High invasiveness is a hallmark of human hepatocellular carcinoma (HCC). Large tumors predict invasion and metastasis. Epithelial‐mesenchymal transition (EMT) is crucial for cancer invasion and ...metastasis. However, the mechanisms whereby large tumors tend to undergo EMT remain unclear. We conducted a subgenome‐wide screen and identified KLHL23 as an HCC invasion suppressor by inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT was suppressed by KLHL23 through its action on actin dynamics. Traditionally, actin cytoskeleton remodeling is downstream of EMT reprogramming. It is therefore intriguing to ask why and how KLHL23 inversely regulates EMT. Activation of actin cytoskeleton remodeling by either KLHL23 silencing or treatment with actin cytoskeleton modulators augmented cellular hypoxic responses in a cell‐density–dependent manner, resulting in hypoxia‐inducible factor (HIF) and Notch signals and subsequent EMT. Environmental hypoxia did not induce EMT unless actin cytoskeleton remodeling was simultaneously activated and only when cells were at high density. The resulting EMT was reversed by either adenosine 5′‐triphosphate supplementation or actin polymerization inhibitors. Down‐regulation of KLHL23 was associated with invasion, metastasis, and poor prognosis of HCC and pancreatic cancer. Correlations of tumor size with EMT and inverse association of expression of KLHL23 with HIF/Notch signals were further validated in patient‐derived xenograft HCCs in mice. Conclusion: Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down‐regulation) or microenvironment cues is crucial for cell‐density–dependent and hypoxia‐mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (Hepatology 2018;67:2226‐2243).
persists in a dormant state with a protective cyst wall for transmission. It is incompletely known how three cyst wall proteins (CWPs) are coordinately synthesized during encystation. Meiotic ...recombination is required for sexual reproduction in animals, fungi, and plants. It is initiated by formation of double-stranded breaks by a topoisomerase-like Spo11. It has been shown that exchange of genetic material in the fused nuclei occurs during
encystation, suggesting parasexual recombination processes of this protozoan.
possesses an evolutionarily conserved Spo11 with typical domains for cleavage reaction and an upregulated expression pattern during encystation. In this study, we asked whether Spo11 can activate encystation process, like other topoisomerases we previously characterized. We found that Spo11 was capable of binding to both single-stranded and double-stranded DNA in vitro and that it could also bind to the
promoters in vivo as accessed in chromatin immunoprecipitation assays. Spo11 interacted with WRKY and MYB2 (named from myeloblastosis), transcription factors that can activate
gene expression during encystation. Interestingly, overexpression of Spo11 resulted in increased expression of
-
and
genes and cyst formation. Mutation of the Tyr residue for the active site or two conserved residues corresponding to key DNA-binding residues for
Spo11 reduced the levels of
and
gene expression and cyst formation. Targeted disruption of
gene with CRISPR/Cas9 system led to a significant decrease in
and
gene expression and cyst number. Our results suggest that Spo11 acts as a positive regulator for
differentiation into cyst.
Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer and the fourth leading malignancy among males in Taiwan. Some pathogenic bacteria are associated with periodontitis and oral cancer. ...However, the comprehensive profile of the oral microbiome during the cancer's progression from the early stage to the late stage is still unclear. We profiled the oral microbiota and identified bacteria biomarkers associated with OSCC. The microbiota of an oral rinse from 51 healthy individuals and 197 OSCC patients at different stages were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. The oral microbiota communities from stage 4 patients showed significantly higher complexity than those from healthy controls. The populations also dynamically changed with the cancer's progression from stage 1 to stage 4. The predominant phyla in the oral samples showed variation in the relative abundance of
, and
. The abundance of
increased significantly with the progression of oral cancer from the healthy controls (2.98%) to OSCC stage 1 (4.35%) through stage 4 (7.92%). At the genus level, the abundance of
increased, while the number of
, and
decreased with cancer progression.
, and
were associated with OSCC, and they progressively increased in abundance from stage 1 to stage 4. The abundances of
, and
were inversely associated with OSCC progression. We selected a bacterial marker panel of three bacteria (upregulated
, down-regulated
, and
), which had an AUC of 0.956 (95% CI = 0.925-0.986) in discriminating OSCC stage 4 from the healthy controls. Furthermore, the functional prediction of oral bacterial communities showed that genes involved in carbohydrate-related metabolism, such as methane metabolism, and energy-metabolism-related parameters, such as oxidative phosphorylation and carbon fixation in photosynthetic organisms, were enriched in late-stage OSCC, while those responsible for amino acid metabolism, such as folate biosynthesis and valine, leucine, and isoleucine biosynthesis, were significantly associated with the healthy controls. In conclusion, our results provided evidence of oral bacteria community changes during oral cancer progression and suggested the possibility of using bacteria as OSCC diagnostic markers.
Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening lung disease with increasing prevalence and incidence worldwide. Increasing evidence suggests that lung microbiomes ...might play a physiological role in acute exacerbations of COPD. The objective of this study was to characterize the association of the microbiota and exacerbation risk or airflow limitation in stable COPD patients.
The sputum microbiota from 78 COPD outpatients during periods of clinical stability was investigated using 16S rRNA V3-V4 amplicon sequencing. The microbiome profiles were compared between patients with different risks of exacerbation, i.e., the low risk exacerbator (LRE) or high risk exacerbator (HRE) groups, and with different airflow limitation severity, i.e., mild to moderate (FEV1 ≥ 50; PFT I) or severe to very severe (FEV1 < 50; PFT II).
The bacterial diversity (Chao1 and observed OTUs) was significantly decreased in the HRE group compared to that in the LRE group. The top 3 dominant phyla in sputum were Firmicutes, Actinobacteria, and Proteobacteria, which were similar in the HRE and LRE groups. At the genus level, compared to that in the LRE group (41.24%), the proportion of Streptococcus was slightly decreased in the HRE group (28.68%) (p = 0.007). However, the bacterial diversity and the proportion of dominant bacteria at the phylum and genus levels were similar between the PFT I and PFT II groups. Furthermore, the relative abundances of Gemella morbillorum, Prevotella histicola, and Streptococcus gordonii were decreased in the HRE group compared to those in the LRE group according to linear discriminant analysis effect size (LEfSe). Microbiome network analysis suggested altered bacterial cooperative regulation in different exacerbation phenotypes. The proportions of Proteobacteria and Neisseria were negatively correlated with the FEV1/FVC value. According to functional prediction of sputum bacterial communities through Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis, genes involved in lipopolysaccharide biosynthesis and energy metabolism were enriched in the HRE group.
The present study revealed that the sputum microbiome changed in COPD patients with different risks of exacerbation. Additionally, the bacterial cooperative networks were altered in the HRE patients and may contribute to disease exacerbation. Our results provide evidence that sputum microbiome community dysbiosis is associated with different COPD phenotypes, and we hope that by understanding the lung microbiome, a potentially modifiable clinical factor, further targets for improved COPD therapies during the clinically stable state may be elucidated.
A series of donor–acceptor–donor triazine‐based molecules with thermally activated delayed fluorescence (TADF) properties were synthesized to obtain highly efficient blue‐emitting OLEDs with ...non‐doped emitting layers (EMLs). The targeted molecules use a triazine core as the electron acceptor, and a benzene ring as the conjugated linker with different electron donors to alternate the energy level of the HOMO to further tune the emission color. The introduction of long alkyl chains on the triazine core inhibits the unwanted intermolecular D–D/A–A‐type π–π interactions, resulting in the intermolecular D–A charge transfer. The weak aggregation‐caused quenching (ACQ) effect caused by the suppressed intermolecular D–D/A–A‐type π–π interaction further enhances the emission. The crowded molecular structure allows the electron donor and acceptor to be nearly orthogonal, thereby reducing the energy gap between triplet and singlet excited states (ΔEST). As a result, blue‐emitting devices with TH‐2DMAC and TH‐2DPAC non‐doped EMLs showed satisfactory efficiencies of 12.8 % and 15.8 %, respectively, which is one of the highest external quantum efficiency (EQEs) reported for blue TADF emitters (λpeak<475 nm), demonstrating that our tailored molecular designs are promising strategies to endow OLEDs with excellent electroluminescent performances.
Getting the blues: A series of donor–acceptor–donor triazine‐based molecules with thermally activated delayed fluorescence (TADF) properties were synthesized to obtain highly efficient blue‐emitting OLEDs with non‐doped emitting layers (EMLs). The targeted molecules use a triazine core as the electron acceptor, and a benzene ring as the conjugated linker with different electron donors to alternate the energy level of the HOMO to further tune the emission color.
In this study, we investigate whether different types of business strategy are related to financial opacity and, if so, whether financial constraints and decreasing production demand exacerbate or ...mitigate financial opacity. Using a sample of listed firms in Taiwan from 2013 to 2018, we find that defenders mitigate financial opacity through loss avoidance and exacerbate financial opacity through aggressive earnings, especially when they face lower financial constraints and during decreasing production demand. However, prospectors do not exacerbate financial opacity by smoothing earnings especially when they face higher financial constraints and their production demand is increasing. Our study should be of interest to researchers and financial statement users, as well as others concerned with understanding the effects of different types of business strategy on different levels of financial opacity.
Objective To assess the associations of the Assessment of Spondyloarthritis International Society Health Index (ASAS HI) with gender and other factors in patients with ankylosing spondylitis (AS). ...Methods From November 2017 to October 2018, we measured the Ankylosing Spondylitis Disease Activity Score (ASDAS), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and the ASAS HI score for AS patients at the Taichung Veterans General Hospital. After adjusting for disease activity (ASDAS-erythrocyte sedimentation rate ESR, ASDAS- C-reactive protein CRP, BASDAI+ESR or BASDAI+CRP), mSASSS and other potential confounders including medications, comorbidities, and laboratory data, any associations between gender and the sum score of ASDAS HI were assessed using multiple linear regression analysis, as well as any associations between gender and an ASAS HI score >5 using multivariable logistic regression analysis. Results A total of 307 AS patients (62 20.2% females, mean age 46.4 years S.D. 13.3, mean symptom duration 20.6 years S.D. 12.1) were included. Multiple linear regression analysis showed that the male gender was significantly associated with a lower ASAS HI (B = -1. 91, 95% confidence interval CI, -2.82--1.00, p 5 than females (odds ratio = 0.15, 95% CI, 0.07-0.36, p 0.001). Disease activity measures, including ASDAS-ESR, ASDAS-CRP and BASDAI, had positive correlations with ASAS HI. Conclusion This single-center, cross-sectional study revealed that a higher ASAS HI score was significantly associated with female gender and higher disease activity measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bone marrow stem cell can differentiate to osteoblast by growth factors, pulsed low-intensity ultrasound and electric magnetic field. In the research, bone marrow stem cells were cultured; bone ...marrow stem cells in culture can be stimulated by platelet-rich plasma and electric field.
The culture well of the co-cultivation device has a radius of 7.5 mm and a depth of 7 mm. It is divided into two sub-chambers separated by a 3 mm high and 1 mm wide barrier. The bone marrow stem cells were seeded at a density of 2 × 10
cells and the medium volume was 120μl. Platelet-rich plasma (PRP) or platelet-poor plasma (PPP) was added to the other sub-chamber at a volume of 10μl. The bone marrow stem cells were subjected to different electric fields (0 ~ 1 V/cm) at a frequency of 70 kHz for 60 min.
The highest osteogenic capacity of bone marrow stem cells was achieved by addition of PRP to electric field stimulation (0.25 V/cm) resulted in a proliferation rate of 599.78%. In electric field stimulation (0.75 V/cm) with PPP, the proliferation rate was only 10.46%.
Bone marrow stem cell with PRP in the co-culture device combined with electric field at 0.25 V/cm strength significantly promoted the growth of bone marrow stem cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau ...neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear.
We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology.
In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA methylation is a critical epigenetic regulator in mammalian development. Here, we present a whole-genome comparative view of DNA methylation using bisulfite sequencing of three cultured cell ...types representing progressive stages of differentiation: human embryonic stem cells (hESCs), a fibroblastic differentiated derivative of the hESCs, and neonatal fibroblasts. As a reference, we compared our maps with a methylome map of a fully differentiated adult cell type, mature peripheral blood mononuclear cells (monocytes). We observed many notable common and cell-type-specific features among all cell types. Promoter hypomethylation (both CG and CA) and higher levels of gene body methylation were positively correlated with transcription in all cell types. Exons were more highly methylated than introns, and sharp transitions of methylation occurred at exon-intron boundaries, suggesting a role for differential methylation in transcript splicing. Developmental stage was reflected in both the level of global methylation and extent of non-CpG methylation, with hESC highest, fibroblasts intermediate, and monocytes lowest. Differentiation-associated differential methylation profiles were observed for developmentally regulated genes, including the HOX clusters, other homeobox transcription factors, and pluripotence-associated genes such as POU5F1, TCF3, and KLF4. Our results highlight the value of high-resolution methylation maps, in conjunction with other systems-level analyses, for investigation of previously undetectable developmental regulatory mechanisms.
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