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177Lu- prostate specific membrane antigen (PSMA) radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China. Based on domestic clinical practice and experimental data and referred to international experience and viewpoints, the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Objective: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with an unclear pathogenetic mechanism in the labial gland. This study aims to investigate the cellular and molecular mechanisms contributing to the development of this disease. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on 32,337 cells of labial glands from three pSS patients and three healthy individuals. We analyzed all cell subsets implicated in pSS pathogenesis. Results: Our research revealed diminished differentiation among epithelial cells, concomitant with an enhancement of interferons (IFNs)-mediated signaling pathways. This indicates a cellular functional shift in reaction to inflammatory triggers. Moreover, we observed an augmentation in the population of myofibroblasts and endothelial cells, likely due to the intensified IFNs signaling, suggesting a possible reconfiguration of tissue structure and vascular networks in the impacted regions. Within the immune landscape, there was an apparent increase in immunosuppressive macrophages and dendritic cells (DCs), pointing to an adaptive immune mechanism aimed at modulating inflammation and averting excessive tissue harm. Elevated activation levels of CD4+T cells, along with a rise in regulatory T (Treg) cells, were noted, indicating a nuanced immune interplay designed to manage the inflammatory response. In the CD8+T cell subsests, we detected a notable increase in cells expressing granzyme K (GZMK), signaling an intensified cytotoxic activity. Additionally, the escalated presence of T cells with high levels of heat shock proteins (HSPs) suggests a cellular stress condition, possibly associated with persistent low-grade inflammation, mirroring the chronic aspect of the condition. Conclusions: Our research identified distinct stromal and immune cell populations linked to pSS, revealing new potential targets for its management. The activation of myeloid, B, and T cells could contribute to pSS pathogenesis, providing important guidance for therapeutic approaches.

Air pollution significantly impacts lung cancer progression, but there is a lack of a comprehensive molecular characterization of clinical samples associated with air pollution. Here, we performed a proteogenomic analysis of lung adenocarcinoma (LUAD) in 169 female never-smokers from the Xuanwei area (XWLC cohort), where coal smoke is the primary contributor to the high lung cancer incidence. Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors. Mutational signature analysis suggested that Benzo[a]pyrene (BaP) is the major risk factor in XWLC. The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common EGFR mutations. Multi-omics clustering of XWLC identified four clinically relevant subtypes. These subgroups exhibited distinct features in biological processes, genetic alterations, metabolism demands, immune landscape, and radiomic features. Finally, MAD1 and TPRN were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.

Abstract Background Despite the existence of numerous studies investigating the diagnostic potential of blood microRNAs for colorectal cancer, the microRNAs under consideration vary widely, and comparative analysis of their diagnostic value is lacking. Consequently, this systematic review aims to identify the most effective microRNA blood tumor markers to enhance clinical decision-making in colorectal cancer screening. Method A comprehensive search of databases, including PubMed, Embase, Web of Science, Scopus, and Cochrane, was conducted to identify case‒control or cohort studies that examined the diagnostic value of peripheral blood microRNAs in colorectal cancer. Studies were included if they provided sensitivity and specificity data, were published in English and were available between January 1, 2000, and February 10, 2023. The Critical Appraisal Skills Programme (CASP) checklist was employed for quality assessment. A Bayesian network meta-analysis was performed to estimate combined risk ratios (RRs) and 95% confidence intervals (CIs), with results presented via rankograms. This study is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), 202,380,092. Results From an initial pool of 2254 records, 79 met the inclusion criteria, encompassing a total of 90 microRNAs. The seven most frequently studied microRNAs (43 records) were selected for inclusion, all of which demonstrated moderate to high quality. miR-23, miR-92, and miR-21 exhibited the highest sensitivity and accuracy, outperforming traditional tumor markers CA19-9 and CEA in terms of RR values and 95% CI for both sensitivity and accuracy. With the exception of miR-17, no significant difference was observed between each microRNA and CA19-9 and CEA in terms of specificity. Conclusions Among the most extensively researched blood microRNAs, miR-23, miR-92, and miR-21 demonstrated superior diagnostic value for colorectal cancer due to their exceptional sensitivity and accuracy. This systematic review and network meta-analysis may serve as a valuable reference for the clinical selection of microRNAs as tumor biomarkers.

Abstract Purpose Chordoma is a rare and aggressive bone cancer driven by the developmental transcription factor brachyury. Efforts to target brachyury are hampered by the absence of ligand-accessible small-molecule binding pockets. Genome editing with CRISPR systems provides an unprecedented opportunity to modulate undruggable transcription factor targets. However, delivery of CRISPR remains a bottleneck for in vivo therapy development. The aim was to investigate the in vivo therapeutic efficiency of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) delivery through a novel virus-like particle (VLP) by fusing an aptamer-binding protein to the lentiviral nucleocapsid protein. Methods The p24 based ELISA and transmission electron microscopy were used to determine the characterization of engineered VLP-packaged Cas9/gRNA RNP. The deletion efficiency of brachyury gene in chordoma cells and tissues was measured by genome cleavage detection assay. RT-PCR, Western blot, immunofluorescence staining, and IHC were employed to test the function of brachyury deletion. Cell growth and tumor volume were measured to evaluate the therapeutic efficiency of brachyury deletion by VLP-packaged Cas9/gRNA RNP. Results Our “all-in-one” VLP-based Cas9/gRNA RNP system allows for transient expression of Cas9 in chordoma cells, but maintains efficient editing capacity leading to approximately 85% knockdown of brachyury with subsequent inhibition of chordoma cell proliferation and tumor progression. In addition, this VLP-packaged brachyury-targeting Cas9 RNP avoids systemic toxicities in vivo. Conclusion Our preclinical studies demonstrate the potential of VLP-based Cas9/gRNA RNP gene therapy for the treatment of brachyury-dependent chordoma.

Interleukin-18 (IL18) has a pivotal role in interferon signalling and T cell development, but increasingly recognized as an adipokine that regulates energy metabolism in fat tissue. Authors here dissect the function of IL18 signalling in the adipose compartment by targeted genomic deletion of its two receptors individually and in combination in brown and white adipose tissues.

Structured light illumination is widely applied for surface defect detection due to its advantages in terms of speed, precision, and non-contact capabilities. However, the high reflectivity of metal surfaces often results in the loss of point clouds, thus reducing the measurement accuracy. In this paper, we propose a novel quaternary categorization strategy to address the high-reflectivity issue. Firstly, we classify the pixels into four types according to the phase map characteristics. Secondly, we apply tailored optimization and reconstruction strategies to each type of pixel. Finally, we fuse point clouds from multi-type pixels to accomplish precise measurements of high-reflectivity surfaces. Experimental results show that our strategy effectively reduces the high-reflectivity error when measuring metal surfaces and exhibits stronger robustness against noise compared to the conventional method.

This study aims to improve the evaluation of residual oil saturation in water flooded zones based on the material balance model (MBM) with variable multiple for injected water. We investigated the change patterns of rock-electro parameters during waterflooding through the analysis of displacement tests. Our work differentiated the waterflooding into numerous displacement processes and accordingly propose an improved time-differentiated variable multiple MBM. The calculation results of the improved model are more consistent with the displacement experiment data of cores. Furthermore, the improved method was integrated into the comprehensive interpretation platform of offshore logging to analyze water flooded zones of a well in the A oilfield. As a result, the residual oil saturation calculated is in close agreement with the results of experiments on cores. Our results indicate that the time-differentiation and variable multiplier for injected water can effectively enhance the assessment accuracy of the residual oil saturation of water-flooded zones.

Abstract Development of abdominal aortic aneurysms (AAA) enhances lesion group‐2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/flIl7rCre/+ mice or induced ILC2 depletion in Icosfl‐DTR‐fl/+Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild‐type (WT) mice, but not ILC2 from Il5−/− mice induces EOS differentiation in bone‐marrow cells from Rorafl/flIl7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5−/− and Il13−/− mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5−/− mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5−/− ILC2 slows AAA growth in Rorafl/flIl7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

Abstract Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.

Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.

Zirconium sheet has been widely used in various fields, e.g., chemistry and aerospace. The surface scratches on the zirconium sheets caused by complex processing environment have a negative impact on the performance, e.g., working life and fatigue fracture resistance. Therefore, it is necessary to detect the defect of zirconium sheets. However, it is difficult to detect such scratch images due to lots of scattered additive noise and complex interlaced structural texture. Hence, we propose a framework for adaptively detecting scratches on the surface images of zirconium sheets, including noise removing and texture suppressing. First, the noise removal algorithm, i.e., an optimized threshold function based on dual-tree complex wavelet transform, uses selected parameters to remove scattered and numerous noise. Second, the texture suppression algorithm, i.e., an optimized relative total variation enhancement model, employs selected parameters to suppress interlaced texture. Finally, by connecting disconnection based on two types of connection algorithms and replacing the Gaussian filter in the standard Canny edge detection algorithm with our proposed framework, we can more robustly detect the scratches. The experimental results show that the proposed framework is of higher accuracy.

Immunotherapy has demonstrated great clinical success in the field of oncology in comparison with conventional cancer therapy. However, cancer immunotherapy still encounters major challenges that limit its efficacy against different types of cancers and the patients show minimal immune response to the immunotherapy. To overcome these limitations, combinatorial approaches with other therapeutics have been applied in the clinic. Simultaneously, nano-drug delivery system has played an important role in increasing the antitumor efficacy of various treatments and has been increasingly utilized for synergistic immunotherapy to further enhance the immunogenicity of the tumors. Specifically, they can promote the infiltration of immune cells within the tumors and create an environment that is more sensitive to immunotherapy, particularly in solid tumors, by accelerating tumor accumulation and permeability. Herein, this progress report provides a brief overview of the development of nano-drug delivery systems, classification of combinatory cancer immunotherapy and recent progress in tumor immune synergistic therapy in the application of nano-drug delivery systems.

Abstract Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

A soundscape is a sound environment of the awareness of auditory perception and social or cultural understandings. Based on a soundscape investigation in 2019 in the historical and ethnic village of Dong Nationality in Zhaoxing County, Guizhou Province of China, a case study on the soundscape analysis with the acoustical sound pressure level and an impressive sound event or soundmark is introduced in this paper. Furthermore, in order to determine the subjective soundscape experience and its influence by the length of background music listening, the independent variable “Length of Listening” and six adjective pairs, such as “Monotonous” to “Rich”, “Clamorous” to “Quiet”, “Stressing” to “Relaxing”, “Boring” to “Vivid”, “Noisy” to “Musical” and “Disliked” to “Preferable” are chosen to obtain a curve-fit, which shows that the length of the music listening background has a higher correlation to the subjective experience, and no sufficient attention has been paid to the context of the traditional soundscape preservation, ethnic music and quiet and soft ambient sounds.

Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.

Background. Accumulating evidence has demonstrated the role of differentially expressed miRNAs in glioma progression. Our previous bioinformatics analyses revealed a role of miR-138-5p in glioma. miR-138-5p was decreased in various tumors, and He et al. found that miR-138-5p had an inhibitory effect on glioma cells in 2021. However, the role of miR-138-5p in the development of glioma and the underlying mechanism is unknown. In this study, we explored whether miR-138-5p affects the biology of glioma by regulating WEE1 expression. Methods. miR-138-5p and WEE1 G2 checkpoint kinase (WEE1) RNA and protein expression levels in glioma tissues were detected with qRT-PCR and western blotting, respectively. The effects of miR-138-5p and WEE1 on glioma cell migration and invasion were investigated using Transwell assays. CCK-8 assay was used to measure the effects of miR-138-5p and WEE1 on glioma cell proliferation. The mortality of glioma cells transfected with miR-138-5p and WEE1 was measured with flow cytometry. The relationship between miR-138-5p and WEE1 was explored using a luciferase reporter analysis. Results. Functional studies indicated that overexpression of miR-138-5p suppressed cell proliferation, migration, and invasion and promoted death in glioma cell lines. WEE1 was identified as a target of miR-138-5p, and overexpression of miR-138-5p significantly suppressed the levels of WEE1. Moreover, reintroduction of WEE1 partially abrogated miR-138-5p-induced suppression of motility and invasion in glioma cells. Conclusion. The low expression of miR-138-5p in glioma suggests a tumor suppressor role for this miRNA. miR-138-5p suppresses glioma progression by regulating WEE1. These data provide new insights into the molecular mechanism of glioma.

Smart wearable systems for health monitoring are highly desired in personal wisdom medicine and telemedicine. These systems make the detecting, monitoring, and recording of biosignals portable, long-term, and comfortable. The development and optimization of wearable health-monitoring systems have focused on advanced materials and system integration, and the number of high-performance wearable systems has been gradually increasing in recent years. However, there are still many challenges in these fields, such as balancing the trade-off between flexibility/stretchability, sensing performance, and the robustness of systems. For this reason, more evolution is required to promote the development of wearable health-monitoring systems. In this regard, this review summarizes some representative achievements and recent progress of wearable systems for health monitoring. Meanwhile, a strategy overview is presented about selecting materials, integrating systems, and monitoring biosignals. The next generation of wearable systems for accurate, portable, continuous, and long-term health monitoring will offer more opportunities for disease diagnosis and treatment.

Background: The novel coronavirus-2019 (COVID-19) disease has spread quickly throughout China and around the world, endangering human health and life. Individuals' perceptions and attitudes as well as related health education measures may affect disease progression and prognosis during the COVID-19 outbreak. To promote and implement health education, research must focus on the perceptions and attitudes towards COVID-19 among Chinese people. The present study aimed to examine the profiles and predictive factors of the perceptions and attitudes towards COVID-19 in a sample of Chinese people.Methods: A sample of 2,663 Chinese people comprising medical staff and members of the general public completed an online survey on Wenjuanxing. The survey measured demographic variables (e.g., gender, age, education level, and place of residence) and perceptions and attitudes towards COVID-19.Results: Two profiles of perceptions and attitudes towards COVID-19 (positive and negative perceptions and attitudes) were identified in the sample. Place of residence during the COVID-19 pandemic and first response to COVID-19 were found to be independent predictive factors for COVID-19 related perceptions and attitudes.Conclusion: In addition to drug therapy and mental health services, the perceptions and attitudes of Chinese people towards COVID-19 should be considered when promoting health education during the COVID-19 pandemic.

This study aimed to explore the relationship between plasma interleukin 6 (IL-6) levels, adverse cardiovascular events, and the severity of acute coronary syndrome (ACS). A literature review was performed of studies regarding IL-6 and ACS extracted from databases including EMBASE, Cqvip, MEDLINE, Web of Knowledge, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang data. The Newcastle-Ottawa scale (NOS) was used to evaluate the quality of the literature. The literature was screened, its quality was evaluated, and relevant data were extracted for performing meta-analysis using RevMan software (version 5.3). A total of 524 studies were included in the initial survey. After several rounds of screening and analysis, six studies met the inclusion criteria and underwent meta-analysis using a fixed-effect model. Patients were divided into non-severe and severe groups based on the concentration of high-sensitivity C-reactive protein. Meta-analysis of the relationship between IL-6 and the severity of ACS showed that the plasma IL-6 level of patients in the severe group was significantly higher than that of patients in the non-severe group (p

Radioresistance is a crucial factor for the failure of iodine 131 ( 131 I)-based radiotherapy for differentiated thyroid carcinoma (DTC). This study aimed to explore the effect of circ_NEK6 on the development of 131 I resistance in DTC and its potential mechanism. In this study, we demonstrated that circ_NEK6 expression was significantly elevated in 131 I-resistant DTC tissues and cell lines. Knockdown of circ_NEK6 significantly repressed 131 I resistance via inhibiting cell proliferation, migration, invasion abilities, and inducing cell apoptosis and DNA damage in 131 I-resistant DTC cells. Mechanistically, knockdown of circ_NEK6 suppressed 131 I resistance in DTC by upregulating the inhibitory effect of miR-370-3p on the expression of myosin heavy chain 9 (MYH9). In vivo experiments showed that circ_NEK6 inhibition aggravated 131 I radiation-induced inhibition of xenograft tumor growth. Taken together, knockdown of circ_NEK6 repressed 131 I resistance in DTC cells by regulating the miR-370-3p/MYH9 axis, indicating that circ_NEK6 may act as a potential biomarker and therapeutic target for DTC patients with 131 I resistance.

Asthma is a frequently diagnosed chronic pulmonary disease that is increasing in incidence. It is characterized by airway narrowing due to an immune response to allergens, infections, or air pollutants. Several types of cells participate in the initiation and development of asthma, including bronchial epithelial cells, smooth muscle cells, and immune cells (mast cells, T and B cells, and dendritic cells). Exosomes released in the asthmatic microenvironment exert a crucial function in intercellular signaling by transporting their contents, such as RNA, DNA, proteins, and lipid mediators, to recipient cells, which play key roles in the pathogenesis of asthma. In the present review, we summarize currently available information on the function of exosomes in the asthmatic microenvironment.

Abstract Objectives The intention of our study was to investigate the relationship between miR‐144‐3p and EZH2 as well as the effects of their interaction on cell propagation and invasiveness in lung adenocarcinoma (LUAD). Methods The expression levels of miR‐144‐3p and EZH2 in LUAD tissues and normal tissues were determined by qRT‐PCR. The dual‐luciferase reporter assay was utilized to validate the targeting relationship between miR‐144‐3p and EZH2. MTT assay and colony formation assay were performed to evaluate the viability and propagation of LUAD cells, while the effects of miR‐144‐3p and EZH2 on LUAD cell invasiveness were confirmed by transwell assay. Protein expression levels of VEGFA, MMP2, and MMP9 were measured by Western blot. Furthermore, xenograft tumor models were established to verify the effects of miR‐144‐3p on tumor formation and EZH2, VEGFA, MMP2 and MMP9 expressions in vivo. Results miR‐144‐3P was downregulated in LUAD tissues, and overexpression of miR‐144‐3p inhibited propagation and invasiveness of LUAD cells. EZH2 was a target of miR‐144‐3p and was highly expressed in LUAD cells. Knockdown of EZH2 could suppress the propagation and invasion of LUAD cells. Increased miR‐144‐3p expression exerted an inhibitory effect on LUAD tumor formation in vivo. Conclusion Overexpression of miR‐144‐3p impeded the propagation and invasiveness of LUAD cells by targeting EZH2.

Abstract Background SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Methods Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. Results SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. Conclusion SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.

It is difficult to comprehensively master and precisely regulate the external factors distribution of automobile weathering in non-uniform thermal environment as well as the consequent disequilibrium weathering problem, while exploring weather-resistant materials in uniform thermal environment. Thus, a numerical calculation method for the weathering external factors is proposed, on the basis of annual experimental study on the outdoor weathering inconsistencies of auto-parts. The time–space distribution characteristics and day–night variation rules of the external factors are studied, and the disequilibrium weathering mechanism among parts is revealed from the perspective of non-uniform distribution of external factors. The laws of automotive physical parameters, orientations and locations, as well as their influences on external factors distribution are analyzed in detail, and hereby the targeted schemes to effectively reduce the local external factor intensity and the thermal gradient between parts are investigated. The method can be used to rapidly predict weathering external factors distribution of vehicle exposed to outdoor in any direction during day and night, so as to provide auto-parts with differentiated test schemes in accelerated tests and IP/DP box tests, and it also contributes to present some pertinence guidance for the accurate regulation of automobile disequilibrium weathering on regions at different levels.

Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built.

Primary Sjögren's syndrome (pSS) is a common autoimmune disease involving abnormal Th17 activation. The aim of the current study was to investigate the immunosuppression effect of Cyclosporine A (Cys A), a potent immunosuppressor on the proliferation and activation of T cells, on the activation of Th17 cells. Blood samples from both inactive and active pSS patients as well as healthy controls were collected and serum and peripheral blood mononuclear cells (PBMCs) were collected and tested for IL-17 and RORγt expression. Subsequently, PBMCs were treated in vitro with Cys A in a series of doses and incubation time and the effect of Cys A on inhibiting Th17 activation was tested by measuring IL-17 and RORγt expression. IL-17 in both serum and PBMCs as well as RORγt in PBMCs from active pSS patients were significantly elevated on both the mRNA and protein levels comparing to those from both inactive pSS patients and healthy controlCys A in the final concentration of 80ng/ml and the treatment time of 24h showed strong inhibition effect on the expression of IL-17 and RORγt in PBMCs from active pSS patients. However, Cys A in various doses and incubation times did not show much impact on inhibiting IL-17 as well as RORγt expression in PBMCs from healthy donors and inactive pSS patients. Cys A possesses the capability in immunosuppressing the activation of Th17 cells, suggesting that Cys A may be a potential treatment for pSS and maybe other autoimmune diseases.

Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation.

This study aimed to identify the primary pathogenic bacteria responsible for the mortality of the Chinese giant salamander (Andriasd davidianus). A pathogenic bacterium was isolated from a diseased Chinese giant salamander exhibiting typical symptoms under aseptic conditions and then identified by morphological examinations, biochemical analysis, and the sequence analysis of bacterial 16S rRNA. Artificial infection testing was then conducted to determine the pathogenicity of the isolated bacteria strain. Drug susceptibility tests were conducted using the agar diffusion method. The isolated pathogenic bacteria, named DN-2, was successfully identified as Acinetobacter lwoffii. The artificial infection showed that the typical symptoms of the disease could be replicated as the ones originally occurred, and this bacterium exhibited high pathogenicity to the Chinese giant salamander. In the Chinese giant salamander, the median lethal dosage (LD50) of A. lwoffii DN-2 for A. davidianus was determined to be 4.63*104 CFU/g. Drug sensitivity testing showed that these bacteria were highly sensitive to erythromycin, gentamicin, neomycin, streptomycin, midecamycin, ciprofloxacin, piperacillin, florfenicol, doxycycline, carbenicillin, and sulfanilamide. In summary, A. lwoffii was identified as the primary pathogen responsible for the demise of A. davidianus. Our study first presents how these bacteria harm Chinese giant salamanders. [ABSTRACT FROM AUTHOR]

At a particular aquaculture facility in Zhangjiajie in China, the Chinese giant salamander (Andrias davidianus) exhibited analogous clinical manifestations, culminating in sequential mortalities. This study used rigorous aseptic sampling methods to isolate bacteria from the affected liver of salamanders to determine the causative agent behind the decline in amphibians. A bacterial pathogen was isolated from diseased A. davidianus, and the strain was named DN-3. This isolate was subjected to bacterial identification, antibiotic susceptibility assays, reinfection experiments, and biochemical profiling. The isolated bacterial strain was definitively identified as Acinetobacter schindleri using 16S rRNA sequence analysis and biochemical identification. Antibiotic susceptibility testing revealed that this isolate was susceptible to neomycin, macrolides, doxycycline, piperacillin, nitrofurantoin, and carbenicillin. Subsequent reinfection assays, in which varying concentrations of the bacterial inoculum were administered to healthy salamanders, confirmed that the pathogen elicited varying degrees of morbidity or mortality within an eight-day observation period. The median lethal dose (LD50) of A. schindleri DN-3 for A. davidianus was calculated to be 6.25×104 CFU/mL. This result supports the significant pathogenicity of the strain for A. davidianus. The findings of this study provide empirical insights into the clinical management and epidemiological control of diseases affecting A. davidianus. [ABSTRACT FROM AUTHOR]

L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and a2d2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/a2d2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies. [ABSTRACT FROM AUTHOR]