The Efficacy of Wearable Cueing Devices on Gait and Motor Function in Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To summarize the efficacy of wearable cueing devices for improving gait and motor function of patients with Parkinson disease (PWP). DATA SOURCES: PubMed, Embase, and Cochrane CENTRAL databases were searched for papers published in English, from inception to October 23, 2022. STUDY SELECTION: Randomized controlled trials focusing on the effects of wearable cueing devices on gait and motor function in PWP were included. DATA EXTRACTION: Two reviewers independently selected articles and extracted the data. The Cochrane Bias Risk Assessment Tool was used to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the quality of evidence. DATA SYNTHESIS: Seven randomized controlled trials with 167 PWP were included in the meta-analysis. Significant effect of wearable cueing devices on walking speed (mean difference [MD]=0.07 m/s, 95% confidence interval [CI]: [0.05, 0.09], P<.00001) was detected; however, after sensitivity analysis, no significant overall effect on walking speed was noted (MD=0.04 m/s, 95% CI: [-0.03, 0.12], P=.25). No significant improvements were found in stride length (MD=0.06 m, 95% CI: [0.00, 0.13], P=.05), the Unified Parkinson's Disease Rating Scale-III score (MD=-0.61, 95% CI: [-4.10, 2.88], P=.73), Freezing of Gait Questionnaire score (MD=-0.83, 95% CI: [-2.98, 1.33], P=.45), or double support time (MD=-0.91, 95% CI: [-3.09, 1.26], P=.41). Evidence was evaluated as low quality. CONCLUSIONS: Wearable cueing devices may result in an immediate improvement on walking speed; however, there is no evidence that their use results in a significant improvement in other gait or motor functions.

Nomogram-based geometric and hemodynamic parameters for predicting the growth of small untreated intracranial aneurysms.

Previous studies have shown that the growth status of intracranial aneurysms (IAs) predisposes to rupture. This study aimed to construct a nomogram for predicting the growth of small IAs based on geometric and hemodynamic parameters. We retrospectively collected the baseline and follow-up angiographic images (CTA/ MRA) of 96 small untreated saccular IAs, created patient-specific vascular models and performed computational fluid dynamics (CFD) simulations. Geometric and hemodynamic parameters were calculated. A stepwise Cox proportional hazards regression analysis was employed to construct a nomogram. IAs were stratified into low-, intermediate-, and high-risk groups based on the total points from the nomogram. Receiver operating characteristic (ROC) analysis, calibration curves, decision curve analysis (DCA) and Kaplan-Meier curves were evaluated for internal validation. In total, 30 untreated saccular IAs were grown (31.3%; 95%CI 21.8%-40.7%). The PHASES, ELAPSS, and UIATS performed poorly in distinguishing growth status. Hypertension (hazard ratio [HR] 4.26, 95%CI 1.61-11.28; P = 0.004), nonsphericity index (95%CI 4.10-25.26; P = 0.003), max relative residence time (HR 1.01, 95%CI 1.00-1.01; P = 0.032) were independently related to the growth status. A nomogram was constructed with the above predictors and achieved a satisfactory prediction in the validation cohort. The log-rank test showed significant discrimination among the Kaplan-Meier curves of different risk groups in the training and validation cohorts. A nomogram consisting of geometric and hemodynamic parameters presented an accurate prediction for the growth status of small IAs and achieved risk stratification. It showed higher predictive efficacy than the assessment tools.

Targeting ferroptosis in cardio-metabolic-diseases: Mechanisms and therapeutic prospects.

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.

NamiRNA-enhancer network of miR-492 activates the NR2C1-TGF-ß/Smad3 pathway to promote epithelial-mesenchymal transition of pancreatic cancer.

Pancreatic cancer (PaCa) is one of the most fatal malignancies of the digestive system, and most patients are diagnosed at advanced stages due to the lack of specific and effective tumor-related biomarkers for the early detection of PaCa. miR-492 has been found to be upregulated in PaCa tumor tissue and may serve as a potential therapeutic target. However, the molecular mechanisms by which miR-492 promotes PaCa tumor growth and progression are unclear. In this study, we first found that miR-492 in enhancer loci activated neighboring genes (NR2C1/NDUFA12/TMCC3) and promoted PaCa cell proliferation, migration, and invasion in vitro. We also observed that miR-492-activating genes significantly enriched the TGF-ß/Smad3 signaling pathway in PaCa to promote epithelial-mesenchymal transition (EMT) during tumorigenesis and development. Using CRISPR-Cas9 and ChIP assays, we further observed that miR-492 acted as an enhancer trigger, and that antagomiR-492 repressed PaCa tumorigenesis in vivo, decreased the expression levels of serum TGF-ß, and suppressed the EMT process by downregulating the expression of NR2C1. Our results demonstrate that miR-492, as an enhancer trigger, facilitates PaCa progression via the NR2C1-TGF-ß/Smad3 pathway.

Evaluation of novel anti-CEACAM6 antibody-based conjugates for radioimmunotheranostics of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor that lacks early diagnostic methods. Recently, targeted immunotherapy and radiotherapy have been integrated with radionuclide-antibody conjugate drugs, which can be used for targeted diagnosis and dynamic imaging of tumors. CEACAM6 is overexpressed in pancreatic tumors and is a potential theranostic target for PDAC. We aimed to develop a novel targeted carrier for theranostics of PDAC and other solid tumors. METHODS: Based on camelid heavy-chain-only antibodies, we developed a CEACAM6-targeting recombinant antibody NY004, and evaluated it as a novel antibody-carrier for imaging and therapy of cancer in tumor models. We labeled NY004 with theranostic nuclides and applied this self-developed antibody platform in diagnostic imaging and antitumor assessment in PDAC models. RESULTS: Through microPET, IHC, and biodistribution assays, targeting and biodistribution of [89Zr]-NY004 in solid tumors including PDAC was examined, and the investigated tumors were all CEACAM6-positive malignancies. We found that NY004 was suitable for use as a drug carrier for radioimmunotheranostics. Our study showed that NY004 was characterized by high targeted uptake and a long retention time in PANC-1 tumors (up to 6 days post-injection), with good specificity and high imaging efficiency. Therapeutic evaluation of the radionuclide-labeled antibody drug [177Lu]-NY004 in PDAC tumor-bearing model revealed that NY004 had high and prolonged uptake in tumors, relatively low non-target organ uptake, and good anti-tumor efficacy. CONCLUSION: As a drug platform for radiotheranostics, CEACAM6-specific antibody NY004 met the requirements of easy-labeling, targeting specificity, and effective persistence in pancreatic adenocarcinoma tissues. KEY POINTS: • [89Zr]-NY004 has good specificity and high imaging efficiency, and is characterized by high tumor-targeting uptake and a long tumor retention time as a PET molecular imaging tracer. • Therapeutic radionuclide-conjugated antibody drug [177Lu]-NY004 has high uptake and prolonged uptake duration in tumors, low non-target organ uptake, and significant tumor-inhibiting efficacy in PDAC model. • The self-developed antibody structure NY004 is a promising drug platform for radioimmunotheranostics of CEACAM6-positive tumors including pancreatic ductal adenocarcinoma.

Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.

Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg-1·d-1, ip) or DFP (100 mg·kg-1·d-1, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL+ cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.

Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Apostasia Mitochondrial Genome Analysis and Monocot Mitochondria Phylogenomics.

Apostasia shenzhenica belongs to the subfamily Apostasioideae and is a primitive group located at the base of the Orchidaceae phylogenetic tree. However, the A. shenzhenica mitochondrial genome (mitogenome) is still unexplored, and the phylogenetic relationships between monocots mitogenomes remain unexplored. In this study, we discussed the genetic diversity of A. shenzhenica and the phylogenetic relationships within its monocotyledon mitogenome. We sequenced and assembled the complete mitogenome of A. shenzhenica, resulting in a circular mitochondrial draft of 672,872 bp, with an average read coverage of 122× and a GC content of 44.4%. A. shenzhenica mitogenome contained 36 protein-coding genes, 16 tRNAs, two rRNAs, and two copies of nad4L. Repeat sequence analysis revealed a large number of medium and small repeats, accounting for 1.28% of the mitogenome sequence. Selection pressure analysis indicated high mitogenome conservation in related species. RNA editing identified 416 sites in the protein-coding region. Furthermore, we found 44 chloroplast genomic DNA fragments that were transferred from the chloroplast to the mitogenome of A. shenzhenica, with five plastid-derived genes remaining intact in the mitogenome. Finally, the phylogenetic analysis of the mitogenomes from A. shenzhenica and 28 other monocots showed that the evolution and classification of most monocots were well determined. These findings enrich the genetic resources of orchids and provide valuable information on the taxonomic classification and molecular evolution of monocots.

Construction of Ultrafine Ag2S NPs Anchored onto 3D Network Rodlike Bi2SiO5 and Insight into the Photocatalytic Mechanism.

A novel three-dimensional (3D) network rodlike Ag2S/Bi2SiO5 photocatalyst with a p-n heterostructure composed of ultrafine Ag2S nanoparticles (NPs) and Bi2SiO5 nanosheets was prepared using an anionic self-regulation strategy by a two-step hydrothermal process. The architecture facilitated the efficient transfer and separation of photogenerated electron-hole pairs. The optimal Ag2S/Bi2SiO5 composite (ABSO0.10) exhibited an excellent reduction activity (93.5% Cr(VI) removal in wastewater containing 50 mg·L-1 Cr(VI) within 90 min under visible light), which was about 11.2 and 25.6 times higher than that of the pristine Ag2S and virgin Bi2SiO5, respectively. Assisted by experiments and density functional theory (DFT) calculations, a possible photocatalytic mechanism for Cr(VI) reduction over the Ag2S/Bi2SiO5 composite under visible-light irradiation was proposed.

Segmentation Method of Cerebral Aneurysms Based on Entropy Selection Strategy.

The segmentation of cerebral aneurysms is a challenging task because of their similar imaging features to blood vessels and the great imbalance between the foreground and background. However, the existing 2D segmentation methods do not make full use of 3D information and ignore the influence of global features. In this study, we propose an automatic solution for the segmentation of cerebral aneurysms. The proposed method relies on the 2D U-Net as the backbone and adds a Transformer block to capture remote information. Additionally, through the new entropy selection strategy, the network pays more attention to the indistinguishable blood vessels and aneurysms, so as to reduce the influence of class imbalance. In order to introduce global features, three continuous patches are taken as inputs, and a segmentation map corresponding to the central patch is generated. In the inference phase, using the proposed recombination strategy, the segmentation map was generated, and we verified the proposed method on the CADA dataset. We achieved a Dice coefficient (DSC) of 0.944, an IOU score of 0.941, recall of 0.946, an F2 score of 0.942, a mAP of 0.896 and a Hausdorff distance of 3.12 mm.

OrchidBase 4.0: a database for orchid genomics and molecular biology.

BACKGROUND: The Orchid family is the largest families of the monocotyledons and an economically important ornamental plant worldwide. Given the pivotal role of this plant to humans, botanical researchers and breeding communities should have access to valuable genomic and transcriptomic information of this plant. Previously, we established OrchidBase, which contains expressed sequence tags (ESTs) from different tissues and developmental stages of Phalaenopsis as well as biotic and abiotic stress-treated Phalaenopsis. The database includes floral transcriptomic sequences from 10 orchid species across all the five subfamilies of Orchidaceae. DESCRIPTION: Recently, the whole-genome sequences of Apostasia shenzhenica, Dendrobium catenatum, and Phalaenopsis equestris were de novo assembled and analyzed. These datasets were used to develop OrchidBase 4.0, including genomic and transcriptomic data for these three orchid species. OrchidBase 4.0 offers information for gene annotation, gene expression with fragments per kilobase of transcript per millions mapped reads (FPKM), KEGG pathways and BLAST search. In addition, assembled genome sequences and location of genes and miRNAs could be visualized by the genome browser. The online resources in OrchidBase 4.0 can be accessed by browsing or using BLAST. Users can also download the assembled scaffold sequences and the predicted gene and protein sequences of these three orchid species. CONCLUSIONS: OrchidBase 4.0 is the first database that contain the whole-genome sequences and annotations of multiple orchid species. OrchidBase 4.0 is available at http://orchidbase.itps.ncku.edu.tw/.

The genome of Cymbidium sinense revealed the evolution of orchid traits.

The Orchidaceae is of economic and ecological importance and constitutes ˜10% of all seed plant species. Here, we report a genome physical map for Cymbidium sinense, a well-known species belonging to genus Cymbidium that has thousands of natural variation varieties of flower organs, flower and leaf colours and also referred as the King of Fragrance, which make it arose into a unique cultural symbol in China. The high-quality chromosome-scale genome assembly was 3.52 Gb in size, 29 638 protein-coding genes were predicted, and evidence for whole-genome duplication shared with other orchids was provided. Marked amplification of cytochrome- and photosystem-related genes was observed, which was consistent with the shade tolerance and dark green leaves of C. sinense. Extensive duplication of MADS-box genes, and the resulting subfunctional and expressional differentiation, was associated with regulation of species-specific flower traits, including wild-type and mutant-type floral patterning, seasonal flowering and ecological adaption. CsSEP4 was originally found to positively regulate gynostemium development. The CsSVP genes and their interaction proteins CsAP1 and CsSOC1 were significantly expanded and involved in the regulation of low-temperature-dependent flowering. Important genetic clues to the colourful leaf traits, purple-black flowers and volatile trait in C. sinense were also found. The results provide new insights into the molecular mechanisms of important phenotypic traits of Cymbidium and its evolution and serve as a powerful platform for future evolutionary studies and molecular breeding of orchids.

Jmjd3 regulates inflammasome activation and aggravates DSS-induced colitis in mice.

The intracellular NOD-like receptor nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) is a pivotal regulator of intestinal homeostasis through regulating a variety of inflammatory and autoimmune diseases. The Jumonji domain-containing 3 (Jmjd3) plays important role in inflammatory responses and thus has been proposed as a novel attractive epigenetic target for the treatment of inflammatory diseases. We here investigated whether targeting Jmjd3 regulates NLRP3 inflammasome during experimental colitis. Jmjd3 specific inhibitor GSK J4 or knocking down Jmjd3 significantly inhibited NLRP3 inflammasome activation in lipopolysaccharide (LPS) and nigericin-stimulated bone marrow-derived macrophages. Chromatin immunoprecipitation-PCR analysis validated that GSK J4 rescued the decreased repressive H3K27me3 recruitment level on the promotors of nuclear factor-erythroid 2-related factor 2 (Nrf2) in LPS plus nigericin-induced macrophages. Nrf2 knockdown abolished NLRP3 inflammasome activation. Notably, oral administration of GSK J4 attenuated the disease progression in dextran sodium sulfate-induced colitis mouse model, including reduced disease activity index, improved body weight, rescued bowel shortening and NLRP3 inflammasome activation. Overall, our study reveals that Jmjd3 is a potential epigenetic regulator for the treatment of inflammatory bowel disease (IBD), suggesting that Nrf2 is a potential target gene of Jmjd3 by mediating methylation status of trimethylated H3 lysine 27 (H3K27me3) in the promotor and is required for NLRP3 inflammasome activation, thereby providing the platform for potential future therapeutic interventions in IBD.

iTRAQ- and LC-MS/MS-based quantitative proteomics reveals Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway during fasting.

Glucose homeostasis is tightly controlled by balance between glucose production and uptake in liver tissue upon energy shortage condition. Altered glucose homeostasis contributes to the pathophysiology of metabolic disorders including diabetes and obesity. Here, we aimed to analyse the change of proteomic profile upon prolonged fasting in mice with isobaric tag for relative and absolute quantification (iTRAQ) labelling followed by liquid chromatography-mass spectrometry (LC/MS) technology. Adult male mice were fed or fasted for 16 hours and liver tissues were collected for iTRAQ labelling followed by LC/MS analysis. A total of 322 differentially expressed proteins were identified, including 189 upregulated and 133 downregulated proteins. Bioinformatics analyses, including Gene Ontology analysis (GO), Kyoto encyclopaedia of genes and genomes analysis (KEGG) and protein-protein interaction analysis (PPI) were conducted to understand biological process, cell component, and molecular function of the 322 differentially expressed proteins. Among 322 hepatic proteins differentially expressed between fasting and fed mice, we validated three upregulated proteins (Pqlc2, Ehhadh and Apoa4) and two downregulated proteins (Uba52 and Rpl37) by western-blotting analysis. In cultured HepG2 hepatocellular cells, we found that depletion of Pqlc2 by siRNA-mediated knockdown impaired the insulin-induced glucose uptake, inhibited GLUT2 mRNA level and suppressed the insulin-induced Akt phosphorylation. By contrast, knockdown of Pqlc2 did not affect the cAMP/dexamethasone-induced gluconeogenesis. In conclusion, our study provides important information on protein profile change during prolonged fasting with iTRAQ- and LC-MS/MS-based quantitative proteomics, and identifies Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway in this process.

[Review on identity feature extraction methods based on electroencephalogram signals].

Biometrics plays an important role in information society. As a new type of biometrics, electroencephalogram (EEG) signals have special advantages in terms of versatility, durability, and safety. At present, the researches on individual identification approaches based on EEG signals draw lots of attention. Identity feature extraction is an important step to achieve good identification performance. How to combine the characteristics of EEG data to better extract the difference information in EEG signals is a research hotspots in the field of identity identification based on EEG in recent years. This article reviewed the commonly used identity feature extraction methods based on EEG signals, including single-channel features, inter-channel features, deep learning methods and spatial filter-based feature extraction methods, etc. and explained the basic principles application methods and related achievements of various feature extraction methods. Finally, we summarized the current problems and forecast the development trend.

WD repeat-containing protein 1 maintains ß-Catenin activity to promote pancreatic cancer aggressiveness.

BACKGROUND: The molecular signature underlying pancreatic ductal adenocarcinoma (PDAC) progression may include key proteins affecting the malignant phenotypes. Here, we aimed to identify the proteins implicated in PDAC with different tumour-node-metastasis (TNM) stages. METHODS: Eight-plex isobaric tags coupled with two-dimensional liquid chromatography-tandem mass spectrometry were used to analyse the proteome of PDAC tissues with different TNM stages. A loss-of-function study was performed to evaluate the oncogenic roles of WD repeat-containing protein 1 (WDR1) in PDAC. The molecular mechanism by which WDR1 promotes PDAC progression was studied by real-time qPCR, Western blotting, proximity ligation assay and co-immunoprecipitation. RESULTS: A total of 5036 proteins were identified, and 4708 proteins were quantified with high confidence. Compared with normal pancreatic tissues, 37 proteins were changed significantly in PDAC tissues of different stages. Moreover, 64 proteins were upregulated or downregulated in a stepwise manner as the TNM stages of PDAC increased, and 10 proteins were related to tumorigenesis. The functionally uncharacterised protein, WDR1, was highly expressed in PDAC and predicted a poor prognosis. WDR1 knockdown suppressed PDAC tumour growth and metastasis in vitro and in vivo. Moreover, WDR1 knockdown repressed the activity of the Wnt/ß-Catenin pathway; ectopic expression of a stabilised form of ß-Catenin restored the suppressive effects of WDR1 knockdown. Mechanistically, WDR1 interacted with USP7 to prevent ubiquitination-mediated degradation of ß-Catenin. CONCLUSION: Our study identifies several previous functional unknown proteins implicated in the progression of PDAC, and provides new insight into the oncogenic roles of WDR1 in PDAC development.

Identification of novel biomarkers for hepatocellular carcinoma using transcriptome analysis.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer in the world. To comprehensively investigate the utility of microRNAs (miRNAs) and protein-encoding transcripts (messenger RNAs [mRNAs]) in HCC as potential biomarkers for early detection and diagnosis, we exhaustively mined genomic data from three available omics datasets (GEO, Oncomine, and TCGA), analyzed the overlaps among gene expression studies from 920 hepatocellular carcinoma samples and 508 healthy (or adjacent normal) liver tissue samples available from six laboratories, and identified 178 differentially expressed genes (DEGs) associated with HCC. Paired with miRNA and lncRNA data, we identified 23 core genes that were targeted by nine differentially expressed miRNAs and 21 HCC-specific lncRNAs. We further demonstrated that alterations in these 23 genes were quite frequent, with five genes altered in over 5% of the population. Patients with high levels of YWHAZ, ENAH, and HMGN4 tended to have high-grade tumors and shorter overall survival, suggesting that these genes could be promising candidate biomarkers for disease and poor prognosis in patients with HCC. Our comprehensive mRNA, miRNA, and lncRNA omics analyses from multiple independent datasets identified robust molecules that may be used as biomarkers for early HCC detection and diagnosis.

microRNA-146a and Hey2 form a mutual negative feedback loop to regulate the inflammatory response in chronic apical periodontitis.

Chronic apical periodontitis (CAP) is defined as chronic inflammation of the dental pulp and root canal system. Porphyromonas endodontalis lipopolysaccharide ( P. endodontalis LPS) plays an important role in inducing an inflammatory response in CAP. microRNA-146a (miR-146a) is a key regulator of inflammation and is induced by LPS. Hairy and enhancer-of-split related with YRPW motif 2 (Hey2) has been confirmed to be induced by the Notch signaling pathway, which is involved in tooth development, pulp regeneration, and repair after injury. Our study aimed to investigate the functional role of miR-146a via the targeting of Hey2 in CAP as well as the underlying mechanism. Compared with 13 healthy controls, miR-146a and Hey2 expressions were significantly higher in 20 patients with CAP. In addition, miR-146a, Hey2, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α expressions were significantly increased in MC3T3-E1 cells stimulated with different concentrations (0-20 µg/mL) of P. endodontalis LPS for different amounts of time (0-48 hours). Moreover, miR-146a, which acts as an anti-inflammatory mediator, negatively regulated the expression of IL-6, IL-1ß, and TNF-α, and Hey2 was confirmed as a target gene of miR-146a by a luciferase reporter assay. Hey2 also negatively regulated miR-146a, IL-6, IL-1ß, and TNF-α expressions, and P. endodontalis LPS strongly induced Hey2 recruitment to the IL-6 promoter (-400 ~ -200 bp). These findings suggest that miR-146a and Hey2 form a mutual negative feedback regulatory loop, demonstrating a novel mechanism that regulates inflammatory responses in CAP.

Discovery of new chromen-4-one derivatives as telomerase inhibitors through regulating expression of dyskerin.

A series of new trimethoxyphenyl-4H-chromen derivatives as telomerase inhibitors through regulation dyskerin were designed and synthesised. The anticancer activity assay in vitro showed that compound 5i 3-(4-(4-isonicotinoylpiperazin-1-yl)butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one exhibited high activity against Hela, SMMC-7721, SGC-7901, U87 and HepG2 cell lines. Compound 5i also showed potent inhibitory activity against telomerase. The further results confirmed this title compound could significantly improve pathological changes induced rat hepatic tumor in vivo. Preliminary mechanisms showed that compound 5i inhibited telomerase activity through decrease expression of dyskerin.

The effect of immunoregulation of Streptococcus lactis L16 strain upon Staphylococcus aureus infection.

BACKGROUND: Staphylococcus aureus is an important pathogen that causes various infections in medical facilities. However, resistance to multiple drugs has made this infection difficult to manage. Thus, new therapeutic strategies are urgently needed to solve this worldwide public health problem. The Streptococcus lactis L16 strain was isolated from the fermented hot chili sauce. To explore whether it can be used as a protective agent against S. aureus infection, we designed a mouse model of S. aureus infection to evaluate the therapeutic potency of S. lactis. Mice were grouped into pre-(P) and post-(T) S. aureus infection groups following oral administration of S. lactis L16. The protection and treatment effects were assessed by examining body weight, internal organ weight, serum cytokines and intestinal secretory IgA alternations. RESULT: Oral administration of the S. lactis L16 strain reduced the loss of body weight in mice post-infection and alleviated infection-induced hepatomegaly. In particular, the PL16 group (protection with L16) showed more effective resistance to S. aureus than the TL16 group (treatment with L16). The level of serum cytokine interferon gamma following oral administration of the L16 strain was remarkably increased during infection, as were interleukin-4 levels during convalescence. The probiotic L16 strain induced more sIgA production than S. aureus. CONCLUSION: Our data suggest that S. lactis L16 is an effective strain with anti-Staphylococcus activity. By regulating the Th1/Th2 response, S. lactis can effectively reduce lesions from infection, indicating its therapeutic potential in overcoming antibiotic resistance in this mouse infection model that mimics infections observed in humans.