mean, standard deviation (SD), variance, coefficient of variation (CV), skewness, kurtosis, entropy, and 1st-99th percentiles. Then investigated their relationship with the Ki-67 proliferation index. The skewness-T1C, kurtosis-T1C, minimum-ADC, mean-ADC, CV-ADC and 1st - 90th ADC percentiles were significantly different between the SCLC and NSCLC groups (all p < 0.05). When the 10th-ADC percentile was 668, the sensitivity, specificity, and accuracy (90.80%, 76.70% and 86.32%, respectively) for distinguishing SCLC from NSCLC reached their maximum values, with an AUC of 0.895 (0.824 - 0.966). Mean-T1C, CV-T1C, skewness-T1C, 1st - 50th T1C percentiles, maximum-ADC, SD-ADC, variance-ADC and 75th - 99th ADC percentiles were significantly different between the AC and SCC groups (all p < 0.05). When the CV-T1C percentiles was 3.13, the sensitivity, specificity and accuracy (75.00%, 75.60% and 75.38%, respectively) for distinguishing AC and SCC reached their maximum values, with an AUC of 0.829 (0.728-0.929). The 5th-ADC and 10th-ADC percentiles were strongly correlated with the Ki-67 proliferation index in BMs. Multi-parametric MRI histogram parameters can be used to identify the histological subtypes of lung cancer BMs and predict the Ki-67 proliferation index.

Identification and experimental validation of key extracellular proteins as potential targets in intervertebral disc degeneration.

Aims: This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD). Methods: The gene expression profile of GSE23130 was downloaded from the Gene Expression Omnibus (GEO) database. Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases, and we used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze the functions and pathways of EP-DEGs. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and identify hub EP-DEGs. NetworkAnalyst was used to analyze transcription factors (TFs) and microRNAs (miRNAs) that regulate hub EP-DEGs. A search of the Drug Signatures Database (DSigDB) for hub EP-DEGs revealed multiple drug molecules and drug-target interactions. Results: A total of 56 EP-DEGs were identified in the differential expression analysis. EP-DEGs were enriched in the extracellular structure organization, ageing, collagen-activated signalling pathway, PI3K-Akt signalling pathway, and AGE-RAGE signalling pathway. PPI network analysis showed that the top ten hub EP-DEGs are closely related to IDD. Correlation analysis also demonstrated a significant correlation between the ten hub EP-DEGs (p＜0.05), which were selected to construct TF-gene interaction and TF-miRNA coregulatory networks. In addition, ten candidate drugs were screened for the treatment of IDD. Conclusion: The findings clarify the roles of extracellular proteins in IDD and highlight their potential as promising novel therapeutic targets.

Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.

Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. Methods: AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis. Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß 1-40 and Aß 1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation and microgliosis, which are increased in 5xFAD mice, were significantly reduced by dHc DUSP6 overexpression in both males and females. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulated expression of genes involved in inflammatory and extracellular signal-regulated kinase (ERK) pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. A limited number of differentially expressed genes (DEGs) (FDR<0.05) were identified in male mice; gene ontology analysis of DEGs (p<0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Notably, the msh homeobox 3 gene, Msx3 , previously shown to regulate microglial M1/M2 polarization and reduce neuroinflammation, was one of the most robustly upregulated genes in female and male wild type and 5xFAD mice overexpressing DUSP6. Conclusions: In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.

Interactive effects between the invasive weed Stellera chamaejasme and grass: can arbuscular mycorrhizal fungi and fungal pathogens coregulate interspecific relationships?

The interaction between poisonous weeds and neighboring plants is complex. Poisonous weeds frequently have a competitive advantage in the interaction between poisonous weeds and neighboring plants. Arbuscular mycorrhizal fungi (AMF) and plant pathogenic fungi (PPF) are closely related to the interspecific relationships of plants. However, the role of AMF and PPF between poisonous weeds and neighboring grasses remains unclear. Here, we designed a pot experiment to determine the interspecific relationship between Leymus chinensis and Stellera chamaejasme and the regulation of AMF and PPF. The results showed that interactive effects between L. chinensis and S. chamaejasme significantly inhibited the aboveground growth of both but promoted the underground growth of L. chinensis. As the proportions of S. chamaejasme increased, the total nitrogen content and pH in the rhizosphere soil of L. chinensis were reduced, the soil pH of S. chamaejasme was reduced, and the relative abundance of AMF in the rhizosphere soil of L. chinensis significantly increased and that of S. chamaejasme decreased considerably. The relative abundances of PPF in the rhizosphere soil of both in the mono-cultures were significantly higher than those in the mixed cultures. Structural equation modeling indicated that soil abiotic (pH and N availability) and biotic (AMF and PPF) factors are major drivers explaining the interactive effects between L. chinensis and S. chamaejasme. We provided new evidence for the interspecific interactions between poisonous weeds and neighboring grasses and revealed the regulatory role of AMF and PPF in the interactive effects of both plants. This study will provide a scientific basis for the prevention and control of poisonous weeds and the vegetation restoration of degraded grasslands in the future.