MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic ...pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of
,
, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.
What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic ...variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill (Sinosuthora webbiana) in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.
Introduction
Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on ...the clinical characteristics and outcomes of GTS in children with MGCTs are limited.
Methods
We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS.
Results
The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety‐five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event‐free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5‐year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001).
Conclusion
For patients with high‐risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy.
Here, we describe a novel interaction between the RNA helicase DDX3 and the deubiquitinase ubiquitin‐specific peptidase 9 X‐linked (USP9X) in human cells. Domain mapping studies reveal that the ...C‐terminal region of DDX3 interacted with the N terminus of USP9X. USP9X was predominantly localized in the cytoplasm where the interaction between DDX3 and USP9X occurred. USP9X was not visibly enriched in cytoplasmic stress granules (SGs) under oxidative stress conditions, whereas overexpression of GFP‐DDX3 induced SG formation and recruited USP9X to SGs in HeLa cells. Luciferase reporter assays showed that depletion of USP9X had no significant effect on DDX3‐mediated translation. Given that DDX3 is not ubiquitinated upon ubiquitin overexpression, it is unlikely that DDX3 serves as a substrate of USP9X. Importantly, we found that ubiquitinated MCL1 was accumulated upon depletion of USP9X and/or DDX3 in MG132‐treated cells, suggesting that USP9X and DDX3 play a role in regulating MCL1 protein stability and anti‐apoptotic function. This study indicates that DDX3 exerts anti‐apoptotic effects probably by coordinating with USP9X in promoting MCL1 deubiquitination.
A new model of the anti‐apoptotic function of DDX3 was proposed to understand the significance of DDX3 in cancer development. DDX3 might promote anti‐apoptotic Bcl‐xL gene expression and repress pro‐apoptotic Bax gene expression through transcriptional and/or translational regulation. DDX3 also stabilizes anti‐apoptotic MCL1 protein level by post‐translational modification (deubiquitination).
Lipid metabolism dysfunction is related to clinical disorders including obesity, cancer, liver steatosis, and cardiomyopathy. Impaired lipolytic enzymes result in altered release of free fatty acids. ...The dramatic change in dyslipidemia is important in lipotoxic cardiomyopathy. Adipose triglyceride lipase (ATGL) catalyzes the lipolysis of triacylglycerol to reduce intramyocardial triglyceride levels in the heart and improve myocardial function. We examined the role of ATGL in metabolic cardiomyopathy by developing an Atgl knockout (ALKO) zebrafish model of metabolic cardiomyopathy disease by continuously expressing CRISPR/Cas9 protein and
gene guide RNAs (gRNAs). The expressed Cas9 protein bound to four gRNAs targeting the
gene locus, facilitating systemic gene KO. Ablation of Atgl interfered with lipid metabolism, which induced hyperlipidemia and hyperglycemia. ALKO adults and embryos displayed hypertrophic hearts. ALKO presented a typical dilated cardiomyopathy profile with a remarkable reduction in four sarcomere genes (
, and
) and two Ca
handling regulator genes (
and
). Immune cell infiltration in cardiac tissue of ALKO provided direct evidence of advanced metabolic cardiomyopathy. The presently described model could become a powerful tool to clarify the underlying mechanism between metabolic disorders and cardiomyopathies.
Recently, unmanned aerial vehicles (UAVs) have been broadly applied to the remote sensing field. For a great number of UAV images, deep learning has been reinvigorated and performed many results in ...agricultural applications. The popular image datasets for deep learning model training are generated for general purpose use, in which the objects, views, and applications are for ordinary scenarios. However, UAV images possess different patterns of images mostly from a look-down perspective. This paper provides a verified annotated dataset of UAV images that are described in data acquisition, data preprocessing, and a showcase of a CNN classification. The dataset collection consists of one multi-rotor UAV platform by flying a planned scouting routine over rice paddies. This paper introduces a semi-auto annotation method with an ExGR index to generate the training data of rice seedlings. For demonstration, this study modified a classical CNN architecture, VGG-16, to run a patch-based rice seedling detection. The k-fold cross-validation was employed to obtain an 80/20 dividing ratio of training/test data. The accuracy of the network increases with the increase of epoch, and all the divisions of the cross-validation dataset achieve a 0.99 accuracy. The rice seedling dataset provides the training-validation dataset, patch-based detection samples, and the ortho-mosaic image of the field.
Background
Preoperative carcinoembryonic antigen (CEA) has yet to be used as a prognostic or adjuvant chemotherapy factor for colorectal cancer (CRC).
Methods
This retrospective cohort study included ...all stage I–III CRC patients with different preoperative serum CEA levels (≤ 5, 5–10, and > 10 ng/ml) at a single center between 1995 and 2010. Propensity score matching was performed in a 1:1 ratio between the two elevated CEA groups (5–10 ng/ml and > 10 ng/ml) and in a 1:2 ratio between the elevated and non-elevated groups (≤ 5 ng/ml), with a caliper of 0.05.
Results
After exclusion and matching, 3857 patients had preoperative CEA levels ≤ 5 ng/ml, 1121 patients had CEA levels between 5 and 10 ng/ml, and 1121 patients had CEA levels > 10 ng/ml. Elevated preoperative CEA showed an increased risk of overall survival (5–10 ng/ml: hazard ratio HR 1.376; > 10 ng/ml: HR 1.523; both
p
< 0.001), cancer-specific survival (5–10 ng/ml: HR 1.404; > 10 ng/ml: HR 1.712; both
p
< 0.001), and recurrence free interval (5–10 ng/ml: HR 1.190; > 10 ng/ml: HR 1.468; both
p
< 0.05). Patients with negative lymph node staging (LNs) and CEA > 10 ng/ml, as well as those with positive LNs and CEA ≤ 5 ng/ml, showed similar overall survival (5-year survival: 72% vs. 69%;
p
= 0.542) and recurrence free intervals (19.9 vs. 21.72 months;
p
= 0.662).
Conclusions
A preoperative CEA level can be an independent prognostic factor for stage I–III CRC after curative resection. Patients with negative LNs and preoperative CEA level > 10 ng/ml should be considered for intensive follow-up or adjuvant chemotherapy.
Cholesterol‐α‐glucosyltransferase (CGT) encoded by the type 1 capsular polysaccharide biosynthesis protein J (capJ) gene of Helicobacter pylori converts cellular cholesterol into cholesteryl ...glucosides. H. pylori infection induces autophagy that may increase bacterial survival in epithelial cells. However, the role of H. pylori CGT that exploits lipid rafts in interfering with autophagy for bacterial survival in macrophages has not been investigated. Here, we show that wild‐type H. pylori carrying CGT modulates cholesterol to trigger autophagy and restrain autophagosome fusion with lysosomes, permitting a significantly higher bacterial burden in macrophages than that in a capJ‐knockout (∆CapJ) mutant. Knockdown of autophagy‐related protein 12 impairs autophagosome maturation and decreases the survival of internalised H. pylori in macrophages. These results demonstrate that CGT plays a crucial role in the manipulation of the autophagy process to impair macrophage clearance of H. pylori.
Wireless networks have evolved from 1G to 4G networks, allowing smart devices to become important tools in daily life. The 5G network is a revolutionary technology that can change consumers' Internet ...use habits, as it creates a truly wireless environment. It is faster, with better quality, and is more secure. Most importantly, users can truly use network services anytime, anywhere. With increasing demand, the use of bandwidth and frequency spectrum resources is beyond expectations. This paper found that the frequency spectrum and network information have considerable relevance; thus, spectrum utilization and channel flow interactions should be simultaneously considered. We considered that software defined radio (SDR) and software defined networks (SDNs) are the best solution. We propose a cross-layer architecture combining SDR and SDN characteristics. As the simulation evaluation results suggest, the proposed architecture can effectively use the frequency spectrum and considerably enhance network performance. Based on the results, suggestions are proposed for follow-up studies on the proposed architecture.
In Taiwan, many ammunition depots have become outdated after having been in service for a long period of time, and if they are not properly managed, then accidental explosions might erupt inside. ...Leakage pressure after an explosion is closely related to the opening of the structure and the thickness of the wall. In order to reduce the risk of implosion, it is necessary to design a new structure or strengthen the existing ammunition libraries for the storage of ammunition required for combat. In order to evaluate the applicability of an existing ammunition depot design, making management simpler and safer, this study integrates the scale model experiment of an ammunition depot with computer simulation, the arbitrary Lagrangian–Eulerian (ALE) algorithm in ANSYS/LS-DYNA software, and it compares the results with the UFC3-340-02 specification in order to verify its applicability. The results show that computer simulation can verify that the data related to an implosion of an ammunition depot is similar to the specification. Therefore, the design results of the ammunition depot optimized by computer simulation can be used as a reference for the construction or strengthening of ammunition depots.
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