Saccorhytus is an early ecdysozoan and not the earliest deuterostome.

The early history of deuterostomes, the group composed of the chordates, echinoderms and hemichordates1, is still controversial, not least because of a paucity of stem representatives of these clades2-5. The early Cambrian microscopic animal Saccorhytus coronarius was interpreted as an early deuterostome on the basis of purported pharyngeal openings, providing evidence for a meiofaunal ancestry6 and an explanation for the temporal mismatch between palaeontological and molecular clock timescales of animal evolution6-8. Here we report new material of S. coronarius, which is reconstructed as a millimetric and ellipsoidal meiobenthic animal with spinose armour and a terminal mouth but no anus. Purported pharyngeal openings in support of the deuterostome hypothesis6 are shown to be taphonomic artefacts. Phylogenetic analyses indicate that S. coronarius belongs to total-group Ecdysozoa, expanding the morphological disparity and ecological diversity of early Cambrian ecdysozoans.

Disruption of mitochondrial complex I induces progressive parkinsonism.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.

Characterization of the genome and cell invasive phenotype of Vibrio diabolicus Cg5 isolated from mass mortality of Pacific oyster, Crassostrea gigas.

Vibrio is an important group of aquatic animal pathogens, which has been identified as the main pathogenic factor causing mass summer mortality of Crassostrea gigas in northern China. This study aims to investigate the potential pathogenic mechanisms of Vibrio Cg5 isolate in C. gigas. We sequenced and annotated the genome of Vibrio Cg5 to analyze potential virulence factors. The gentamicin protection assays were performed with C. gigas primary cells to reveal the cell-invasive behavior of Cg5. The genome analysis showed that Cg5 was a strain of human disease-associated pathogen with multiple antibiotic resistance, and four virulence factors associated with intracellular survival were present in the genome. The gentamicin protection assays showed that Cg5 could potentially invade the cells of C. gigas, indicating that Cg5 could be a facultative intracellular pathogen of C. gigas. These results provide insights into the pathogenic mechanism of V. diabolicus, an emerging pathogenic Vibrio on aquatic animals, which would be valuable in preventing and controlling diseases in oysters.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas.

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Predicting major adverse cardiovascular events within 3 years by optimization of radiomics model derived from pericoronary adipose tissue on coronary computed tomography angiography: a case-control study.

BACKGROUND: Coronary inflammation induces changes in pericoronary adipose tissue (PCAT) can be detected by coronary computed tomography angiography (CCTA). Our aim was to investigate whether different PCAT radiomics model based on CCTA could improve the prediction of major adverse cardiovascular events (MACE) within 3 years. METHODS: This retrospective study included 141 consecutive patients with MACE and matched to patients with non-MACE (n = 141). Patients were randomly assigned into training and test datasets at a ratio of 8:2. After the robust radiomics features were selected by using the Spearman correlation analysis and the least absolute shrinkage and selection operator, radiomics models were built based on different machine learning algorithms. The clinical model was then calculated according to independent clinical risk factors. Finally, an overall model was established using the radiomics features and the clinical factors. Performance of the models was evaluated for discrimination degree, calibration degree, and clinical usefulness. RESULTS: The diagnostic performance of the PCAT model was superior to that of the RCA-model, LAD-model, and LCX-model alone, with AUCs of 0.723, 0.675, 0.664, and 0.623, respectively. The overall model showed superior diagnostic performance than that of the PCAT-model and Cli-model, with AUCs of 0.797, 0.723, and 0.706, respectively. Calibration curve showed good fitness of the overall model, and decision curve analyze demonstrated that the model provides greater clinical benefit. CONCLUSION: The CCTA-based PCAT radiomics features of three major coronary arteries have the potential to be used as a predictor for MACE. The overall model incorporating the radiomics features and clinical factors offered significantly higher discrimination ability for MACE than using radiomics or clinical factors alone.

Integrated analysis of mRNAs and lncRNAs reveals candidate marker genes and potential hub lncRNAs associated with growth regulation of the Pacific Oyster, Crassostrea gigas.

BACKGROUND: The Pacific oyster, Crassostrea gigas, is an economically important shellfish around the world. Great efforts have been made to improve its growth rate through genetic breeding. However, the candidate marker genes, pathways, and potential lncRNAs involved in oyster growth regulation remain largely unknown. To identify genes, lncRNAs, and pathways involved in growth regulation, C. gigas spat was cultured at a low temperature (15 ℃) to yield a growth-inhibited model, which was used to conduct comparative transcriptome analysis with spat cultured at normal temperature (25 ℃). RESULTS: In total, 8627 differentially expressed genes (DEGs) and 1072 differentially expressed lncRNAs (DELs) were identified between the normal-growth oysters (cultured at 25 ℃, hereinafter referred to as NG) and slow-growth oysters (cultured at 15 ℃, hereinafter referred to as SG). Functional enrichment analysis showed that these DEGs were mostly enriched in the AMPK signaling pathway, MAPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process. LncRNAs analysis identified 265 cis-acting pairs and 618 trans-acting pairs that might participate in oyster growth regulation. The expression levels of LNC_001270, LNC_003322, LNC_011563, LNC_006260, and LNC_012905 were inducible to the culture temperature and food abundance. These lncRNAs were located at the antisense, upstream, or downstream of the SREBP1/p62, CDC42, CaM, FAS, and PIK3CA genes, respectively. Furthermore, the expression of the trans-acting lncRNAs, including XR_9000022.2, LNC_008019, LNC_015817, LNC_000838, LNC_00839, LNC_011859, LNC_007294, LNC_006429, XR_002198885.1, and XR_902224.2 was also significantly associated with the expression of genes enriched in AMPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process. CONCLUSIONS: In this study, we identified the critical growth-related genes and lncRNAs that could be utilized as candidate markers to illustrate the molecular mechanisms underlying the growth regulation of Pacific oysters.

Vulnerable plaque of the petrous internal carotid artery in embolic stroke of undetermined source.

BACKGROUND AND PURPOSE: The association between nonstenotic plaque at the petrous internal carotid artery (ICA) and embolic stroke of undetermined source (ESUS) remains unknown. We aimed to test the hypothesis that the presence of a larger build-up of petrous plaque is more prevalent in the ipsilateral versus the contralateral side among ESUS patients without plaque in the intracranial and proximal ICA. METHODS: From a total of 243 patients with ESUS and 160 patients with small-vessel disease (SVD) without proximal ICA plaque, we enrolled 88 ESUS and 103 SVD patients without ipsilateral nonstenotic intracranial and proximal ICA plaque in the present study. Targeting the petrous segment of the ICA on two sides, plaque burden including plaque thickness, lumen area, vessel area, wall area, and percentage of luminal stenosis, and composition features (presence/absence of the ruptured fibrous cap, ulcer plaque, thrombus, discontinuity of plaque surface [DPS], intraplaque hemorrhage and complicated plaque) were assessed by high-resolution magnetic resonance imaging. RESULTS: We found a higher prevalence of petrous plaque thickness ≥3.5 mm ipsilateral versus contralateral to the stroke (25/88 [28.4%] vs. 12/88 [13.6%], odds ratio [OR] 3.60, 95% confidence interval [CI] 1.34-9.70), but this imbalance was not seen in SVD. In patients with plaque thickness ≥3.5 mm, the presence of DPS (OR 4.05, 95% CI 1.11-14.78) and complicated plaque (OR 5.00, 95% CI 1.10-22.82) was more closely related to an index ESUS, a finding that was not evident in the subgroup with petrous plaque <3.5 mm (p for interaction = 0.027). CONCLUSIONS: The present study provided the first evidence supporting a potential etiological role of vulnerable petrous plaque in ESUS.

Relationship between quantitative epicardial adipose tissue based on coronary computed tomography angiography and coronary slow flow.

BACKGROUND: The purpose of this study was to explore the relationship between quantitative epicardial adipose tissue (EAT) based on coronary computed tomography angiography (CCTA) and coronary slow flow (CSF). METHODS: A total of 85 patients with < 40% coronary stenosis on diagnostic coronary angiography were included in this retrospective study between January 2020 and December 2021. A semi-automatic method was developed for EAT quantification on CCTA images. According to the thrombolysis in myocardial infarction flow grade, the patients were divided into CSF group (n = 39) and normal coronary flow group (n = 46). Multivariate logistic regression was used to explore the relationship between EAT and CSF. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of EAT in CSF. RESULTS: EAT volume in the CSF group was significantly higher than that of the normal coronary flow group (128.83± 21.59 mL vs. 101.87± 18.56 mL, P < 0.001). There was no significant difference in epicardial fat attenuation index between the two groups (P > 0.05). Multivariate logistic regression analysis showed that EAT volume was independently related to CSF [odds ratio (OR) = 4.82, 95% confidence interval (CI): 3.06-7.27, P < 0.001]. The area under ROC curve for EAT volume in identifying CSF was 0.86 (95% CI: 0.77-0.95). The optimal cutoff value of 118.46 mL yielded a sensitivity of 0.80 and a specificity of 0.94. CONCLUSIONS: Increased EAT volume based on CCTA is strongly associated with CSF. This preliminary finding paves the way for future and larger studies aimed to definitively recognize the diagnostic value of EAT in CSF.

Detection and Classification of Cotton Foreign Fibers Based on Polarization Imaging and Improved YOLOv5.

It is important to detect and classify foreign fibers in cotton, especially white and transparent foreign fibers, to produce subsequent yarn and textile quality. There are some problems in the actual cotton foreign fiber removing process, such as some foreign fibers missing inspection, low recognition accuracy of small foreign fibers, and low detection speed. A polarization imaging device of cotton foreign fiber was constructed based on the difference in optical properties and polarization characteristics between cotton fibers. An object detection and classification algorithm based on an improved YOLOv5 was proposed to achieve small foreign fiber recognition and classification. The methods were as follows: (1) The lightweight network Shufflenetv2 with the Hard-Swish activation function was used as the backbone feature extraction network to improve the detection speed and reduce the model volume. (2) The PANet network connection of YOLOv5 was modified to obtain a fine-grained feature map to improve the detection accuracy for small targets. (3) A CA attention module was added to the YOLOv5 network to increase the weight of the useful features while suppressing the weight of invalid features to improve the detection accuracy of foreign fiber targets. Moreover, we conducted ablation experiments on the improved strategy. The model volume, mAP@0.5, mAP@0.5:0.95, and FPS of the improved YOLOv5 were up to 0.75 MB, 96.9%, 59.9%, and 385 f/s, respectively, compared to YOLOv5, and the improved YOLOv5 increased by 1.03%, 7.13%, and 126.47%, respectively, which proves that the method can be applied to the vision system of an actual production line for cotton foreign fiber detection.

Chemical Enhancement and Quenching in Single-Molecule Tip-Enhanced Raman Spectroscopy.

Despite intensive research in surface enhanced Raman spectroscopy (SERS), the influence mechanism of chemical effects on Raman signals remains elusive. Here, we investigate such chemical effects through tip-enhanced Raman spectroscopy (TERS) of a single planar ZnPc molecule with varying but controlled contact environments. TERS signals are found dramatically enhanced upon making a tip-molecule point contact. A combined physico-chemical mechanism is proposed to explain such an enhancement via the generation of a ground-state charge-transfer induced vertical Raman polarizability that is further enhanced by the strong vertical plasmonic field in the nanocavity. In contrast, TERS signals from ZnPc chemisorbed flatly on substrates are found strongly quenched, which is rationalized by the Raman polarizability screening effect induced by interfacial dynamic charge transfer. Our results provide deep insights into the understanding of the chemical effects in TERS/SERS enhancement and quenching.

Comprehensive characterization of costimulatory molecule gene for diagnosis, prognosis and recognition of immune microenvironment features in sepsis.

The present study, which involved 10 GEO datasets and 3 ArrayExpress datasets, comprehensively characterized the potential effects of CMGs in sepsis. Based on machine learning algorithms (Lasso, SVM and ANN), the CMG classifier was constructed by integrating 6 hub CMGs (CD28, CD40, LTB, TMIGD2, TNFRSF13C and TNFSF4). The CMG classifier exhibit excellent diagnostic values across multiple datasets and time points, and was able to distinguish sepsis from other critical diseases. The CMG classifier performed better in predicting mortality than other clinical characteristics or endotypes. More importantly, from clinical specimens, the CMG classifier showed more superior diagnostic values than PCT and CRP. Alternatively, the CMG classifier/hub CMGs is significantly correlated with immune cells infiltration (B cells, T cells, Tregs, and MDSC), pivotal immune and molecular pathways (inflammation-promoting, complement and coagulation cascades), and several cytokines. Collectively, CMG classifier was a robust tool for diagnosis, prognosis and recognition of immune microenvironment features in sepsis.

The characteristics of intracranial plaques of unilateral, anterior circulation embolic stroke of undetermined source: An analysis of different subtypes based on high-resolution imaging.

BACKGROUND AND PURPOSE: The aim was to investigate the characteristics of non-stenotic intracranial plaque (NSIP) in embolic stroke of undetermined source (ESUS) subtypes by high-resolution magnetic resonance imaging. METHODS: Consecutive patients with ESUS who were mandatory for high-resolution magnetic resonance imaging were retrospectively enrolled. Based on the location and arterial supply of the infarct, the ESUS were categorized into three types: cortical ESUS, subcortical ESUS and mixed ESUS. The NSIP parameters including plaque location, morphology (plaque distribution, remodeling index and plaque burden) and composition (thick fibrous cap, discontinuity of plaque surface, intraplaque hemorrhage and complicated plaque) were evaluated amongst the subtypes. RESULTS: Of 243 patients, there were 87 (35.8%) cortical ESUS, 127 (52.3%) subcortical ESUS and 29 (11.9%) mixed ESUS. Significant differences were found in plaque location (p < 0.001), plaque quadrant (p < 0.001), remodeling index (p < 0.001), plaque burden (p < 0.001), discontinuity of plaque surface (p < 0.001), intraplaque hemorrhage (p = 0.001) and complicated plaque (p < 0.001) of ipsilateral NISP amongst the different ESUS subtypes, except for fibrous cap (p = 0.135). However, no differences were found amongst contralateral NISP. In addition, the clinical characteristics of the differences between ESUS subtypes were striking, including age (p = 0.004), initial National Institutes of Health Stroke Scale (p < 0.001), coronary artery disease (p = 0.039), serum urea (p = 0.011) and creatinine (p = 0.002). CONCLUSION: This is the first report of significantly heterogeneous characteristics of ipsilateral NSIP and clinical findings amongst ESUS subtypes, which may suggest their different underlying mechanisms.

Relationship between epicardial fat volume on cardiac CT and atherosclerosis severity in three-vessel coronary artery disease: a single-center cross-sectional study.

BACKGROUND: The ideal treatment strategy for stable three-vessel coronary artery disease (CAD) patients are difficult to determine and for patients undergoing conservative treatment, imaging evidence of coronary atherosclerotic severity progression remains limited. Epicardial fat volume (EFV) on coronary CT angiography (CCTA) has been considered to be associated with coronary atherosclerosis. Therefore, this study aims to evaluate the relationship between EFV level and coronary atherosclerosis severity in three-vessel CAD. METHODS: This retrospective study enrolled 252 consecutive patients with three-vessel CAD and 252 normal control group participants who underwent CCTA between January 2018 and December 2019. A semi-automatic method was developed for EFV quantification on CCTA images, standardized by body surface area. Coronary atherosclerosis severity was evaluated and scored by the number of coronary arteries with ≥ 50% stenosis on coronary angiography. Patients were subdivided into groups on the basis of lesion severity: mild (score = 3 vessels, n = 85), moderate (3.5 vessels ≤ score < 4 vessels, n = 82), and severe (4 vessels ≤ score ≤ 7 vessels, n = 85). The independent sample t-test, analysis of variance, and logistic regression analysis were used to evaluate the associations between EFV level and severity of coronary atherosclerosis. RESULTS: Compared with normal controls, three-vessel CAD patients had significantly higher EFV level (65 ± 22 mL/m2 vs. 48 ± 19 mL/m2; P < 0.001). In patients with three-vessel CAD, there was a progressive decline in EFV level as the score of coronary atherosclerosis severity increased, especially in those patients with a body mass index (BMI) ≥ 25 kg/m2 (75 ± 21 mL/m2 vs. 72 ± 22 mL/m2 vs. 62 ± 17 mL/m2; P < 0.05). Multivariable regression analysis showed that both BMI (OR 3.40, 95% CI 2.00-5.78, P < 0.001) and the score of coronary atherosclerosis severity (OR 0.49, 95% CI 0.26-0.93, P < 0.05) were independently related to the change of EFV level. CONCLUSION: Three-vessel CAD patients do have higher EFV level than the normal controls. While, there may be an inverse relationship between EFV level and the severity of coronary atherosclerosis in patients with three-vessel CAD.

Rock structures improve seedling establishment, litter catchment, fungal richness, and soil moisture in the first year after installation.

Grasslands are essential natural and agricultural ecosystems that encompass over one-third of global lands. However, land conversion and poor management have caused losses of these systems which contributed to a 10% reduction of net primary production, a 4% increase in carbon emissions, and a potential loss of US $42 billion a year. It is, therefore, important to restore, enhance and conserve these grasslands to sustain natural plant communities and the livelihoods of those that rely on them. We installed low cost rock structures (media lunas) to assess their ability to restore grasslands by slowing water flow, reducing erosion and improving plant establishment. Our treatments included sites with small and large rock structures that were seeded with a native seed mix as well as sites with no seed or rock and sites with only seed addition. We collected summer percent cover for plants, litter, and rock and spring seedling count data. We also collected soil for nutrient, moisture, and microbial analysis. Within the first year, we found no change in plant cover between rock structures of two rock sizes. We did find, however, an increase in soil moisture, litter, fungal richness, and spring seedling germination within the rock structures, despite a historic drought. This work demonstrates that rock structures can positively impact plants and soils of grasslands even within the first year. Our results suggest that managers should seriously consider employing these low-cost structures to increase short-term plant establishment and possibly, soil health, in grasslands.

Targeting RNF8 effectively reverses cisplatin and doxorubicin resistance in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.

Degradable Photonic Synaptic Transistors Based on Natural Biomaterials and Carbon Nanotubes.

Artificial synaptic devices have potential for overcoming the bottleneck of von Neumann architecture and building artificial brain-like computers. Up to now, developing synaptic devices by utilizing biocompatible and biodegradable materials in electronic devices has been an interesting research direction due to the requirements of sustainable development. Here, a degradable photonic synaptic device is reported by combining biomaterials chlorophyll-a and single-walled carbon nanotubes (SWCNTs). Several basic synaptic functions, including excitatory postsynaptic current (EPSC), paired pulse facilitation (PPF), transition from short-term memory (STM) to long-term memory (LTM), and learning and forgetting behaviors, are successfully emulated through the chlorophyll-a/SWCNTs synaptic device. Furthermore, decent synaptic behaviors can still be achieved at a low drain voltage of -0.0001 V, which results in quite low energy consumption of 17.5 fJ per pulse. Finally, the degradability of this chlorophyll-a/SWCNTs transistor array is demonstrated, indicating that the device can be environmentally friendly. This work provides a new guide to the development of next-generation green and degradable neuromorphic computing electronics.

Crosstalk between dopamine and insulin signaling in growth control of the oyster.

Neuroendocrine hormones such as dopamine and insulin/insulin-like peptides play indispensable roles in growth regulation of animals, while the interplay between dopamine and insulin signaling pathways remains largely unknown in invertebrates. In the present study, we showed that tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, was highly expressed in all tissues of the fast-growing oysters, and gradually increased with the development, which indicated the potential role of dopamine in growth regulation. Incubated with dopamine hydrochloride and insulin-like peptide recombinant proteins in vitro induced the expression of TH, suggesting a mutual regulatory relationship between insulin and dopamine signaling. Fasting and re-feeding experiments confirmed the role of TH in food intake regulation, also provide a clue about the potential regulatory relationship between the FoxO and TH. Further luciferase assay experiment confirmed that FoxO was involved in transcriptional regulation of TH gene through binding to its specific promoter region. This work provided insights into the crosstalk between dopamine and insulin signaling in growth control of mollusks.

Inhibition of DNA-PKcs activity re-sensitizes uveal melanoma cells to radio- and chemotherapy.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite of important progress in the local therapy, high radioresistance in primary tumor and chemoresistance in metastatic disease are the major obstacles for UM therapy. Therefore, strategies to overcome resistance to radiation or chemotherapy in UM are urgently needed. In this study, we found that phosphorylation of DNA-PKcs, which is the key factor of non-homologous end joining (NHEJ) pathway, was remarkably overexpressed in ionizing radiation (IR)- and Selumetinib resistant UM cells. Increased amount of NHEJ events were also observed in resistant UM cells. Inhibition of DNA-PKcs by NU7441 significantly impaired DNA repair and re-sensitized resistant UM cells to radiation and Selumetinib both in vitro and in vivo. The results demonstrate increased DNA double strand break repair as a mechanism of resistance to ionizing radiation and Selumetinib, and identify DNA-PKcs as a promising target for radio-and chemotherapy in UM patients.

Association analysis of high-mobility group box-1 protein 1 (HMGB1)/toll-like receptor (TLR) 4 with nasal interleukins in allergic rhinitis patients.

BACKGROUND: High mobility group box 1 (HMGB1) acts as an inflammatory mediator initiator, and has shown to increase in nasal secretions of allergic rhinitis (AR) patients. The purpose of the present study was to investigate the association of HMGB1 and its receptor, toll-like receptor (TLR) 4 with proinflammatory interleukins in AR patients. METHODS: The interleukin (IL) -4, -5, -13, -17A, -10 in nasal lavage fluid and the serum IgE were examined with enzyme-linked immunosorbent assay (ELISA) in 125 AR patients or 87 healthy subjects (as control). The mRNA levels of HMGB1, receptor for advanced glycation end products (RAGE) and TLR 2, 3 and 4 were examined in these participants with real-time quantitative PCR (RT-qPCR) method. Spearman rank correlation was adopted to analyze the relationship between any two factors of clinical characteristics and laboratory-examined biomarkers. RESULTS: IL-4, -5, -13 and -17A were significantly higher, whereas IL-10 was markedly lower in the nasal lavage fluid samples from AR patients, compared with the control subjects. High expression of HMGB1, TLR2 and TLR4 were observed in the nasal brushing samples from these AR patients, whereas there was no significant difference for the mRNA levels of TLR3 and RAGE. Besides, HMGB1/TLR4 mRNA levels correlated positively with IL-4, -5, -13 and -17A, whereas negatively with IL-10. A linear regression of HMGB1/TLR4 was also found positively with IL-4, -5 (only for TLR4), -13 or -17A, whereas negatively with IL-10. CONCLUSION: High mRNA levels of HMGB1 and TLR4 were found in the nasal brushing samples in AR patients, correlating positively with IL-4, -5, -13 or -17A, wheareas negatively with IL-10. HMGB1/TLR4 signaling pathway might be well responsive targets as immunotherapy for allergic rhinitis.