Mir-382 Promotes Differentiation of Rat Liver Progenitor Cell WB-F344 by Targeting Ezh2

Background/Aims: Liver progenitor cells (LPCs) were considered as a promising hepatocyte source of cell therapy for liver disease due to their self-renewal and differentiation capacities, while little is known about the mechanism of LPC differentiate into hepatocytes. This study aims to explore the effect of miR-382, a member of Dlk1-Dio3 microRNA cluster, during hepatic differentiation from LPCs. Methods: In this study, we used rat liver progenitor cell WB-F344 as LPC cell model and HGF as inducer to simulate the process of LPCs hepatic differentiation, then microRNAs were quantified by qPCR. Next, WB-F344 cell was transfected with miR-382 mimics, then hepatocyte cell trait was characterized by multiple experiments, including that periodic acid schiff staining and cellular uptake and excretion of indocyanine green to evaluate the hepatocellular function, qPCR and Western Blotting analysis to detect the hepatocyte-specific markers (ALB, Ttr, Apo E and AFP) and transmission electron microscopy to observe the hepatocellular morphology. Moreover, Luciferase reporter assay was used to determine whether Ezh2 is the direct target of miR-382. Results: We found that miR-382 increased gradually and was inversely correlated with the potential target, Ezh2, during WB-F344 hepatic differentiation. In addition, functional studies indicated that miR-382 increased the level of hepatocyte-specific genes. Conclusions: This study demonstrates that miR-382 may be a novel regulator of LPCs differentiation by targeting Ezh2

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia : The CREAM Consortium

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).Peer reviewe

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Background High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ −6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. Methods The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. Findings In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17–21%), 2% (1–3%), 8% (7–10%) and 6% (3–9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75–0.81), 0.58 (0.53–0.64), 0.71 (0.69–0.74) and 0.67 (0.62–0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92–1.24). Interpretation Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted fo

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Peroxins in Peroxisomal Receptor Export System Contribute to Development, Stress Response, and Virulence of Insect Pathogenic Fungus <i>Beauveria bassiana</i>

In filamentous fungi, recycling of receptors responsible for protein targeting to peroxisomes depends on the receptor export system (RES), which consists of peroxins Pex1, Pex6, and Pex26. This study seeks to functionally characterize these peroxins in the entomopathogenic fungus Beauveria bassiana. BbPex1, BbPex6, and BbPex26 are associated with peroxisomes and interact with each other. The loss of these peroxins did not completely abolish the peroxisome biogenesis. Three peroxins were all absolutely required for PTS1 pathway; however, only BbPex6 and BbPex26 were required for protein translocation via PTS2 pathway. Three gene disruption mutants displayed the similar phenotypic defects in assimilation of nutrients (e.g., fatty acid, protein, and chitin), stress response (e.g., oxidative and osmotic stress), and virulence. Notably, all disruptant displayed significantly enhanced sensitivity to linoleic acid, a polyunsaturated fatty acid. This study reinforces the essential roles of the peroxisome in the lifecycle of entomopathogenic fungi and highlights peroxisomal roles in combating the host defense system

Cells and Fugu Response to Capsid of BFNNV Genotype

The nervous necrosis virus (NNV) of the BFNNV genotype is the causative agent of viral encephalopathy and retinopathy (VER) in cold water fishes. Similar to the RGNNV genotype, BFNNV is also considered a highly destructive virus. In the present study, the RNA2 of the BFNNV genotype was modified and expressed in the EPC cell line. The subcellular localization results showed that the capsid and N-terminal (1–414) were located in the nucleus, while the C-terminal (415–1014) of the capsid was located in the cytoplasm. Meanwhile, cell mortality obviously increased after expression of the capsid in EPC. EPC cells were transfected with pEGFP-CP and sampled at 12 h, 24 h and 48 h for transcriptome sequencing. There are 254, 2997 and 229 up-regulated genes and 387, 1611, and 649 down-regulated genes post-transfection, respectively. The ubiquitin-activating enzyme and ubiquitin-conjugating enzyme were up-regulated in the DEGs, indicating that cell death evoked by capsid transfection may be related to ubiquitination. The qPCR results showed that heat stock protein 70 (HSP70) is extremely up-regulated after expression of BFNNV capsid in EPC, and N-terminal is the key region to evoke the high expression. For further study, the immunoregulation of the capsid in fish pcDNA-3.1-CP was constructed and injected into the Takifugu rubripes muscle. pcDNA-3.1-CP can be detected in gills, muscle and head kidney, and lasted for more than 70 d post-injection. The transcripts of IgM and interferon inducible gene Mx were up-regulated after being immunized in different tissues, and immune factors, such as IFN-γ and C3, were also up-regulated in serum, while C4 was down-regulated one week after injection. It was suggested that pcDNA-3.1-CP can be a potential DNA vaccine in stimulating the immune system of T. rubripes; however, NNV challenge needs to be conducted in the following experiments

Optimization Model of Electric Vehicles Charging and Discharging Strategy Considering the Safe Operation of Distribution Network

Against the background of carbon neutrality, the power dispatching operation mode has undergone great changes. It not only gradually realizes the coordinated control of source–grid–load–storage, but also strives to realize the multi-level coordination of the transmission network, distribution network and microgrid. Disorderly charging and discharging of large-scale electric vehicles (EVs) will have a great negative impact on the distribution network, but aggregating EVs and guiding them to charge and discharge in an orderly manner will play a positive role in delaying investment in the distribution network. Therefore, it is urgent to adopt an effective scheduling control strategy for electric vehicle charging and discharging. First, a variety of indexes were set to analyze the influence of EVs access on distribution network and the correlation between the indexes. Then, by defining the EVs penetration rate and the load simultaneous rate, the charging load planning of EVs was calculated. Based on the simultaneous load rate, the regional electricity load plan was calculated, and a configuration model of distribution capacity suitable for charging loads in different regions was constructed. Finally, an optimal dispatch model for electric vehicles considering the safety of distribution network was proposed and the distribution transformer capacity allocation model was used as the optimization target constraint. Compared with most optimized dispatch models used to maximize aggregator revenues and reduce peak-to-valley differences and load fluctuations in distribution networks, this model could effectively reduce unnecessary investment while meeting regional distribution transformer needs and maintaining distribution network security. Taking the improved IEEE 34-bus systems as an example, the simulation analysis was carried out and the investment demand of distribution network under the condition of disordered and orderly charge and discharge was compared. The results show that the proposed optimal scheduling method can effectively reduce the load fluctuation of distribution network, keep the voltage offset within the allowable voltage deviation range, and can effectively delay the investment of distribution network

Optimization Model of Electric Vehicles Charging and Discharging Strategy Considering the Safe Operation of Distribution Network

Against the background of carbon neutrality, the power dispatching operation mode has undergone great changes. It not only gradually realizes the coordinated control of source&ndash;grid&ndash;load&ndash;storage, but also strives to realize the multi-level coordination of the transmission network, distribution network and microgrid. Disorderly charging and discharging of large-scale electric vehicles (EVs) will have a great negative impact on the distribution network, but aggregating EVs and guiding them to charge and discharge in an orderly manner will play a positive role in delaying investment in the distribution network. Therefore, it is urgent to adopt an effective scheduling control strategy for electric vehicle charging and discharging. First, a variety of indexes were set to analyze the influence of EVs access on distribution network and the correlation between the indexes. Then, by defining the EVs penetration rate and the load simultaneous rate, the charging load planning of EVs was calculated. Based on the simultaneous load rate, the regional electricity load plan was calculated, and a configuration model of distribution capacity suitable for charging loads in different regions was constructed. Finally, an optimal dispatch model for electric vehicles considering the safety of distribution network was proposed and the distribution transformer capacity allocation model was used as the optimization target constraint. Compared with most optimized dispatch models used to maximize aggregator revenues and reduce peak-to-valley differences and load fluctuations in distribution networks, this model could effectively reduce unnecessary investment while meeting regional distribution transformer needs and maintaining distribution network security. Taking the improved IEEE 34-bus systems as an example, the simulation analysis was carried out and the investment demand of distribution network under the condition of disordered and orderly charge and discharge was compared. The results show that the proposed optimal scheduling method can effectively reduce the load fluctuation of distribution network, keep the voltage offset within the allowable voltage deviation range, and can effectively delay the investment of distribution network

Strengthening and fracture mechanisms of a precipitation hardening high-entropy alloy fabricated by selective laser melting

A precipitation hardening high-entropy alloy (HEA) (FeCoNi)86Al7Ti7 was fabricated by selective laser melting (SLM) and ageing treated under different temperatures and time conditions. Yield strength of the aged HEA increases substantially from 710 to 934 and then to 1203 MPa. Theoretical analyses reveal that the coherent L12 precipitate contributes most of the improved strength for the aged HEAs, whereas recovery during ageing causes the decrease of dislocation density thus exerts a softening effect. In addition, it is found that ductility decreases with increasing volume fraction of the incoherent L21 precipitates. Based on a void growth model, the trend is qualitatively explained. Moreover, a new fracture mode, intercellular fracture, is proposed to account for the strong dependence of fracture dimple size on the dislocation cells, also directly validated by delicate microstructural examination. The findings provide an effective strengthening method and propose a unique fracture mechanism for the additively manufactured HEA